appendix 1 cam data

APPENDIX 1 CAM DATA .................................................................................................................... 4

A PPENDIX 1.1

S EARCH SUMMARY INFORMATION .................................................................................. 4

A PPENDIX 1.2

A VAILABLE DATASET FOR ALL HERBAL MEDICINES AND ESSENTIAL OILS CONSIDERED

AND THEIR ACTIVE CONSTITUENTS ........................................................................................................ 7

B ILOBALIDE .......................................................................................................................................... 9

G INKGOLIDE A .................................................................................................................................... 11

G INKGOLIDE B .................................................................................................................................... 13

G INKGOLIDE C .................................................................................................................................... 15

Q UERCETIN ......................................................................................................................................... 17

S T J OHN

’

S W ORT ( HYPERICUM EXTRACT ) ........................................................................................... 19

H YPERICIN .......................................................................................................................................... 21

G INSENG ............................................................................................................................................. 23

G INSENOSIDE R B 1 ............................................................................................................................... 25

G INSENOSIDE R B 2 ............................................................................................................................... 27

G INSENOSIDE R G 1 ............................................................................................................................... 29

G INSENOSIDE R H 2 ............................................................................................................................... 31

G ARLIC OIL ......................................................................................................................................... 33

A LLICIN ............................................................................................................................................... 35

E CHINACEA ......................................................................................................................................... 37

E CHINACEIN ........................................................................................................................................ 39

V ALERIAN ROOT .................................................................................................................................. 41

V ALTRATE ........................................................................................................................................... 43

B LACK COHOSH EXTRACT ................................................................................................................... 45

A CTEIN ................................................................................................................................................ 47

F ORMONONETIN .................................................................................................................................. 49

27DEOXYACTEIN ................................................................................................................................ 51

M A HUANG /E PHEDRA ......................................................................................................................... 53

E PHEDRINE .......................................................................................................................................... 55

P SEUDOPHEDRINE ............................................................................................................................... 58

F EVERFEW ........................................................................................................................................... 60

P ARTHENOLIDE ................................................................................................................................... 62

E VENING PRIMROSE OIL ....................................................................................................................... 64

L INOLEIC ACID .................................................................................................................................... 66

Γ -L INOLEIC ACID ................................................................................................................................. 69

T YLOPHORA INDICA ............................................................................................................................ 71

T YLOPHORINE ..................................................................................................................................... 73

G LUCOSAMINE .................................................................................................................................... 75

G LUCOSAMINE SULPHATE AND HYDROCHLORIDE ............................................................................... 77

L AVENDER ESSENTIAL OIL .................................................................................................................. 80

L INALYL ACETATE .............................................................................................................................. 82

P INENE ................................................................................................................................................ 84

T EA T REE O IL ..................................................................................................................................... 87

C INEOLE .............................................................................................................................................. 89

T ERPINEN -4OL ................................................................................................................................... 91

O RANGE ESSENTIAL OIL ...................................................................................................................... 93

D -L IMONENE ....................................................................................................................................... 95

LL IMONENE ....................................................................................................................................... 99

C ITRAL .............................................................................................................................................. 103

L INALOOL ......................................................................................................................................... 105

P EPPERMINT OIL ................................................................................................................................ 107

M ENTHOL .......................................................................................................................................... 109

M ENTHONE ....................................................................................................................................... 111

M ENTHYL ACETATE .......................................................................................................................... 113

T HYME ESSENTIAL OIL ...................................................................................................................... 116

T HYMOL ............................................................................................................................................ 118

C ARVACROL ...................................................................................................................................... 121

B ORNEOL .......................................................................................................................................... 123

C AMPHOR .......................................................................................................................................... 125

W ORMWOOD ..................................................................................................................................... 127

A BSINTHIN ........................................................................................................................................ 129

Α -S ANTONIN ...................................................................................................................................... 131

Α -T HUJONE ....................................................................................................................................... 133

Β THUJONE ........................................................................................................................................ 135

A PPENDIX 1.3

S UMMARY OF F INDINGS FOR I NDIVIDUAL H ERBAL R EMEDIES .................................. 137

1. Black Cohosh ............................................................................................................................ 137

2. Camphor ................................................................................................................................... 137

3. Echinacea ................................................................................................................................. 138

4. Evening Primrose Oil ............................................................................................................... 138

5. Feverfew ................................................................................................................................... 139

6. Garlic........................................................................................................................................ 140

7. Ginkgo biloba extract ............................................................................................................... 140

8. Ginseng ..................................................................................................................................... 142

9. Glucosamine ............................................................................................................................. 143

10. Ma huang ................................................................................................................................ 144

11. St John’s Wort ........................................................................................................................ 146

12. Valerian .................................................................................................................................. 148

A PPENDIX 1.4

–

S UMMARY OF F INDINGS FOR I NDIVIDUAL E SSENTIAL O ILS ..................................... 150

1. Lavender Oil ............................................................................................................................. 150

2. Orange Essential Oil ................................................................................................................ 152

3. Peppermint Essential Oil .......................................................................................................... 153

4. Tea Tree oil .............................................................................................................................. 155

5. Thyme essential oil ................................................................................................................... 155

6. Wormwood ................................................................................................................................ 157

A PPENDIX 1.5

G LOSSARY AND LIST OF ABBREVIATIONS ................................................................... 159

APPENDIX 2 PESTICIDE/BIOCIDES DATA ......... ОШИБКА! ЗАКЛАДКА НЕ ОПРЕДЕЛЕНА.

A PPENDIX 2.1: R EGULATORY REQUIREMENTS FOR APPROVAL OF PESTICIDES PERMITTED IN EU

O RGANIC R EGULATIONS IN VARIOUS EU M EMBER S TATES . . О ШИБКА !

З АКЛАДКА НЕ ОПРЕДЕЛЕНА .

A PPENDIX 2.2

U SAGE , PROPERTIES , ECOTOXICITY AND HAZARD CLASSIFICATION FOR MAJOR

SYNTHETIC PESTICIDES ..........................................................

О ШИБКА !


A PPENDIX 2.3

UK P OLICY CONTEXT

– T IMETABLE ............... О ШИБКА !


A PPENDIX 2.4

A PPROVED C OMMODITY SUBSTANCES ........... О ШИБКА !


A PPENDIX 2.5

EPA B IOPESTICIDE FACT SHEETS .................... О ШИБКА !


A PPENDIX 2.6

A VAILABLE DATASET FOR ALL PESTICIDES / BIOCIDES .............

О ШИБКА !

З АКЛАДКА НЕ

ОПРЕДЕЛЕНА .

NATURAL ORGANIC PESTICIDES ...................................... Ошибка! Закладка не определена.

A BAMECTIN ........................................................................ О ШИБКА !


4-A LLYL -2METHOXYPHENOL ......................................... О ШИБКА !


A MINOETHOXYVINYLGLYCINE ........................................ О ШИБКА !


A ZADIRACHTIN .................................................................. О ШИБКА !


6-B ENZYLAMINOPURINE ................................................... О ШИБКА !


B ILANAFOS ......................................................................... О ШИБКА !


B

LASTICIDIN

-S ...................................................................

О ШИБКА !


3-[NBUTYL -NACETYL ]AMINOPROPRIONIC ACID , ETHYL ESTER ..... О ШИБКА !



C ANOLA OIL ........................................................................ О ШИБКА !


C APSAICIN .......................................................................... О ШИБКА !


C ITRONELLA ....................................................................... О ШИБКА !


C YTOKININS ........................................................................ О ШИБКА !


D IHYDROAZADIRACHTIN .................................................. О ШИБКА !


DMDP ................................................................................. О ШИБКА !


E MAMECTIN BENZOATE .................................................... О ШИБКА !


O LEIC ACID (F ATTY ACIDS ) .............................................. О ШИБКА !


G ARLIC EXTRACT .................................................................. О ШИБКА !


G IBBERELLIC ACID ................................................................ О ШИБКА !


LGLUTAMIC ACID PLUS GAMMA AMINOBUTYRIC ACID ...................... О ШИБКА !



H ARPIN PROTEIN ................................................................ О ШИБКА !


I NDOL -3YLACETIC ACID .................................................. О ШИБКА !


J OJOBA OIL .......................................................................... О ШИБКА !


K ASUGAMYCIN .................................................................. О ШИБКА !


M APLE LACTONE ............................................................... О ШИБКА !


P -M ENTHANE -3,8DIOL ..................................................... О ШИБКА !


M

ILBEMECTIN ....................................................................

О ШИБКА !


M

ILDIOMYCIN ....................................................................

О ШИБКА !


M ILSANA , R EYNOUTRIA SACHALINENSIS EXTRACT .........

О ШИБКА !


N

ATAMYCIN .......................................................................

О ШИБКА !


N ICOTINE ............................................................................ О ШИБКА !


1-O CTEN -3OL .................................................................... О ШИБКА !


O XYTETRACYCLINE ........................................................... О ШИБКА !


P ELARGONIC ACID ............................................................. О ШИБКА !


P LANT DERIVED PORPHYRIN DERIVATIVES ................... О ШИБКА !


P OLY -DGLUCOSAIME ....................................................... О ШИБКА !


P OLYNACTINS ..................................................................... О ШИБКА !


P OLYOXIN B ....................................................................... О ШИБКА !


P YRETHRINS ....................................................................... О ШИБКА !


R OTENONE .......................................................................... О ШИБКА !


R YANIA EXTRACTS ............................................................ О ШИБКА !


S ABADILLA ......................................................................... О ШИБКА !


S OFT SOAP ........................................................................... О ШИБКА !


S PINOSAD ............................................................................ О ШИБКА !


S TREPTOMYCIN .................................................................. О ШИБКА !


V ALIDAMYCIN .................................................................... О ШИБКА !


NATURAL INORGANIC PESTICIDES .................................. Ошибка! Закладка не определена.

B ORAX ................................................................................. О ШИБКА !


B ORDEAUX MIXTURE ........................................................ О ШИБКА !


C ALCIUM POLYSULPHIDE ................................................. О ШИБКА !


C OPPER HYDROXIDE .......................................................... О ШИБКА !


C OPPER O XYCHLORIDE ..................................................... О ШИБКА !


C OPPER O CTANAOTE ......................................................... О ШИБКА !


C OPPER SULPHATE ............................................................. О ШИБКА !


M ERCURIC C HLORIDE ....................................................... О ШИБКА !


M ERCURIC OXIDE .............................................................. О ШИБКА !


M ERCUROUS CHLORIDE .................................................... О ШИБКА !


P ETROLEUM OILS ............................................................... О ШИБКА !


S ULPHUR ............................................................................. О ШИБКА !


S ULPHURIC ACID ................................................................ О ШИБКА !


APPENDIX 3 WORKSHOP INFORMATION ......... ОШИБКА! ЗАКЛАДКА НЕ ОПРЕДЕЛЕНА.

A TTENDEES ........................................................................... О ШИБКА !


A GENDA ................................................................................ О ШИБКА !


APPENDIX 4 DATA GENERATED FROM MODELS ...................... ОШИБКА! ЗАКЛАДКА НЕ

ОПРЕДЕЛЕНА.

A PPENDIX 4.1

P REDICTED PROPERTIES AND PERSISTENCE OF IDENTIFIED NON SYNTHETIC CHEMICALS

..............................................................................................

О ШИБКА !


A PPENDIX 4.2

P REDICTED ECOTOXICITY VALUES FOR THE IDENTIFIED CHEMICALS ............... О ШИБКА !


A PPENDIX 4.3

PBT H AZARD CLASSIFICATION CRITERIA ....... О ШИБКА !


A PPENDIX 4.4

A DDITIONAL CAM DATA ............................... О ШИБКА !


Appendix 1 CAM data

Appendix 1.1 Search summary information

Search summary

Search term Operator Search term or subheading

Alternative medicine.ti,ab.

Complementary medicine.ti,ab.

Herbal medicine.ti,ab.

Plants medicinal#

Plant preparations#

Neutraceutical$1.ti,ab.

Aromatherapy.de.

With

And

Toxicity search database summary

Database Database producer

Medline

ToxFile

National Library of Medicine

Dialog Corporation AG 1

Elsevier B.V.

Embase

Biosis

Summary of toxicity terms

Biosis

Medline - Set 1 Medline - Set 2

Subheading – veterinary.de.

Veterinary drugs#

Veterinary medicine#

Coverage

1951-present

1965-present

1974-present

1969-present

Toxicity.de.

Adverse adj effect$1.de.

Metabolism.de.

Urine.de.

Health adj effect$1.ti,ab,de.

Adverse adj effect$1.ti,ab.

Toxicology#

Toxicity-tests#

Toxic$8.ti,ab.

Carcinogen$5.ti,de,ab.

Teratogen$5.ti,de,ab.

Mutagen$5.ti,de,ab.

Neurotoxic$8.ti,de,ab.

Cytotoxic$8.ti,de,ab.

Genotoxic$8.ti,de,ab.

Poison$3.ti,de,ab.

Toxicokinetics$1.ti,ab.

Metabolism#

Tolerable adj daily intake$1.ti,de,ab.

TDI.ti,ab.

ADI.ti,ab.

Allowable adj daily adj intake$1.ti,de,ab.

Reference adj dose$1.ti,ab.

Reference-values#

Guidelines#

Embase - Set 1

Health adj effect$1.ti,de,ab.

Adverse adj effect$1.ti,de,ab.

Toxic$8.ti,de,ab.

Toxicity#

Toxicity-testing#

Embase – Set 2

Drug adj toxicity.de.

Pharmacokinetics.de.

1 using data provided by the National Library of Medicine


Mutagen$5.ti,de,ab.





Poison$3.ti,de,ab.

Toxicokinetic$1.ti,de,ab.

Tolerable adj daily adj intake.ti,de,ab.

TDI.ti,de,ab.

Acceptable adj daily adj intake$1.ti,de,ab.

ADI.ti,de,ab.

Reference adj dose$1.ti,de,ab.

Guideline adj value$1.ti,de,ab.

Toxicology#

Pharmacokinetics#

Biosis

Health adj effect$1.ti,de,ab.

Adverse adj effect$1.ti,de,ab.

225# 2 toxic$8.ti,de,ab.



Mutagen$5.ti,de,ab.




Poison$3.ti,de,ab.

Toxicokinetic$1.ti,de,ab.

Tolerable adj daily adj intake.ti,de,ab.

TDI.ti,de,ab.

Acceptable adj daily adj intake.ti,de,ab.

ADI.ti,de,ab.

Reference adj dose$1.ti,de,ab.

Reference adj value$1.ti,de,ab.

Guideline adj value$1.ti,de,ab.

Pharmacokinetic$1.ti,de,ab.

2 Concept code for toxicity

Fate and behaviour search terms

Set 1

Absorbance Bioaccumulation

Bioconcentration

Biodegradation

Compartmentalisation or compartmentalization

Magnification

Photodegradation

Volatilisation or volatilization

Halflife or (half (w) life)

Kow

Octanol (w) water (w) co (w) efficient

Octanol (w) water (w) coefficient

Body (w) (load or burden)

Set 2 Operator Set 3

Accumulation

Behaviour or behavior

Concentration

Deposition

Distribution

Dispersal

Exposure

Fate

Level

Load

5N 3 Environment?

Water

Air

Food

Sediment

Soil

3 operator used on the host Dialog to search for terms within 5 words of each other in any order.

Appendix 1.2 - Available dataset for all herbal medicines and essential oils considered and their active constituents

Parameter Preferred units/format

Preparation/chemical name Ginkgo biloba extract

Therapeutic activity Used in traditional medicine for asthma and vascular disease. Nootropic: used in treatment of vascular insufficiency.

4

Herbal/dietary supplement.

5

An extract of the leaves has

Chemical structure been used in cerebrovascular and peripheral vascular disorders. It has also been investigated in Alzheimer’s disease and multi-infarct dementia.

6

N/A

Chemical name

CAS no

Molecular formula

N/A

90045-36-6

N/A

Molecular weight

Major emission routes

Application/emission rates

Proportion metabolised

Identity of metabolites

Density

Melting point

Boiling point

Octanol-partition coefficient

(Kow, P)

Solubility in water

Acid dissociation constant

(pKa)

Vapour pressure

Henry’s Law Constant

Soil/sediment water partition coefficient (Kp)

Organic carbon normalised soil/sediment water partition coefficient (Koc)

Photolysis half life

Hydrolysis half life

Persistence in air

Supporting information

4 O’Neil MJ, Smith A, Heckelman PE et al. (2001) The Merck Index. An Encyclopedia of Chemicals, Drugs, and Biologicals.

Thirteenth Edition . New Jersey, USA, Merck & Co., Inc.

5

National Toxicology Program Executive Summary, available [April 2004] at: http://ntpserver.niehs.nih.gov/htdocs/Chem_Background/ExecSumm/Ginkgo.html

6

Sweetman SC (2002) Martindale. The Complete Drug Reference. Thirty-third edition . London, UK, Pharmaceutical Press.

Persistence in activated sludge

Persistence in soil

Persistence in sediment

Identity of degradates from above studies

Fate in the field

Bioconcentration factor

Biota-sediment/soil accumulation factor

Mammalian oral toxicity

Mammalian skin/eye toxicity

Mammalian ADI

Mammalian inhalation toxicity

Ecotoxicity (Bird)

Ecotoxicity (Fish)

Ecotoxicity (Daphnia)

Ecotoxicity (Algae)

Ecotoxicity (Other aquatics)

Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Mouse (oral) LD50 7.73g kg

-1

7

Standardised extract corresponding to 2.3 g kg

-1

of active ingredients, 1.9 g kg

-1 of flavone glycosides, and 464 mg kg -1 of terpene lactones

7

http://ntp-server.niehs.nih.gov/htdocs/Chem_Background/ExecSumm/Ginkgo.html viewed April 2004


Preparation/chemical name

Therapeutic activity

Chemical structure

Bilobalide

O

O


-

(Beilstein, 2004)

O

O

O

Chemical name

CAS no

Molecular formula

Molecular weight





Density

Melting point

Boiling point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure






Persistence in air


Persistence in soil



Fate in the field

O

O

O

9tert -butyl-8,9-dihydroxydihydro-furo[2,3b

]furo[3’,2’:2,3]cyclopental[1,2c]furan-2,4,7-trione

33570-04-6

C

15

H

18

O

8

326.3 g mol

-1

(Beilstein, 2004)

-

-

-





Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)




Chemical structure

Ginkgolide A

O

O

O

H

O

O

O


O

O

O

Chemical name

CAS no

Molecular formula

Molecular weight





Density

Melting point

Boiling point

Octanol-partition coefficient (Kow, P)

15291-75-5

C

20

H

24

O

9

408.40 g mol

-1

Decomposes at ~300°C 8

Solubility in water


(pKa)

Vapour pressure






Persistence in air


Persistence in soil





Fate in the field





Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)




Chemical structure

Ginkgolide B

H

O

O

O

O

O


-

(Beilstein, 2004)

O

O





Persistence in air


Persistence in soil



Fate in the field


O

O

H

O

H

Chemical name

CAS no

Molecular formula

Molecular weight





Density

Melting point

Boiling point


(1β)-1-Hydroxyginkgolide A

15291-77-7

C

20

H

24

O

10

424.40 g mol -1


Solubility in water


(pKa)

Vapour pressure







Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Parameter



Chemical structure

O

Preferred units/format

Ginkgolide C

Used in treatment of severe sepsis.

a

O

O

O

H

O

O


O

O

H

O

O

O

Chemical name

CAS no

Molecular formula

Molecular weight





Density

Melting point

Boiling point


(Kow, P)


N/A

(1α,7β)-1,7-Dihydroxyginkgolide

15291-76-6

C

20

H

24

O

11

440.40 g mol

-1

Solubility in water


(pKa)

Vapour pressure






Persistence in air


Persistence in soil



Fate in the field







Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Parameter



Chemical structure


Quercetin

O

O

O

O

-


-

O

O

O

Chemical name

CAS no

3,3’,4’,5,7-Pentahydroxyflavone

117-39-5

Molecular formula

Molecular weight


C

15

H

10

O

7

302.24 g mol

-1




Density

Melting point 316.5 °C

11

Boiling point

Octanol-partition

Sublimes a

2.04

12 coefficient (Kow, P)

Solubility in water 0.16 g L

-1 13

Acid dissociation constant (pKa) pKa

1:

7.03 pKa

2

: 9.15 b

-

-

-

-

Vapour pressure 3.74 x 10 -12 Pa 14


6.68 x 10

-16

Pa m

3

mol

-1 15

Soil/sediment water partition coefficient

(Kp)

Organic carbon normalised soil/sediment water partition coefficient

(Koc)

Determined at 16°C

Determined at 25°C using a spectrophotometric method

Estimated at 25°C

Estimated at 25°C

11

IARC (1999) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Some Chemicals that Caus Tumours of the Kidney or Urinary Bladder in Rodents and Some Other Substances. Volume 73.

Lyon, France, International Agency for

Research on Cancer

12

Beilstein database (2004)

13

Seidell (1941) cited in SRC PhysProp Database

14

Neely WB & Blau GE (1985) cited in SRC PhysProp Database

15

Meylan WM & Howard PH (1991) cited in SRC Phys Prop Database



Persistence in air


62–105 days

b

Persistence in soil



Fate in the field

Bioconcentration factor ?

Biota-sediment/soil


? accumulation factor

Mammalian oral toxicity Mouse (oral) LD50 159 mg kg

-1

Rat (oral) LD50 161 mg kg

-1 16

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Sludge from municipal wastewater.

Anaerobic degradation at 37°C.

Test species and method

Test method and species

16

Material Safety Datasheet at https://fscimage.fishersci.com/msds/56284.htm

Parameter




Chemical structure

Chemical name

CAS no

Molecular formula

Molecular weight





Density

Melting point

Boiling point

St John’s Wort

(hypericum extract)

Antidepressant

17

Used, frequently for selfmedication, in the treatment of depression. Such preparations are also promoted for the treatment of other nervous disorders such as insomnia and anxiety, particularly if associated with the menopause.

18

N/A

68917-49-7


(Kow, P)

Solubility in water


(pKa)

Vapour pressure






Persistence in air


Persistence in soil


Identity of degradates from




18


above studies

Fate in the field





Mammalian ADI


Rats, mice: NOEL > 5000 mg kg

-1

(Hammerness et al.

,

2003)

Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)




Chemical structure

Hypericin

Antidepressant

19

Hypericin oil has been used as an astringent.

20

O

O O


O

O

O O O

Chemical name 1,3,4,6,8,13-Hexahydroxy-

10,11-dimethylphenanthro[1,10,9,8opqra ]perylene-7,14-dione

548-04-9 CAS no

Molecular formula

Molecular weight



C

30

H

16

O

8

504.45 g mol -1



Density

Melting point

Boiling point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure


320 °C

21

3.43

b

8.78

22

0.04 g L

-1 b


Organic carbon normalised soil/sediment water

Estimated

Determined at 30°C



20


21

Beilstein, 2004

22

Meylan WM & Howard PH (1995) cited in SRC PhysProp Database

partition coefficient (Koc)



Persistence in air


Persistence in soil



Fate in the field





Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Parameter





Density

Ginseng

Therapeutic activity Tonic

23

Reported to enhance the natural resistance and recuperative power of the body and to reduce fatigue.

24

N/A Chemical structure

Chemical name

CAS no

Molecular formula

Molecular weight



50647-08-0

Melting point

Boiling point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure






Persistence in air


Persistence in soil



Fate in the field






24





-1

Mouse (oral) LD50 200 mg kg

-1 25

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Panax ginseng

25

http://ntp-server.niehs.nih.gov/htdocs/Chem_Background/ExecSumm/Ginseng.html


Preparation/chemical name Ginsenoside Rb1


Chemical structure

O

O

O O

O

O

O

O

O

O

O

O

H

H

O

O

O

O

H

H

O

O

O

O

O

O

O

Chemical name

CAS no


41753-43-9

Molecular formula C

54

H

92

O

23

Molecular weight 1109.31 g mol

-1


2-O-β-Glucopyranosyl-(3β,12β)-20-((6-O-β-Dglucopyranosyl-β-D-glucopyranosyl)oxy-12hydroxydammar-24-en-3-yl-β-D-glycopyranoside



Density

Melting point

Boiling point


Solubility in water

Acid dissociation

205–207°C 26

26



constant (pKa)

Vapour pressure

Henry’s Law

Constant


(Kp)


(Koc)



Persistence in air


Persistence in soil



Fate in the field





Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)

Ecotoxicity

(Daphnia)

Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)




Chemical structure

Ginsenoside Rb2

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

Chemical name 20-((6-O-α-L-Arabinopyranosl-β-Dglucopyranosyl)oxy)-12βhydroxydammar-24-en-3β-yl-2-O-β-Dglucopyranosyl-β-D-glucopyranoside

11021-13-9 CAS no

Molecular formula

Molecular weight


C

53

H

90

O

22

1079.28 g mol

-1




Density

Melting point 201°C 27

Boiling point


Solubility in water

Acid dissociation constant (pKa)

Vapour pressure



(Kp)


(Koc)



Persistence in air

27




Persistence in soil



Fate in the field





Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)




Chemical structure

Ginsenoside Rg1

O

O

O

O

O

H

H

O

O

H

O

H

O

O

O

O

O

Chemical name

O

(3β,6α,12β)-3,12-Dihydroxydammar-24-ene-6,20diylbis(β-D-glucopyranoside)

22427-39-0 CAS no

Molecular formula C

42

H

72

O

14


-1





Density

Melting point

Boiling point


Solubility in water


Vapour pressure

Henry’s Law

Constant


202–205°C

28

28



(Kp)


(Koc)



Persistence in air


Persistence in soil



Fate in the field





Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)

Ecotoxicity

(Daphnia)

Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)




Chemical structure

Ginsenoside Rh2

O

O

H

O

H

O

O

H

O

O

H

O

Chemical name

CAS no


78214-33-2

Molecular formula C

36

H

62

O

8


-1



(3β,12β)-12,20-dihydroxydammar-24-en-3-yl-(β-Dglucopyranoside)


Density

Melting point 220–225°C

29

Boiling point


Solubility in water


Vapour pressure

Henry’s Law

Constant


(Kp)


29



Solvent methanol

(Koc)



Persistence in air


Persistence in soil



Fate in the field





Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)

Ecotoxicity

(Daphnia)

Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Parameter

Preparation/Chemical name

Data Supporting info.

-


Chemical structure

Chemical name

CAS no

Molecular formula

Molecular weight

Major emission routs

Application/emission rates e.g. kg ha

-1



Density

Melting Point

Boiling Point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure


Garlic oil

Treatment of hypertension and hyperlipidemia 30 .

Expectorant, diaphoretic, disinfectant and diuretic properties 31 and recently investigated for antimicrobial, antihypertensive, lipid lowering, fibrinolytic, antiplatelet and cancer protective effects.

-

-

8000-78-0

-

-

-0

-

-

1.04 - 1.09 (25 °C)

-

-

-

-

-

; dose (mg kg

32

-1

)

-

-

-

-

- e.g. to STP; application to soil

-


Would be nice if all this info. Could also be obtained for the metabolites

Test method

Test method

Test method





-

-

-

-

30

Merck Index (2001) [Garlic, entry 4384]

31

Martindale (2002) [Garlic, p1614]

32

MSDS [Garlic Oil] viewed on-line at http://www.thegoodscentscompany.com; April 2004

Test method

Test method; temperature

Soil/sediment characteristics


Test method

Test method

Persistence in air


Persistence in soil



Fate in the field





Mammalian ADI


-

Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

-

-

-

-

-

-

-

Test method

Test method; aerobic anaerobic

Test method; soil type

Test method

-

Test method



Parameter



Data

Allicin

Constituent of garlic

1,4

.

Treatment of hypertension and hyperlipidemia (as per garlic oil)

1

.

Chemical structure

S

S

O

Supporting info.

-

-

Chemical name

CAS no

Molecular formula

Molecular weight




Prop-2-ene-1-sulphinothioic acid S-2-propenyl ester

539-86-6

C

6

H

10

OS

2

162.28

33

-0


-

Amount produced; Chem draw file

-1

; dose (mg kg

-1

)

-

-

-


-



Density (RD)

Melting Point

Boiling Point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure


-

-

1.11

2

Decomposes on distilling 1 ;

134ºC 34

1.87 (est) 35

25 g/l

1

(pH 6.5)

-

Test method

Test method

Test method


-

Organic carbon normalised -

Test method



Soil/sediment

33

Merck Index (2001) [Allicin, entry 257]

34

Bielstein Database [Allicin]; accessed April 2004

35

SRC PhysProp Database viewed on-line at http://esc.syrres.com/interkow/physdemo.htm; April 2004

4

Martindale (2002) [Garlic, p 1614]

soil/sediment water partition coefficient (Koc)



Persistence in air


Persistence in soil



Fate in the field


-

-

-

-

-

-

-

-

- characteristics

Test method

Test method

Test method



Test method

-



-

Mammalian skin/eye toxicity LD

50

in mice: 60 mg/kg (iv);

120 mg/kg (sc) 1

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)

Ecotoxicity (Other aquatics) LC 50 at 24,48,72 & 96 hrs

6.34, 5.45, 4.48, 3.64 mg L

-1

36

Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Test method



Toxicity to aquatic invertebrates

36

Beilstein Database, 2004.

Parameter Data

Preparation/Chemical name Echinacea

Therapeutic activity Treatment of respiratory infections, e.g. colds

(immunostimulant) 37 .

Used in herbal preparations for prophylaxis of bacterial and viral infections

38

.

Chemical structure -

Chemical name

CAS no

-

Echinacea angustifolia , ext. (84696-11-7)

Echinacea purpurea, ext. (90028-20-9)

Echinacea pallida, ext. (97281-15-7)

Echinacea angustifolia tincture (129677-89-0)

Molecular formula -

Molecular weight -

Major emission routs -



Identity of metabolites e.g. kg ha

-1

; dose (mg kg

-1

)

-


Density

Melting Point

Boiling Point



Vapour pressure

Henry’s Law

Constant


(Kp)

Organic carbon

-

-

-

-

Solubility in water -

-

-

-

-

-

37

Merck Index (2001)

38

Martindale (2002) [Echinacea, p 1606]

-

-

-

Supporting info.

-

-


-



Test method

Test method

Test method

Test method



Soil/sediment

normalised soil/sediment water partition coefficient

(Koc)

Photolysis half life -

Hydrolysis half life -

Persistence in air -


-

Persistence in soil -



Fate in the field


-

-

-

-




Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)

Ecotoxicity

(Daphnia)

Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

-

Rat (oral) LD50 >15000 mg kg

-1

Mouse (oral) LD50 >30000 mg kg -1 39

39 http://ntp-server.niehs.nih.gov./htdocs/Chem_Background/ExecSumm/Echinacea.html viewed, April 2004 characteristics

Test method

Test method

Test method



Test method

-

Test method



Parameter Data

Preparation/Chemical name Echinacein

Therapeutic activity Constituent of Echinacea

2

Chemical structure Echinacein

O

Supporting info.

-

-

N

Chemical name

CAS no

Dodeca-2,6,8,10-tetraenoic acid isobutyl amide

Echinacein (504-97-2, 10076-00-3, 13430-

38-1, 119719-30-1)

40

Molecular formula

Molecular weight

C

16

H

25

NO

247.38

1

Major emission routs -0

-

-

-


- Application/emission rates

Proportion metabolised e.g. kg ha

-

-1 ; dose (mg kg -1 )

Identity of metabolites Amount produced; Chem draw file

Density

Melting Point

Boiling Point


Solubility in water

-

-

69-70ºC

1

-


-

Vapour pressure -

Henry’s Law Constant -


Would be nice if all this info.

Could also be obtained for the metabolites

Test method

Test method

Test method

Test method




(Kp)

Organic carbon

-

- normalised soil/sediment water partition coefficient

(Koc)

40

Beilstein Database 2004 [Echinacein]; accessed April 2004

2

[Echinacea] viewed on-line at http://www.naturalproducts.org April 2004




Persistence in air


Persistence in soil

-

-

-

-

-



Fate in the field


-

-




Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)

-


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

-

-

Test method

Test method

Test method



Test method

-

Test method



Parameter



-


Chemical structure

Chemical name

CAS no

Molecular formula

Molecular weight



-1



Density

Melting Point

Boiling Point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure


-

Valerian root

Sedative

41

Valerian has sedative properties and is used to treat anxiety states; it has also been used as a carminative

42

-

-

-

-

8057-49-6

-0

-


Unitless

-

-

-

-

; dose (mg kg

-1

)

-

-

-

-


-



Test method

Test method

Test method

Test method






-

-



Persistence in air



Persistence in sediment -

Identity of degradates from -

-

-

-

-

Test method

Test method

Test method



Test method

-

41

Merck Index (2001) [Valerian, entry 9969]

42

Martindale (2002) [Valerian, p 1678]

above studies

Fate in the field


-

-




Mammalian ADI

-

Daily dose not to exceed

1800mg 43


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Test method



Short-term use only

43 http://tangcenter.uchicago.edu/herbal_resources/valerian.shtml

Parameter Data

Preparation/Chemical name Valtrate

Therapeutic activity Constituent of valerian

44,45

Chemical structure

O

O

O

O

H

O

O

O

Supporting info.

-

-

O

Chemical name

CAS no

Valtrate

18296-44-1 (22173-55-3)

Molecular formula

Molecular weight

C

22

H

30

O

8

422.47


1

-

-

-


- Application/emission rates

Proportion metabolised e.g. kg ha

-

-1

; dose (mg kg

-1

)


Density

Melting Point

Boiling Point


Solubility in water


Vapour pressure -

Henry’s Law Constant -

-

-

-

-


Would be nice if all this info.

Could also be obtained for the metabolites

Test method

Test method

Test method

Test method


Soil/sediment Soil/sediment water -

44

Beilstein Database [Valtrate]; accessed April 2004

45

The valepotriates valtrate/isovaltrate and dihydrovaltrate are considered to be the main tranquilizing constituents of drugs derived from the roots of several Valerianaceae (von der Hude et al, 1986)

partition coefficient

(Kp)


(Koc)



Persistence in air


Persistence in soil

-

-

-

-

-

-



Fate in the field





Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

-

-

-

-

- characteristics


Test method

Test method

Test method



Test method

-

Test method



Parameter



Chemical structure

Chemical name

CAS no

Molecular formula

Molecular weight



-1



Density

Melting Point

Boiling Point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure


Data

-


-

-

-

-

-

-

Black cohosh extract

Treatment of symptoms associated with premenstrual syndrome (PMS), dysmenorrhea, and menopause 46 .

-

-

-

-

84776-26-1

-

; dose (mg kg

-1

)

Supporting info.

-

-

-

-

-


-



Test method

Test method

Test method

Test method








Persistence in air


-

-

-

-

-

-

Persistence in soil


-

-

Identity of degradates from -

46

NTP summary [Black Cohosh] viewed on-line at http://ntpserver.niehs.nih.gov/htdocs/Chem_Background/ExecSumm/blackcohosh.html April 2004

Test method

Test method

Test method



Test method

-

above studies

Fate in the field





-

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

-

-

Test method



Parameter Data

Preparation/Chemical name Actein

Therapeutic activity Constituent of Black Cohosh

47

.

Chemical structure

O

O

O O

O O

O

Chemical name

CAS no

Actein

18642-44-9

Molecular formula C

37

H

56

O

11

Molecular weight 676.84

48


Application/emission e.g. kg ha

-1

; dose (mg kg

-1

) rates



Density -

-


Melting Point

Boiling Point



Acid dissociation - constant (pKa)

Vapour pressure

Henry’s Law

Constant


(Kp)


(Koc)

-

-

-

-

-

47


48

Beinstein Database [Actein]; accessed April 2004

O

O

O

O




- Persistence in activated sludge


- Persistence in sediment


-

-

-

Fate in the field





Mammalian ADI


-

Ecotoxicity (Bird)

Ecotoxicity (Fish)

Ecotoxicity

(Daphnia)

Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Parameter



Chemical structure

Data

Formononetin

Treatment of menopausal symptoms.

Constituent of Black

Cohosh

49

and major oestrogenic factor in clover species

50

O

Supporting info.

-

-

O

O

Chemical name

CAS no

Molecular formula

Molecular weight





O

7-hydroxy-3-(4-methoxyphenyl)-4-benzopyrone

485-72-3

C

268.27

51

-0

-

16

H

12

O

4


-1

; dose (mg kg

Density

Melting Point

Boiling Point


(Kow, P)

Solubility in water

-

256.5ºC 52 ; 258ºC 2

3.11 (est) 4

-

-1

)

-

-

-


-



Test method

Test method

49

NTP summary [Balck Cohosh] viewed on-line at at http://ntpserver.niehs.nih.gov/htdocs/Chem_Background/ExecSumm/blackcohosh.html April 2004

50

Merck Index (2001) [Formononetin, entry 4268]

51

Beilstein Database [Formononetin]; accessed April 2004

52



(pKa)

Vapour pressure


-

-

-





Persistence in air


Persistence in soil



Fate in the field


-

-

-

-

-

-

-

-

37-95% degraded in 1-3 weeks (from 5 mg/l);

30-60% degraded in 10-15 d 3

-

-

Test method

Test method




Test method

Test method

Test method



Test method

-

Test method






Mammalian ADI


-

Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Parameter Data

Preparation/Chemical name 27-deoxyactein

Therapeutic activity Constituent of Black Cohosh

53

.

Chemical structure

O

O

O O

O O

O

Chemical name

CAS no

27-deoxyacetylacetol-O-D-xylopyranoside

-

Molecular formula -

Molecular weight 660.84


Application/emission e.g. kg ha

-1

; dose (mg kg

-1

) rates



Density -

-


Melting Point

Boiling Point


-


Acid dissociation - constant (pKa)

Vapour pressure

Henry’s Law

Constant


(Kp)


-

- partition coefficient

(Koc)


-

-

53


O

O

O




-

Persistence in soil



Fate in the field

-

-

-

-

- Bioconcentration factor




-

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)

Ecotoxicity

(Daphnia)

Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Parameter



-


Chemical structure

Chemical name

CAS no

Molecular formula

Molecular weight



-1



Density

Melting Point

Boiling Point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure


-

Ma-huang/Ephedra

-

-

-

-

Herbal cold relief. Action of ephedra is due to the presence of ephedrine and pseudoephedrine

54

.

Used in traditional Chinese medicine as a diaphoretic, stimulant and antiasthmatic

55

.

Has also been used to aid weight loss 56 .

-0

-


-

-

-

-

-

; dose (mg kg

-1

)

-

-

-

-


-



Test method

Test method

Test method





-

-

-

-

Test method




Test method

Test method

54

Martindale (2002) [Ephedra, p 1090]

55

Merck Index (2001) [Ephedra, entry 3638]

56

Ephedra and Ephedrine for Weight Loss and Athletic Performance Enhancement: Clinical Efficacy and Side Effects. Viewed on-line at http://www.ahrq.gov/clinic/epcsums/ephedsum.htm April 2004

Persistence in air


Persistence in soil



Fate in the field


-

-

-

-

-

-

-



-


Mammalian ADI


Rat (oral) 600mg kg

-1

Probable oral lethal dose

(human) 5-50mg kg -157

Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Test method



Test method

-

Test method



57

Hazardous Substances Data Bank (HSDB) available [April 2004] at: http://toxnet.nlm.nih.gov/

Parameter



Chemical structure

Data

Ephedrine

Major active constituent of

Ephedra; also prepared synthetically – used as an expectorant and nasal decongestant 4 .

Bronchodilator. Also used for veterinary purposes as a bronchodilator and to treat urinary incontinence 1 .

Supporting info.

-

-

N

O

Chemical name

CAS no

Molecular formula

Molecular weight




(1R,2S)-2-methylamino-1phenyl-propan-1-ol

299-42-3

C

-

10

165.23

58

-0

H

15

NO



-1

; dose (mg kg

-1

)

-

-

-


-



Density

Melting Point

Boiling Point


(Kow, P) g cm

-3

34 ºC 1,59

37-39 ºC

60

36 ºC (anhydrous form, hemihydrate melts at 42 ºC) 5

255 ºC 2

260 ºC (745 mmHg) 1

1.13

2

0.93

61

Test method

58

Merck Index (2001) [Ephedrine, entry 3639]

59


60

Chemfinder viewed on-line at http://chemfinder.cambridgesoft.com

4

Martindale (2002) [Ephedra, Ephedrine p 1090]

Solubility in water


(pKa)

Vapour pressure




63.6 g/l (30 ºC) 2

10.3 (0 ºC) 2

9.6

62

0.11 Pa (est)

2

9 x 10

-

-

-6

Pa m

3

mol

-1

(est)

2

Test method

Test method

Test method






Persistence in air


Persistence in soil

-

-

-

-



Fate in the field

-

-

-

- Test method

Bioconcentration factor - Test species and method




Mammalian ADI

- Test method and species

Rat (oral) LD50 600mg kg

-1 63

LDLO (human) 9mg kg

-1

(route unreported)

64

90-180 mg

65

Treatment of diabetic neuropathic oedema


Ecotoxicity (Bird)

Ecotoxicity (Fish)

LD50 (oral) 562 mg kg

-1 66

Test method

Test method

Test method



Test method

-


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

62

[Ephedrine, PIM 209] viewed on-line via Inchem at http://www.inchem.org/documents/pims/pharm/pim209.htm April 2004

63 http://ptcl.chem.ox.ac.uk/MSDS/EP/(-)-ephedrine_anhydrous.html viewed April 2004

64

Material Safety Datasheet at http://physchem.ox.ac.uk/MSDS/ viewed April 2004

65

Martindale (2002) [Ephedrine, p 1090]

66

Material Safety Datasheet viewed at http://www.sigmaaldrich.com Product number: 134910, viewed April 2004

Parameter



Chemical structure

Data

Pseudophedrine

Active constituent of

Ephedra/Ma huang; similar action to ephedrine – used for relief of cough and cold symptoms 5 .

Nasal decongestant

1

Supporting info.

-

-

H O

N H

Chemical name

CAS no

Molecular formula

Molecular weight


(1S,2S)-2-methylamino-1phenyl-propan-1-ol

90-82-4

C

10

H

15

NO

165.23

67

-0


-1

; dose (mg kg

-1

)

Proportion metabolised -


Density

Melting Point

Boiling Point


(Kow, P)

Solubility in water


(pKa)

1.12 g cm

-3 68

118-119 ºC

1,69

117 ºC 70

-

0.89

3

106 g/l (est at 25 ºC)

3

Sparingly soluble in water

1

10.3 (0 ºC) 2

Test method

Test method

67

Merck Index (2001) [Pseudoephedrine, entry 8007]

68

Beilstein Database (2004)

69


70

Chemfinder viewed on-line at http://esc.syrres.com/interkow/physdemo.htm; April 2004

5

Martindale (2002) [Pseudoephedrine, p 1099]

-

-

-


-



Test method

Vapour pressure






Persistence in air


Persistence in soil



0.11 Pa (est)

-

-

-

-

-

-

-

-

-

2

9 x 10

-6

Pa m

3

mol

-1

(est)

2

Test method




Test method

Test method

Test method



Test method

-

Fate in the field


-

-

Test method

Test species and

Biota-sediment/soil - method

Test method and accumulation factor

Mammalian oral toxicity Rat (oral) LD50 660mg kg

-1

Mouse (oral) LD50 500mg kg

-1 71

Mammalian skin/eye toxicity Irritating to skin and eyes 72 species

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Harmful by inhalation 73

Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

71

Material Safety Datasheet at http://ptcl.chem.ox.ac.uk/MSDS/PS/(+)-pseudoephedrine.html viewed April 2004

72


73


Parameter



Feverfew


Featherfew, featherful, midsummer daisy,

Tanacetum parthenium


Chemical structure

Chemical name

CAS no

Molecular formula

Molecular weight





Density

Melting point

Boiling point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure






Persistence in air


Persistence in soil

Herbal remedy used in the prophylactic treatment of migraine and arthritis.

74



Fate in the field





Mammalian ADI

74



Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Parameter



Chemical structure


Parthenolide


O

O

O

Chemical name

CAS no

Molecular formula

Molecular weight





Density

Melting point

IUPAC format

20554-84-1

C

15

H

20

O

3

248.32 g mol

-1

115–116°C 75

Boiling point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure






Persistence in air


Persistence in soil



Fate in the field







Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Parameter



Chemical structure

Chemical name

CAS no

Molecular formula

Molecular weight



In treatment of atopic eczema and mastalgia; dietary supplement

76

Used for symptomatic relief of atopic eczema and mastalgia. Also investigated in a variety of other disorders including multiple sclerosis, rheumatoid arthritis and the premenstrual syndrome.

77

90028-66-3



Density

Melting point

Boiling point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure






Persistence in air


Persistence in soil


Identity of degradates from


Evening primrose oil

0.9283 g cm

-3




77


above studies

Fate in the field





Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)


Preparation/chemical name Linoleic acid

Therapeutic activity Nutrient (essential fatty acid)

78

Chemical structure

O

O


0.9022 g cm

-3 80

Chemical name Octadeca-9,12-dienoic acid

CAS no


60-33-3

Molecular formula C

18

H

32

O

2


-1


Estimated European per captia intake (eaters only): 133 µg/day

79



Density

Melting point

Boiling point

-5°C

81

230°C a

Octanol-partition 7.05

82 coefficient (Kow, P)

Solubility in water 0.000139 g L

-1 83


Vapour pressure

4.77

84

1.16 x 10

-4

Pa

85

Determined at 20°C

Determined at 16 mm Hg

Henry’s Law

Constant

Soil/sediment water

0.51 Pa m

3

mol

-1 86

Estimated at

25°C

Determined at 25°C

Extrapolated from data at

25°C

Estimated at

25°C



79

IPCS (1999) Satefy Evaluation of Certain Food Additives. WHO Food Additives Series: 42. Genva, Switzerland, World Health

Organisation

80 Lide DR (1997) cited in Hazardous Substances Database (HSBD), available [April 2004] at http://toxnet.nlm.nih.gov/

81

Beilstien Database (2004)

82

Sangster (1993) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com/

83

Meylan WM et al.

(1996) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com/

84

Serjeant EP & Dempsey B (1979) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com

85

Daubert TE & Danner RP (1991) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com

86

Meylan WM & Howard PH (1991) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com


(Kp)


(Koc)



Persistence in air


1.6 x 10

+5 87

0.05–0.125 days

89

1.25 days at 20°C 90

Persistence in soil



Degradation products identified from anaerobic digester sludge study included:

O

Estimated from measured log

Kow.

Not expected to under hydrolysis due to lack of hydrolyzable functional groups

88

Based on estimated half-lives for reaction with hydroxyl radicals and ozone, respectively.

Unacclimated activated sludge inoculum

(an/aerobic not specified)

O acetic acid

O

O hexadecanoic acid

87

Hazardous Substances Database (HSBD), available [April 2004] at http://toxnet.nlm.nih.gov/

88

Hazardous Substances Database (HSBD), available [April 2004] at: http://toxnet.nlm.nih.gov/

89

Hazardous Substances Database (HSBD), available [April 2004] at: http://toxnet.nlm.nih.gov/

90

Novak JT & Jruas DL (1973) cited in Hazardous Substances Database (HSBD), available [April 2004] at: http://toxnet.nlm.nih.gov/

O

Fate in the field


O tetradecanoic acid

1.3 x 10

+591




Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)

Ecotoxicity

(Daphnia)

Mouse (oral) LD50 >50 g kg

-1 92

Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Estimated for aquatic organisms based on measured log

Kow

91

Hazardous Substances Database (HSBD), available [April 2004] at http://toxnet.nlm.nih.gov/

92 Material Safety Datasheet at https://fscimage.fishersci.com/msds/70654.htm viewed April, 2004



γ-Linoleic acid

Therapeutic activity In treatment of atopic eczema

93

Chemical structure

O


O

Chemical name

CAS no

Molecular formula C

18

H

30

O

2


-1





Density

Octadeca-6,9,12-trienoic acid

506-26-3

Melting point

Boiling point


Solubility in water


Vapour pressure

Henry’s Law

Constant


(Kp)


(Koc)



Persistence in air


Persistence in soil





Fate in the field





Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)

Ecotoxicity Reduced mean survival time at conc 9 – 24 mg l

-1 94

(Daphnia)

Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

94

Beilstein database [



-linoleic acid 1712253] accessed April 2004.

Parameter



Chemical structure

Chemical name

CAS no

Molecular formula

Molecular weight





Density

Melting point

Boiling point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure




Inconclusive evidence for treatment of asthma.

95



Persistence in air


Persistence in soil



Fate in the field





Mammalian ADI

Mammalian inhalation


Tylophora indica


(aka

95

Huntley A & Ernst E (2000) Herbal medicines for asthma: a systematic review. Thorax, 55 , 925–929

Tylophora astmatica )

toxicity

Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)




Chemical structure

Tylophorine

O

O

H

N


O

Chemical name

O

2,3,6,7-Tetramethoxy-

9,10,11,12,12a,13-hexahydro-

9a-azacylcopenta[ b ]triphenylene

CAS no

Molecular formula

Molecular weight



482-20-2

C

24

H

27

NO

4

393.48 g mol

-1



Density

Melting point

Boiling point


(Kow, P)

Solubility in water

282–284°C

4.40

97

96


(pKa)

Vapour pressure






Persistence in air

Decomposes

Estimated



97

Meylan WM & Howard PH (1995) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com/


Persistence in soil



Fate in the field





Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Parameter



Chemical structure

Data

Glucosamine

Antiarthritic

98

.

Used for treatment of rheumatic disorders including osteoarthritis. It is isolated from chitin or prepared synthetically

4

.

O

-

Supporting info.

-

H

O

H

H

N

H

O

O

Chemical name

CAS no

Molecular formula

Molecular weight



O

2-Amino-2-deoxy-D-glucose -

3416-24-8 (28905-11-5 for α - form & 28905-10-4 for β)

C

6

H

13

NO

5

1

179.17

1

-0

- e.g. kg ha

-1

; dose (mg kg

-1

)


-



Density

Melting Point

-


88˚C (α form) 1 ; β decomposes at 110˚C

-

-4.23 (est) 99



Test method

Boiling Point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure

β form very soluble in water 1

Test method

6.47 at 20˚C

(potentiometric)

100

-

Test method

Test method

98

Merck Index (2001) [Glucosamine, entry 4471]

99

SRC PhysProp Database [Glucosamine 3416-24-8] Viewed online at http://esc.syrres.com/interkow/physdemo.htm April 2004

100

Beilstein Database 2004 [Glucosamine 3416-24-8] accessed April 2004

4

Martindale (2002) [Glucosamine, p 1616]


-





Persistence in air


Persistence in soil

-

-

-

-

-

-



Fate in the field


‘Turnover time’ of 303.4 h -1

101

-

-

-

-




-

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)




Test method

Test method

Test method



Test method

-

Test method



101

Swindoll et al (1988) Aerobic biodegradation of natural and xenobiotic organic compounds by subsurface microbial communities. Environmental Toxicology and Chemistry, Vol 7: 291-299

Parameter



Chemical structure

Data

O

Glucosamine sulphate and hydrochloride

Antiarthritic 102 .

Glucosamine salts are given in the treatment of rheumatic disorders, including osteoarthritis

6

.

O

S

O O O

O O

Supporting info.

-

-

O N

O

Glucosamine sulphate

O

C l

H

H

H

H

O

N

H

O

O

Chemical name

CAS no

Molecular formula

Molecular weight


O

Glucosamine hydrochloride

2-Amino-2-deoxy-D-glucose; sulphate &

2-Amino-2-deoxy-D-glucose; hydrochloride

29031-19-4 (sulphate)

66-84-2 (hydrochloride)

2C

6

H

13

NO

5

.H

2

O

4

S (sulphate)

103

C

6

H

13

NO

5

.ClH

(hydrochloride) 104

179.17 + 98.07 (sulphate)

2

179.17 + 36.46 (hydrochloride) 3

-0


-1

; dose (mg kg

-1

)

-

-

-


-

102

Merck Index (2001)

103

Beilstein Database 2004 [Glucosamine sulphate 29031-19-4] April 2004

104

Beilstein Database 2004 [Glucosamine hydrochloride 66-84-2] April 2004



-




Density

Melting Point

-

-

-

Hydrochloride 190-194˚C

(decomposes)

105

;

300˚C 106

Boiling Point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure


100 g/l (hydrochloride)

-

5

Test method

Test method

Test method





Persistence in air


Persistence in soil

-

-

-

-

-

-

-

-

-

Test method




Test method

Test method

Test method



Test method

-



Fate in the field



Mammalian oral toxicity:

-

-

-

-

-

Mammalian oral toxicity:

Hydrochloride Mouse (oral) 15 g kg

-1 107

Sulphate Mouse (oral) > 5 g kg

-1

108

105

Material Safety Datasheet viewed on-line at http://physchem.ox.ac.uk/MSDS/ April 2004

106

NTP Glucosamine Data Summary, viewed on-line at http://ntpserver.niehs.nih.gov/htdocs/Chem_Background/ExSumPdf/glucosamine.pdf

6

Martindale (2002) [Glucosamine, p 1616]

107 http://www.sigmaaldrich.com Glucosamine Hydrochloride, product code G2206, viewed April 2004

108

NTP Glucosamine Data Summary, viewed on-line at http://ntpserver.niehs.nih.gov/htdocs/Chem_Background/ExSumPdf/glucosamine.pdf

Test method




Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Parameter



-


Chemical structure

Chemical name

CAS no

Molecular formula

Molecular weight


Lavender essential oil

Sleep aid and carminative

109

Insecticide 110

Used in herbal head lice shampoo, in conjunction with

Tea Tree Oil.

-

-

8000-28-0

-

-

-0




- draw file

-1

; dose (mg kg

-1

Amount produced; Chem

)

-

-

-

-


-



Density

Melting Point

Boiling Point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure


0.93 (at 20˚C )111

0.875-0.888 (sg at 25˚C) 112

-

‘Insoluble in water’

-

3

Test method

Test method

Test method





Persistence in air


-

-

-

-

-

-

-

-

Test method




Test method

Test method

Test method


109

Martindale (2002)

110

PAN Pesticides Database, viewed on-line at http://www.pesticideinfo.org/Index.html April 2004

111

Chemfinder [Oil of lavender], viewed on-line at http://chemfinder.cambridgesoft.com/ April 2004

112

Essential oil information viewed on-line at http://www.perfumersworld.com/essoil/oilotm.htm April 2004

Persistence in soil



Fate in the field




-


Mammalian ADI

-


Ecotoxicity (Bird)

Ecotoxicity (Fish)

-

-


Ecotoxicity (Algae)

Ecotoxicity (Other aquatics) -

Ecotoxicity (Bees) -

-

-

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

-

-

-

-

-

-


Test method

-

Test method



Parameter


Data

Linalyl acetate

Constituent of lavender oil

1

Supporting info.

-


Chemical structure -

O

Chemical name 3,7-Dimethyl-1,6-octadien-3ol

115-95-7

C

12

H

20

O

2

196.28

113

-0

O

-

CAS no

Molecular formula

Molecular weight





- draw file

-1

; dose (mg kg

-1


)

-

-


-



Density

Melting Point

Boiling Point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure


0.895 (at 20 ˚C) 1

0.901

114

<25 ˚C 115

220 ˚C 1,2,3

3.93

-

3

8.2 mg/l (est)

3

Test method

Test method

Test method





Persistence in air

14.8 Pa at 25 ˚C (ext) 3

Test method

176 Pa m

3

mol

-1

(est at 25 ˚C)

3


L kg

-1


5800 (est from log Kow)

116


Half life (d)

170 d to 4.8 yr (est at pH 7 and 8, respectively)

4

0.14 d d

Test method

Test method

Test method

113

Merck Index (2001) [Linalyl acetate, entry 5518]

114

Chemfinder [Linalyl acetate] viewed on-line at http://chemfinder.cambridgesoft.com/ April 2004

115

SRC PhysProp Database [Linalyl acetate] viewed on-line at http://esc.syrres.com/interkow/physdemo.htm April 2004

116

HSDB [Linalyl acetate] viewed on-line via TOXNET at http://toxnet.nlm.nih.gov/ April 2004


Persistence in soil



Fate in the field


Thought to be readily degradable see above see above

-

-

1300 (est) 4

4



-

LD

50

rat oral 14.55 g/kg

(13.35 g/kg mouse)

4

Mammalian skin/eye toxicity Rabbit: severe irritant

Mammalian ADI

Guinea pig: moderate irritant

117

0-0.5 mg/kg bw

118


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)



Test method

-

Test method



100mg for 24hrs

100mg for 24hrs

117

Material Safety Datasheet at http://sigmaalrich.com Product number L2807 viewed April 2004

118

JECFA (1998) Linalyl acetate, viewed on-line at http://www.inchem.org/documents/jecfa/jeceval/jec_931.htm April 2004

Parameter


Data


Pinene

Constituent of many volatile oils obtained from plants, including lavender oil

Chemical structure

Supporting info.

-

-

α pinene (dl-racemate)

Chemical name

CAS no

Molecular formula

Molecular weight



Density

Melting Point

β pinene (dl-racemate)

2,6,6-

Trimethylbicyclo[3.1.1]hept-2ene (α pinene)

6,6-Dimethy-2methylenebicyclo[3.1.1]heptane

(β pinene)

80-56-8 (α pinene)

127-91-3 (β pinene)

C

10

H

16

136.23

119

-0

-

-


-1


; dose (mg kg

-1

)


0.859

1 , 0.857

120 (α pinene)

0.87

7

, 0.86

6

(β pinene)

-64 ˚C

121

, -62.5 ˚C

122

(α pinene)

-61.5 ˚C

123

(β pinene)

-


-



119 Merck Index (2001) [α-pinene entry 7527, β-pinene entry 7528]

120

Chemfinder [alpha Pinene] viewed on-line at http://chemfinder.cambridgesoft.com/ April 2004

121

SRC PhysProp Database [Alpha-Pinene] viewed on-line at http://esc.syrres.com/interkow/physdemo.htm April 2004

122

HSDB Profiles [Alpha-Pinene], [Beta-Pinene] viewed on-line via TOXNET at http://toxnet.nlm.nih.gov/ April 2004

123

SRC PhysProp Database [Beta-Pinene] viewed on-line at http://esc.syrres.com/interkow/physdemo.htm April 2004

Boiling Point


(Kow, P)

Solubility in water

155-156 ˚C

(α pinene) 1,3

162-166˚C (β pinene) 5,124

4.83

(α pinene at 25 ˚C) 3

4.16 (β pinene) 5

2.49 mg/l

2 (α pinene)

4.89 mg/l

5

(est, β pinene)

- Acid dissociation constant

(pKa)

Vapour pressure






Persistence in air

633 Pa (α pinene at 25 ˚C) 3

391 Pa (β pinene at 25 ˚C) 5

3x10 4 Pa m 3 mol -1 (α pinene, est: VP/sol)

3

1.6x10

4

Pa m

3

mol

-1

(β pinene, est)

5

2451L kg

-1

(calculated for α pinene based on estimated

K om

) 125

1200 (est from log Kow, α, β pinene)

4


Persistence in soil



Fate in the field




Test method

Test method

Test method

Test method




-

-

0.17 d (est α pinene) 4

0.2 d (est β pinene) 4

Test method

Test method

Test method

Half life (d); ready/non-ready Test method; aerobic anaerobic

Test method; soil type Rapid biodegradation:

‘removal’ in ~250 hr’ (α pinene

) 4

α pinene ‘readily degraded’: observed biodegradation rate of

1.1-2.1 ug g -1 h -1 in soil slurry a

Biodegradation also

‘anticipated’ for β pinene 4

Half life (d) Test method

- Amount produced; ChemDraw structure

Dissipation half life (d);

Measured concs (mg kg -1 ; mg l -

1

)

2800 (est, α pinene) 4

440 (est, β pinene) 4

-

LD

50 rat oral 3.7 g/kg (α

Test method



124 Merck Index (2001) [β Pinene]

7

Chemfinder [beta-Pinene] viewed on-line at http://chemfinder.cambridgesoft.com/ April 2004

125

Misra & Pavlostathis (1997) Biodegradation kinetics of monoterpenes in liquid and soil-slurry systems. Appl Microbiol

Biotechnol, 47: 572-577


Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants) pinene)

4126

Irritating to the skin, eyes and respiratory system

127

LCLO rat inhalation 625

 g m

-3

(



pinene)

LCLO guinea pig 527

 g m -3 (

 pinene)

LCLO mouse 364

 g m

-3

(

 pinene)

128

126


127

Material Safety Datasheet at http://ptcl.chem.ox.ac.uk/MSDS/PI/alpha-pinene.html viewed April 2004

128


Parameter



-


Chemical structure

Chemical name

CAS no

Molecular formula

Molecular weight


Tea Tree Oil

-

-

Antiseptic

129

.

Considered to have anti-viral, anti-bacterial and anti-fungal properties. It is used for the treatment of candida and other infections, ringworm and athlete’s foot 130

.

Used in shampoo for treatment of headlice.

68647-73-4

-

-

-0




- draw file

-1

; dose (mg kg

-1


)

-

-

-

-


-



Density

Melting Point

Boiling Point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure


-

-

0.895-0.905 at 15 ˚C 1

0.89

131

-

-

-

Test method

Test method

Test method





-

-

-

-

-

-

Test method




Test method

Test method

129

Merck Index (2001) [Tea Tree Oil 68647-73-4]

130

Worwood VA (1991) The Fragrant Pharmacy: a complete guide to aromatherapy and essential oils

131

Chemfinder [Tea-tree oils] viewed on-line at http://chemfinder.cambridgesoft.com/ April 2004

Persistence in air


Persistence in soil



Fate in the field


-

-

-

-

-

Test method



Test method

-

-

-


-


Mammalian skin/eye toxicity Rabbit (skin) LD50 5000 mg kg

-1 133

Mammalian ADI


-

1132


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Test method



132

Material Safety Datasheet at http://www.sigmaaldrich.com/ Product number W390208

133 Material Safety Datasheet at http://www.sigmaaldrich.com/ Product number W39020

Parameter



Data

Cineole

Constituent of Tea Tree Oil

1

(and numerous other plants)

Chemical structure

Supporting info.

-

-

O

Chemical name

CAS no

Molecular formula

Molecular weight




1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane

470-82-6

C

10

H

18

O

154.25

134

-0


-


-1 ; dose (mg kg -1 )

-

-

-


-



Density

Melting Point

Boiling Point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure


0.922

135

0.9267 g/cm

3 (20 ˚C) 4

1.5 ˚C 136

176.4 ˚C 3,137

174-176.4 ˚C

1

2.74

3,4

3.5 g/l 3

-

, 3.24 g/l 1

Test method

Test method

Test method




253 Pa (25 ˚C) 3,4

Test method

11 Pa m

3

mol

-1

(est at 25 ˚C)

3


-

-



- Test method

134

Beilstein Database [cineole] accessed April 2004

135

Chemfinder [1,8-Cineole] viewed on-line at http://chemfinder.cambridgesoft.com/ April 2004

136 S RC PhysProp Database [1,8-Cineole] viewed on-line at http://esc.syrres.com/interkow/physdemo.htm April 2004

137

HSDB [Cineole] viewed on-line via TOXNET at http://toxnet.nlm.nih.gov/ April 2004


Persistence in air


Persistence in soil



Fate in the field


-

-

-

-

-

-

Test method

Test method



Test method

-

-

-




Mammalian ADI


-


-1

138

Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)

Ecotoxicity (Other aquatics) LD50 Artemia salina

737ppm

139

Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Test method



Brine shrimp

138

Material Safety Datasheet viewed at http://www.sigmaaldrich.com/ Product number C8144 viewed April 2004

139

Beilstein Database, May 2004

Parameter



Chemical structure


-

Terpinen-4-ol

Constituent of Tea Tree Oil 140

-

O

Chemical name

CAS no

Molecular formula

Molecular weight




4-methyl-1-(1-methylethyl)-3cyclohexen-1-ol

562-74-3

C

10

H

18

O

154.25

141

-0


-


-1

; dose (mg kg

-1

)

-

-

-


-



Density

Melting Point

Boiling Point

0.933

142

-

209 ˚C 143

210-214 ˚C (at 760 mmHg)

2

3.26

4 Octanol-partition coefficient

(Kow, P)

Solubility in water


(pKa)

Vapour pressure

Henry’s Law Constant g L

-

-1

Test method

Test method

Test method




Pa

Pa m

L kg

L Kg

3

mol

-1

-1

-1

Test method




Half life (d) Test method

140

Merck Index (2001) [Tea Tree Oil 68647-73-4]

141

Beilstein Database [562-74-3]

142

Chemfinder [terpinen-4-ol] viewed on-line at http://chemfinder.cambridgesoft.com/ April 2004

143

SRC PhysProp Database [562-74-3] viewed on-line at http://esc.syrres.com/interkow/physdemo.htm April 2004


Persistence in air


Persistence in soil



Fate in the field


Half life (d)

Half life (d)

Test method

Test method

Half life (d); ready/non-ready Test method; aerobic anaerobic

Half life (d)

Half life (d)

Amount produced;

ChemDraw structure

Dissipation half life (d);

Measured concs (mg kg -1 ; mg l

-1

)

-


Test method

-

Test method



Biota-sediment/soil - accumulation factor

Mammalian oral toxicity Rat (oral) LD50 1300 mg kg

-1

144

Mammalian skin/eye toxicity Rabbit (skin) >2500 mg kg

-1

Rabbit skin: moderate irritant

145

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Draize test, 500mg / 24 hr

Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

144

Material Safety Datasheet at http://www.fisher.co.uk/ Catalogue number 27043-1000

145


Parameter



Chemical structure

Chemical name

CAS no

Molecular formula

Molecular weight


Orange essential oil

Expectorant

146

Used as a flavour and in perfumery.

147

8008-57-9


Application/emission rates 2600 µg/day 148



Density

Melting point

Boiling point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure






Persistence in air


Persistence in soil



Fate in the field


0.844–0.847 g cm -3

Slightly soluble in water

a


Used as a flavour and perfume.

Estimated European per captia intake

At 20/20°C



147


148

IPCS (1999) Safety Evaluation of Certain Food Additives. WHO Food Additives Series: 42. Aliphatic, Acyclic and Alicyclic

Terpenoid Tertiary Alcohols and Structuraaly Related Substances.

Geneva, Switzerland, World Health Organization


Mammalian oral toxicity Rat (oral) LD50 >5g kg

-1 149

Mammalian skin/eye toxicity Rabbit (skin) LD50 >5g kg

-1

150

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

149


150


Parameter



Chemical structure


d-Limonene


Chemical name

CAS no

Molecular formula

Molecular weight



5989-27-5

C

10

H

16

136.24 g mol

-1



Density

Melting point

Boiling point

4-Isopropenyl-1-methylcyclohexene

0.8482 g cm

-3 151

-73.97°C

152

175.5–176°C

153

Determined at 4/20°C

Determined at 101725

Pa


(Kow, P)

Solubility in water


(pKa)

Vapour pressure





4.57

154

213 Pa

0.0204 g L

156

2604 Pa m

1501L kg

1030–4780

3

-1 155

mol

159

-1 157 on estimated K om

)

-1

(calculated, based

158

Determined at 25°C

Determined at 25°C

Estimated at 25°C

Estimated soil adsorption coefficients

0.096–0.108

160 Based on experimental rates constants for the gas-phase reaction with photochemically

151


152




154

Li J & Purdue EM (1995) cited in SRC PhysProp Database, avaialble [April 2004) at: http://esc.syrres.com/

155


156


157

VP/WSOL cited in SRC PhysProp Database, avaialble [April 2004] at: http://esc.syrres.com/

158



159


160



Persistence in air


Persistence in soil



H

0.008–0.033 days

161

‘Readily degraded’: observed biodegradation rate of 0.9-1.9 ug g -1 h -1 in soil slurry h

Photolysis of dlimonene in the presence of nitrogen oxides produces:

162

O formaldehyde

O

- produced hydroxyl radicals

Estimated atmospheric lifetime depending on hydroxyl and ozone conc

O

O formic acid

( I I )

C O carbon monoxide

O carbon dioxide

O acetaldehyde

O

O

O

O

N

O peroxyacetyl nitrate

O acetone

161


162


Degradation products of hydrolysis of limonene include:

O formaldehyde

O

H

O acetic acid

O

Fate in the field


O formic acid e

246–262 163

Biota-sediment/soil

Mammalian inhalation toxicity accumulation factor

Mammalian oral toxicity Rat (oral) LD50 4.4g kg

-1


-1

164

Mammalian skin/eye toxicity Rabbit (skin) LD50 >5g kg

-1

Mammalian ADI

165

0.1 mg kg

-1

bw day

-1 166

Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


EC50 0.4mg l

-1 167

Ecotoxicity (Bees)

Ecotoxicity (Worms) Earthworm Eisenia fetida

(Savigny) LD50 6.0ppm

168

Environmental fate

Fate (Animals)

Estimated for aquatic organisms based on water solubility and estimated log Kow

Cutaneous exposure

163

Hazardous Substances Data Bank (HSDB) available, [April 2004] at: http://toxnet.nlm.nih.gov/

164 http://ptcl.chem.ox.ac.uk/MSDS/LI/(R)-(+)-limonene.html viewed April 2004

165 http://ptcl.chem.ox.ac.uk/MSDS/LI/(R)-(+)-limonene.html viewed April 2004

166

Concise International Chemical Assessment Document, viewed April 2004 at http://www.inchem.org/documents/cicads/cicads/cicad05.htm

167

CICAD entry http://www.inchem.org/documents/cicads/cicads/cicad05.htm#PartNumber:9 viewed May 2004

168


Fate (Plants)

Parameter



Chemical structure


L-Limonene


Chemical name

CAS no

Molecular formula

Molecular weight


4-Isopropenyl-1-methylcyclohexene

5989-54-8

C

10

H

16

136.24 g mol

-1




Density

Melting point

Boiling point

0.8407 g cm

-3 169

-73.95°C

170

175.5–176.5°C

171

0.00315 g L -1 173



Pa


(Kow, P)

Solubility in water


(pKa

174

)

Vapour pressure



Organic carbon normalised soil/sediment water partition

4.38

172

191.98 Pa

38503.5 Pa m 3 mol -1 175

1501L kg

-1

(calculated, based on estimated K om

)

176

1030–4780

177

Estimated at 25°C

Determined at 25°C

Estimated at 25°C

Estimated soil adsorption coefficients



170




172

Griffin S et al . (1999) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com/

173

Meylan WM et al.

(1996) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com/

174

Nadais MH & Bernardo-Gil MG (1993) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com/

175


176



177


coefficient (Koc)



Persistence in air


Persistence in soil



H

0.108 days

178

0.008–0.033 days

179

‘Readily degraded’: observed biodegradation rate of 0.9-1.9 ug g

-1

h

-1

in soil slurry h

Photolysis of dlimonene in the presence of nitrogen oxides produces: 180

O formaldehyde

O

Half-life based on experimental rate constant for the gasphase reaction of limonene with photochemically produced hydroxyl radicals.

Estimated atmospheric lifetime depending on hydroxyl and ozone conc

O

O formic acid

( I I )

C O carbon monoxide

O carbon dioxide

O acetaldehyde

178


179


180


O

O

O

O

N

O peroxyacetyl nitrate

O acetone

Degradation products of hydrolysis of limonene include:

O formaldehyde

O

H

O acetic acid

O

Fate in the field


O formic acid

246–262 181


Mammalian oral toxicity Rat (oral) LD50 5000 mg kg

-1

182

Mammalian skin/eye toxicity Rabbit (skin) LD50 >5000 mg kg

-1 183

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Estimated for aquatic organisms based on water solubility and estimated log Kow

181


182

Material Safety Datasheet at http://www.sigmaalrich.com Product number 218367

183

Material Safety Datasheet at http://www.sigmaalrich.com Product number 218367

Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Green alga, LCIC >100

 mol/l

Blue-green alga, LCIC >

100

 mol/l

184

Lowest complete inhibition concentration, rapid microplate assay

184

Beilstein Database, viewed April 2004, Beilstein Registry number 2323991

Parameter



Chemical structure


Citral


Chemical name

CAS no

Molecular formula

Molecular weight



O

5392-40-5

C

10

H

16

O

152.23 g mol

-1

3,7-Dimethyl-2,6-octadienal



Density

Melting point

Boiling point

0.885–0.891 g cm -3 185

<-10°C

186

226–228°C

187

3.45

188


(Kow, P)

Solubility in water


(pKa)

Vapour pressure






Persistence in air

0.5785 g L

12.17 Pa

4.41 Pa m

L kg

150

c

-1

190

-1 189

3

mol

-1 191

0.03–0.12 days

c


Estimated

Determined at 25°C

Estimated at 25°C

Estimated at 25°C using a fragment constant method


Estimated based on molecular connectivity indexes.

Based on rate constant for vapour-phase reaction with ozone and hydroxyl radicals, respectively



186

SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com/

187

Hazardous Substances Data Bank (HSDB), available [April 2004] at: http://toxnet.nlm.nih.gov/

188


189


190

Neely WB & Blau GE (1985) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com/

191



Persistence in soil



-

Fate in the field

Bioconcentration factor 250 192

Biota-sediment/soil

Mammalian inhalation toxicity accumulation factor

Mammalian oral toxicity Rat (oral) LD50 4.96 g kg

-1

Mouse (oral) LD50 6 g kg

-1

193

Mammalian skin/eye toxicity Irritating to skin and eyes

194

Mammalian ADI Human 500

 g kg

-1 195

Estimated for aquatic organisms from an estimated log Kow.

Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

192

Hazardous Substances Data Bank, available [April 2004] at: http://toxnet.nlm.nih.gov/

193

Material Safety Datasheet at http://ptcl.chem.ox.ac.uk/MSDS/CI/citral.html viewed April 2004

194 Material Safety Datasheet at http://ptcl.chem.ox.ac.uk/MSDS/CI/citral.html viewed April 2004

195

Hazardous Substances Data Bank, available [April 2004] at: http://toxnet.nlm.nih.gov/

Parameter



Chemical structure


Linalool

O


Chemical name


Density

Melting point

Boiling point

3,7-Dimethyl-octa-1,6-dien-3ol

CAS no

Molecular formula

78-70-6

C

10

H

18

O

154.25 g mol

-1

Molecular weight



-1

; dose (mg kg

-1

)


0.8685 g cm

-3 196

<25°C 197

198°C 198

2.97

199

-


Determined at 101 325

Pa


(Kow, P)

Solubility in water


(pKa)

Vapour pressure


1.56 g L

-1 200

21.33 Pa

2.18 Pa m

201

3 mol -1 202

Determined at 25°C

Determined at 25°C





75

203

0.033–0.067 days

204

Determined from an experimental water solubility and a recommended regression-derived equation

Photooxidation at

21.9°C in 135L. 2m long reaction chamber

196


197

SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com/

198


199

Li J & Perdue EM (1995) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com/

200


201

Li J & Perdue EM (1995) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com/

202

Altschuh J et al . (1999) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com/

203

Hazardous Substances Data Bank (HSDB), avaialble [April 2004] at: http://toxnet.nlm.nih.gov/

204



Persistence in air 0.03–0.13 days

205

Based on estimated vapour phase reaction rate constants in air with ozone and hydroxyl radicals, respectively.


Persistence in soil



Fate in the field

Bioconcentration factor 106

206



Mammalian ADI

Mouse (oral) LD50 3g kg

-1

(oily solution)


-1

(10% aqueous arabic gum solution)

Rat (oral) LD50 2.79g kg

-1 207

Mammalian skin/eye toxicity Rabbit (skin) 5.61g kg

-1

Rat (skin) 5.61g kg -1

Rabbit (eye) moderate irritant at 100%

208

0-0.5 mg kg -1 bw 209


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Estimated for aquatic organisms from an experimental log Kow

205


206


207


208


209

JECFA (1998) http://www.inchem.org/documents/jecfa/jecmono/v042je17.htm viewed April 2004

Parameter




Peppermint oil

Carminative

210

Aromatic carminative which relaxes gastrointestinal smooth muscle and relieves flatulence and colic. Entericcoated capsules containing peppermint oil are used for the relief of symptoms of the irritable bowel syndrome or gastrointestinal spasm secondary to other disorders.

Also used as a flavour and with other volatile agents in preparations for respiratorytract disorders.

211

8006-90-4

Chemical structure

Chemical name

CAS no

Molecular formula

Molecular weight



-1

; dose (mg kg

-1

)



Density

Melting point

Boiling point

0.896–0.908 g cm -3 212


(Kow, P)

Solubility in water Very slightly soluble in water

213


(pKa)

Vapour pressure





-

-




211








Persistence in air


Persistence in soil



Fate in the field

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)






Rat (oral) LD50 2.4g kg -1


-1

214

Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

214


Parameter



Chemical structure


Menthol

Antipruritic (topical)


O

Chemical name

CAS no

Molecular formula

Molecular weight


2-Isopropyl-5-methylcyclohexanol

89-78-1

C

10

H

20

O

156.27 g mol

-1

Application/emission rates 18 000 µg/day

215



-


Density

Melting point

Boiling point

0.9 g cm

-3 216

41–43°C

217

212–212.5°C

218


(Kow, P)

Solubility in water


(pKa)

Vapour pressure

3.40

219

0.456 g L

-1 220

14.67 Pa 221


1.54 Pa m

3

mol

-1 222

Estimated European per capita intake





Pa

Determined at 25°C

Extrapolated from data at 25°C

Estimated at 25°C

215

ICPS (1999) Safety Evaluation of Certain Food Additives. WHO Food Additives Series: 42. Substances Structurally Related to Menthol. Geneva, Switzerland, World Health Organization

216




218


219

Griffin S et al. (1999) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com/

220

Yalkowsky SH & Dannenfelser RM (1992) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com/

221

Jordan TE (1954) cited in SRC PhysProp Database, available [April 2004] at: http://esc.syrres.com/

222






Persistence in air


Persistence in soil



Fate in the field





Mammalian ADI 0 – 4 mg kg

-1

bw

224


Rat (oral) LD50 3180 mg kg -1

223

Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

223

Hazardous substances Database viewed at http://toxnet.nlm.nih.gov/ April 2004

224

JECFA, 1998 viewed http://www.inchem.org/documents/jecfa/jecmono/v042je04.htm April 2004

Parameter



Chemical structure


Menthone

Used in perfume and flavour compositions

225


Chemical name

CAS no

Molecular formula

Molecular weight

C

10

H

18

O

154.23 g mol

-1


Application/emission rates 1000 µg/day

226

O

2-Isopropyl-5-methylcyclohexanone

10458-14-7



Density

Melting point

Boiling point

0.8924 g cm

-6°C 228

202°C 229

-3 227




Pa


(Kow, P)

Solubility in water


(pKa)

Vapour pressure

0.7 g L

-1 230 Determined at 20°C

13332.2–101325 Pa

231

Determined at 138–

209°C








226


227




229


230


231


Persistence in air


Persistence in soil



Fate in the field





Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Parameter



Chemical structure


Menthyl acetate

Used in perfumery

232

O


O

Chemical name 5-Methyl-2-(1methylehtyl)cyclohexanol acetate

CAS no

Molecular formula

Molecular weight

89-48-5

C

12

H

22

O

2

198.30 g mol

-1


Application/emission rates 420 µg/day 233



Density

Melting point

Boiling point

-


0.9185 g cm

27°C 235

227–228°C

-3 234

236






Pa

Estimated Octanol-partition coefficient

(Kow, P)

Solubility in water


(pKa)

Vapour pressure


4.39

237

Slightly soluble in water 238

13.33 Pa

239

84.10 Pa m

3

mol

-1 240

At 25°C

Estimated using a



233


234


235


236


237




239


fragment constant estimation method





Persistence in air

5800

241

0.875 days

0.875 days

242

270–2666.33 days

244

243

Determined from an estimated log Kow and a regression equation

Based on an estimated base-catalyzed secondorder hydrolysis rate constant, using a structure estimation method. Half-lives correspond to pH 8 and

7, respectively.

Based on estimated half-life for photochemically produced hydroxyl radicals


Persistence in soil



Fate in the field

Bioconcentration factor 1300

245

Estimated for aquatic organisms from an estimated log Kow




Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


240


241


242


243


244


245


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Parameter



-


Chemical structure

Chemical name

CAS no

Molecular formula

Molecular weight



Thyme essential oil

Similarly to thyme, thyme oil has carminative, antiseptic, antitussive, and expectorant properties and is used chiefly in preparations for respiratory-tract disorders.

246

-

-

8007-46-3

-

-

-0


-1

Proportion metabolised - draw file

; dose (mg kg

-1


)

-

-

-

-


-



Density

Melting Point

Boiling Point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure


-

-

-

-

0.915-0.935 (sg at 25 ˚C) 247

- Test method

Test method

Test method





Persistence in air


-

-

-

-

-

-

Test method




Test method

Test method

Test method


246

Martindale (2002) [Thyme, Thyme Oil]

247

The Good Scent Company [Thyme Oil Red, White] viewed on-line at http://www.thegoodscentscompany.com April 2004

Persistence in soil



Fate in the field


-

-

-

-

-



-

Rat (oral) LD50 2840 mg kg -1

248

Mammalian skin/eye toxicity Rabbit (skin) LD50 >5000 mg kg

-1 249

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


LC50 20.5 mg l

-1

(coho salmon)

LC50 16.1 mg l

-1

(rainbow trout) (Stroh et al.

, 1998)

Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)


Test method

-

Test method



96hrs, static acute toxicity in moderately hard fresh water

248

Material Safety Datasheet http://ptcl.chem.ox.ac.uk/MSDS/TH/thyme_oil.html

249

Material Safety Datasheet http://ptcl.chem.ox.ac.uk/MSDS/TH/thyme_oil.html

Parameter



Chemical structure

Data

Thymol

Topical application as an antiseptic and as an antihelmintic.

Veterinary use as an antihelmintic, and as an antiseptic, external and internal.

250

Antifungal and reduces gingivitis 251

O

-

Supporting info.

-

Chemical name

CAS no

Molecular formula

Molecular weight




5-Methyl-2-(1methylethyl)phenol

89-83-8

C

10

H

14

O

150.22

1

-0


-


-1

; dose (mg kg

-1

)

-

-

-


-



Density

Melting Point

Boiling Point


(Kow, P)

Solubility in water


(pKa)

0.9699 (at 25 ˚C) 1

51.5 ˚C 1,252

52 ˚C 2

~233 ˚C 1,253

232.5

3

3.30

2,3

3.89 (at 25 ˚C) 254

~1 g/l 1

900 mg/l (at 25 ˚C) 3

10.6 (at 20 ˚C) 3

10.62

2

9.9

(spectrophotometric at

Test method

Test method

Test method

250

Merck Index (2001) [Thymol, entry 89-93-8]

251

HSDB [Thymol] viewed on-line via TOXNET at http://toxnet.nlm.nih.gov/ April 2004

252

SRC PhysProp Database [Thymol] viewed on-line at http://esc.syrres.com/interkow/physdemo.htm April 2004

253

Chemfinder [Thymol] viewed on-line at http://chemfinder.cambridgesoft.com/ April 2004

254

Beilstein Database [89-83-8] accessed April 2004

Vapour pressure






Persistence in air


Persistence in soil



Fate in the field


-

-

-

-

-

-

-

-

-

-

24.9 ˚C ) & 10.49 (at 25 ˚C) 5

0.29 Pa (at 25 ˚C)2,

3

0.05 Pa m

˚C) 3

3 mol -1 (est at 25

-

Test method




Test method

Test method

Test method



Test method

-



-

Rat (oral) LD50 980mg kg

-1

255

Mouse (oral) LD50 1.8g kg -1

256

Guinea pig (oral) LD50

880mg kg -1257


Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish) LC50 3.2 – 4.2 mg l -1 258

Test method



? Query mouse oral tox

LD50 on sigma msds

640mg kg -1

Ecotoxicity (Daphnia) EC50 1.7 – 3.2 mg l

-1 259

Ecotoxicity (Algae)

Ecotoxicity (Other aquatics) LC50 10.71 mg l

-1 260

Toxic to aquatic organisms

May cause long-term adverse

96 hr

Pimephales promelas

96 hr

Acute toxicity to

Lymnaea acuminata

(snail) measured at 96 hrs

255


256


257


258

Material Safety Datasheet at http://www.sigmaaldrich.com/ Product code 112097 viewed April 2004

259

Material Safety Datasheet at http://www.sigmaaldrich.com/ Product code 112097 viewed April 2004

260

Beilstein Database, viewed April 2004

Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants) effects in the aquatic environment 261

261


Parameter



Chemical structure

Data

Carvacrol

Constituent of Thyme oil.

Used as an anti-infective and as antihelminthic

262

.

O

-

Supporting info.

-

Chemical name

CAS no

Molecular formula

Molecular weight


IUPAC format

499-75-2

C

10

H

14

O

150.22

1

-0




- draw file

-1 ; dose (mg kg -1


)

-

-

-


-



Density

Melting Point

Boiling Point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure


0.976 (at 20 ˚C) 1,3

~0 ˚C 1

1 ˚C 263,264

237-238 ˚C

1

237.7 ˚C 2

3.49

2

1.25 g/l (at 25 ˚C)

10.35 (at 25 ˚C) 265

2

Test method

Test method

Test method



-

-

-

-

Test method




262

Merck Index (2001) [Carvacrol, entry 1887]

263


264

HSDB [Carvacrol] viewed on-line via TOXNET at http://toxnet.nlm.nih.gov/ April 2004

265

Beilsten Database [499-75-2] accessed April 2004

Parameter



Persistence in air


Persistence in soil



Fate in the field


Data

-

-

-

-

-

-

Amount produced;

ChemDraw structure

-

-



-

Rat (oral) LD50 810mg kg -

1266

Mammalian skin/eye toxicity Rabbit (skin) severe irritant

267

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

500mg 24 hr

Supporting info.

Test method

Test method

Test method



Test method

-

Test method



266

Material Safety Datasheet at http://ptcl.chem.ox.ac.uk/MSDS/ME/2-methyl-5-(1-methylethyl)phenol.html viewed April

2004

267

Material Safety Datasheet http://www.sigmaaldrich.com/ Product code 282197 viewed April 2004

Parameter



Chemical structure

Data

Borneol

Constituent of thyme and valerian.

Free or esterified borneol identified in 250 distillates from plants, herbs, leaves etc.

4

Supporting info.

-

-

O

Chemical name

CAS no

Molecular formula

Molecular weight





(dl enantiomers. Natural borneol can be d or l but v.seldom racemic)

4 endo -1,7,7-Trimethylbicyclo-

[2.2.1]heptan-2-ol

507-70-0

C

154.25

268

-0

-

10 file

H

18

O

-1 ; dose (mg kg -1 )

Amount produced; Chem draw

-

-

-


-



Density

Melting Point

Boiling Point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure


1.011 (d-form)

1

206-207 ˚C (dl form)

1a

212 ˚C (d-form) 1

210 ˚C 269

2.69

270

738 mg/l (at 25 ˚C)

-

3

Test method

Test method

Test method


4.7 Pa (est at 25 ˚C) 3

0.7 Pa m

Test method

3

mol

-1 (est at 25 ˚C) 3

Test method;

L kg

-1 temperature


268

Merck Index (2001) [Borneol, entry 1328]. 1a Mpt: 208 ˚C for d-form and 204 ˚C for l-form.

269

Chemfinder [borneol] viewed on-line at http://chemfinder.cambridgesoft.com/ April 2004

270


4

HSDB [Borneol] viewed on-line via TOXNET at http://toxnet.nlm.nih.gov/ April 2004

Parameter




Persistence in air


Persistence in soil

Data

-

-

-

-

-

-



Fate in the field





-

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

-

-

-

-

Supporting info.


Test method

Test method

Test method



Test method

-

Test method



Parameter



Chemical structure

Data

Camphor

Topical analgesic and antipruritic. Veterinary use internally as carminative, externally as an antipruritic, counterirritant and antiseptic 1 .

Also used as a steam inhalant

– popular in respiratory diseases of horse and poultry

3

.

Supporting info.

-

-

O

Chemical name

CAS no

Molecular formula

Molecular weight


(d/l enantiomers: natural form is d-camphor, synthetic form is racemic)

IUPAC format

76-22-2

C

10

H

16

O

152.23

271

-0




- draw file

-1

; dose (mg kg

-1


)

-

-

-


-



Density

Melting Point

Boiling Point

0.992 g/cm

3 (at 25 ˚C) 1

179 ˚C 1

180 ˚C 272 d-Camphor sublimes at 204

˚C 1

2.38

2 Octanol-partition coefficient

(Kow, P)

Solubility in water

1.25 g/l (at 25 ˚C) 1

1.6 g/l (at 25 ˚C) 2

2.04 g/l (at 25 ˚C) 273

-

Test method

Test method


(pKa)

Vapour pressure

87 Pa (at 25 ˚C) 2,274

Test method

Test method

271

Merck Index (2001) [Camphor, entry 1739]

272


273

Beilstein Database [Camphor]






Persistence in air


Persistence in soil



Fate in the field


8.2 Pa m

3

mol

-1

(est at 25 ˚C,

VP/WSOL) 2

-

-

-

-

-

-

-

-

-




Test method

Test method

Test method



Test method

-

-

-



-

Rabbit LDLO 2g kg

-1

Mouse LD50 1.31g kg

-1275

Human lethal dose 50-500 mg kg

-1

(Gibson et al.

, 2004)

Mammalian skin/eye toxicity Mild skin, eye or respiratory irritant

Mammalian ADI

Typical TLV/TWA 2ppm

Typical STEL 3ppm

276


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Test method



274

HSDB [Camphor] viewed on-line via TOXNET at http://toxnet.nlm.nih.gov/ April 2004

275

Material Safety Datasheet viewed at http://physchem.ox.ac.uk/MSDS/CA/camphor.html April 2004

276

Material Safety Datasheet viewed at http://physchem.ox.ac.uk/MSDS/CA/camphor.html April 2004

Parameter



Chemical structure

Chemical name

CAS no

Molecular formula

Molecular weight





Density

Melting point

Boiling point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure






Persistence in air


Persistence in soil



Fate in the field


Biota-sediment/soil


Wormwood

Antihelminthic

277

As flavouring in alcoholic beverages (e.g. vermouth) 278

Used as a bitter. Has been used in homeopathic medicine 279


Absinthium

277

Personal communication



279

Sweetman SC (2002) Martindale. The Complete Drug Reference. Thirty-third edition . London, UK, Pharmaceutical Press

accumulation factor

Mammalian oral toxicity Rat oral LD50 960mg kg

-1 280

Mammalian skin/eye toxicity Rabbit dermal LD50 > 5g kg -1

281

Not irritant in 48 hour patch test in humans

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

280

WHO Food Additives Series viewed online at http://www.inchem.org/documents/jecfa/jecmono/v16je25.htm , May 2004

281

WHO Food Additives Series viewed online at http://www.inchem.org/documents/jecfa/jecmono/v16je25.htm, May 2004

Parameter Preferred units/format Supporting information

- Preparation/chemical name


Chemical structure

Absinthin

O

H

H

H

H

O

-

H

H

H

H

H

O

O

O

Chemical name

O

[3 S-

(3α,3a α,6β,6aα,6bβ,7α,7aβ,8 α,10aβ,11β,13a α,13b

α,13cβ,14bβ)]-

3,3a,4,5,6a,6b,7,7a,8,9,10,10a,13a,13c,14b-

Hexadecahydro-6,8-dihydroxy-3,6,8,11,14,15hexamethyl-2 H -7,13bethenopentaleno[1”,2”:6,7;5”,4”:6’,7’]dicyclohepta[1,2b:1’,2’-b’]difuran-2,12(11

H )-dione

1362-42-1 CAS no

Molecular formula C

30

H

40

O

6


-1





Density

Melting point

Boiling point


Solubility in water


Vapour pressure

Henry’s Law

Constant


(Kp)


179–180°C

-

Decomposes


(Koc)



Persistence in air


Persistence in soil



Fate in the field





Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)

Ecotoxicity

(Daphnia)

Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

Parameter



Chemical structure

O


α-Santonin

Anthelminthic (Nematodes)

282

Formerly used as an anthelminthic in the treatment of roundworm infection, but has been superseded by other less toxic anthelminthics.

Used as a flavour in food.

283


O

O

H

H

Chemical name 3,5a,9-Trimethyl-3a,5,5a,9btetrahydro-3H,4Hnaphthol[1,2-b]furan-2,8dione

CAS no

Molecular formula

Molecular weight



481-06-1

C

15

H

18

O

3

246.3 g mol

-1



Density

Melting point

Boiling point


(Kow, P)

Solubility in water

1.187 g cm

-3 284

175°C 285

1.78

286

0.2 g L

-1 287

Estimated

Experimental determination


(pKa)

Vapour pressure


Soil/sediment water partition

0.000371 Pa 288

0.0053 Pa m

3

mol

-1 289

Estimated at 25°C

Estimated at 25°C



283

Sweetman SC (2002) Martindale. The Complete Drug Reference. Thirty-third edition . London, UK, Pharmaceutical Press



285

SRC PhysProp Database available [May 2004] at: http://esc.syrres.com/

286

Meylan WM & Howard PH (1995) cited in SRC PhysProp Database, available [May 2004] at: http://esc.syrres.com/

287

Yalkowsky SH & Dannenfelser RM (1992) cited in SRC PhysProp Database, available [May 2004] at: http://esc.syrres.com/

288

Neely WB & Blau GE (1985) cited in SRC PhysProp Database, available [May 2004] at: http://esc.syrres.com/

289


coefficient (Kp)




Persistence in air


Persistence in soil



Fate in the field





Mammalian ADI


Mouse oral LD50 900mg kg

-1

290

Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

290

Material Safety Datasheet viewed online at http://www.sigmaaldrich.com Product number 223085, May 2004

Parameter



Chemical structure


α-Thujone

O


Chemical name

CAS no

Molecular formula

Molecular weight


1-isopropyl-4methylbicyclo(3.1.0)hexan-3one

546-80-5

C

10

H

16

O

152.24 g mol

-1




Density

Melting point

Boiling point

0.9101 g cm -3 291

<25°C 292

203°C 293


Pressure at which determination made not specified

Estimated Octanol-partition coefficient

(Kow, P)

Solubility in water


(pKa)

Vapour pressure






Persistence in air

2.65

294

0.408 g L

54.93 Pa

-1 295

296

0.0093 Pa m 3 mol -1 297

Estimated at 25°C

Extrapolated to 25°C

Estimated at 25°C



292

SRC PhysProp Database, available [May 2004] at: http://esc.syrres.com/

293


294


295


296

Perry RH & Green D (1984) cited in SRC PhysProp Database, available [May 2004] at: http://esc.syrres.com/

297



Persistence in soil



Fate in the field





Mouse oral LD50 250mg kg

-1

Guinea pig oral LD50 396 mg kg

-1 298

Rat oral LD50 500 mg kg

-1 299

Mammalian ADI


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Not possible to establish on the data available a

Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants) isomer not specified

298

WHO Food Additives Series viewed at http://www.inchem.org/documents/jecfa/jecmono/v16je25.htm May 2004

299

Material Safety Datasheet viewed at http://www.sigmaaldrich.com Product number 89231, May 2004

Parameter



Chemical structure


β-thujone

H

O


Chemical name

CAS no

Molecular formula

Molecular weight

1-isopropyl-4methylbicyclo(3.1.0)hexan-3one

471-15-8

C

10

H

16

O

152.24 g mol

-1





Density

Melting point

0.9135 g cm

-3 300

<25°C 301

Boiling point


(Kow, P)

Solubility in water


(pKa)

Vapour pressure

203°C

2.65

303

302

0.408 g L

-1 304

54.93 Pa 305


Melting point for thujone

Boiling point for αthujone

Estimated for αthujone

Estimated at 25°C for

α-thujone


0.0093 Pa m

3

mol

-1 306

Extrapolated to 25°C for α-thujone

Estimated at 25°C for

α-thujone






301


302


303

Meylan MW & Howard PH (1995) cited in SRC PhysProp Database, available [May 2004] at: http://esc.syrres.com/

304


305

Perry RH & Green D (1984) cited in SRC PhysProp Database, available [May 2004] at: http://esc.syrres.com/

306



Persistence in air


Persistence in soil



Fate in the field





Dog oral LD50 250mg kg

-1 307

Mammalian ADI Not possible to establish on the data available 1


Ecotoxicity (Bird)

Ecotoxicity (Fish)


Ecotoxicity (Algae)


Ecotoxicity (Bees)

Ecotoxicity (Worms)

Environmental fate

Fate (Animals)

Fate (Plants)

307

WHO Food Additives Series viewed online at http://www.inchem.org/documents/jecfa/jecmono/v16je25.htm , May 2004

Appendix 1.3 Summary of Findings for Individual Herbal Remedies

1. Black Cohosh

Dried preparations of the root of the Black cohosh plant, Cimicifugia racemosa , are used primarily for the treatment of symptoms of the menopause (Sweetman, 1999). In addition, the herb has been included in some cough preparations. The maximum daily dose recommended for Black cohosh preparations available in the UK ranges between

50 and 500 mg/day. In conventional medicine, the symptoms of menopause are managed by synthetic hormone replacement therapy (BMA, 2004).

The mechanism of action (if any) of Black cohosh for improvement of menopausal symptoms is unclear (Huntley & Ernst, 2003). Only limited data are available with regard to the tolerability of Black cohosh, but in general it would appear to be safe, with a small risk of minor adverse effects such as rash and gastrointestinal disturbance.

Black cohosh has little oestrogen receptor binding activity or oestrogenic activity in vitro (Zava et al.

, 1998). Difficulties occur in extrapolating in vitro data to the in vivo situation because of variations in absorption, activation/inactivation, metabolic disposition and bioavailability to target tissues.

A number of active constituents have been identified in Black cohosh preparations, but no pharmacological or toxicological data were identified by our search strategies.

2. Camphor

Camphor is used as a rubefacient and mild analgesic for conditions such as neuralgia.

It is also contained in nasal decongestant preparations for inhalation (Sweetman,

1999). Due to potentially serious toxicity, Camphor concentration should not exceed

11% in preparations for external use. Treatments for neuralgia and muscle pain in conventional medicine include topical non-steroidal anti-inflammatory preparations

(BMA, 2004).

Toxicokinetics

The toxicokinetic data presented here are summarised from the Hazardous Substances

Databank entry for Camphor.

308

Absorption of Camphor from the skin, gastrointestinal and respiratory systems readily and occurs rapidly, and toxic levels can be reached within minutes of ingestion. Camphor is removed from the bloodstream by the liver. On metabolism, Camphor is partially oxidised and partially conjugated to glucuronic acid. In addition, Camphor is hydroxylated by rat and rabbit liver microsomes in vitro . The majority is eliminated as oxidised camphorol in the urine, with less excreted in breath, sweat and faeces.

Toxicity Profile

Acute toxicity

Notable adverse effects include nausea, vomiting, colic, headache, dizziness, delirium, muscle twitching, epileptiform convulsions, CNS depression and coma

(Sweetman, 1999). Infant collapse following local application of Camphor to the nostrils has also been reported.

Camphor (as used as a rubefacient) has been shown to cause abnormal liver function and encephalopathy (Stedman, 2002). Topical use of Camphor has caused erythematous and papulous oedematous skin reactions (Ernst, 2000).

308 Hazardous Substances Databank viewed online at http://toxnet.nlm.nih.gov/ April 2004

Camphor when ingested is extremely toxic, with a rapid onset of action (between 5 and 90 minutes) (Gibson et al.

, 2004). As little as 1g as been fatal in a 19 month old child. Camphor accumulates in fatty tissues and there is no antidote.

Acute toxicity data are summarised on a Material Safety Datasheet.

309

In mice the oral

LD50 for Camphor was 1310mg kg

-1

. The lowest published lethal concentration

(LDLO) is 2000mg kg -1 in rabbits. Intraperitoneal injection of Camphor in mice gave a LD50 of 3000mg kg

-1

. Typical threshold limit values/time weighted average

(TLV/TWA) are 2ppm, with the short term exposure limit (STEL) set at 3ppm.

Repeat dose toxicity

Chronic ingestion may cause granulomatous hepatitis or fatty metamorphosis.

Carcinogenicity and Mutagenicity

Camphor is non-classifiable as a human carcinogen.

310

Reproductive and Developmental Toxicity

Evidence compiled in DART/ETIC (Developmental and Reproductive Toxicology)

308

database suggests from studies in animals that Camphor does not affect fetal growth, viability or morphological development at doses causing minor maternal toxicity.

3. Echinacea

Dried aerial parts of the Echinacea purpera plant is used to boost the immune system

311

, and for the prevention of viral upper respiratory tract infections

(Sweetman, 1999). The maximum recommended daily dose for preparations available in the UK ranges between 500 and 2500 mg/day. No conventional medicines are licensed for prophylaxis of viral infections.

Toxicity Profile

Acute toxicity

Contact sensitisation has been reported for Echinacea purpera (Paulsen, 2002), with the pollen identified as the responsible component.

Acute oral toxicity LD50 values are >15000 and >30000 mg kg

-1

for rats and mice respectively.

312

Carcinogenicity and Mutagencity

A commercial preparation of Echinacea purpera has been tested for mutagenicity in

Salmonella typhimurium , with and without metabolic activation, and has been shown to be negative in the majority of tests.

2

In addition, Echinacea extract produced no significant induction of chromosomal aberrations in human lymphocytes, nor did it increase the number of micronucleated polychromatic erythrocytes in mouse bone marrow. Some tumour inhibition has been shown for Echinacea in vitro.

4. Evening Primrose Oil

The major uses for Evening Primrose Oil are in the treatment of premenstrual syndrome and mastalgia, menopausal symptoms and eczema (Sweetman, 1999).

Other conditions for which it is used include multiple sclerosis and rheumatoid arthritis. Maximum recommended daily does for preparations available in the UK range between 1000 and 3000 mg/day. In conventional medicine, bromocriptine is licensed for use in moderate to severe cyclical breast pain (BMA, 2004).

4.1 Active constituents

309 Material Safety Datasheet viewed at http://physchem.ox.ac.uk/MSDS/CA/camphor.html

310 Hazardous Substances Databank entry viewed at http://toxnet.nlm.nih.gov/ April 2004

311 http://www.pdrhealth.com/drug_info/nmdrugprofiles/herbaldrugs/100980.shtml, May 2004

312 http://ntp-server.niehs.nih.gov./htdocs/Chem_Background/ExecSumm/Echinacea.html viewed,

April 2004

The constituents of Evening Primrose Oil thought to be responsible for its biological effects are linoleic acid and



-linoleic acid. Toxicological data are available for linoleic acid and are detailed below.

Linoleic acid

Toxicokinetics

Linoleic acid is a long chain carboxylic acid and is absorbed as micelle aggregates, esterified with glycerol in chylomicrons and very low density lipoproteins, and transported via the lymphatic system

313

It is readily metabolised in the



oxidation fatty acid metabolism pathway, and consumption presents no safety concern.

Toxicity Profile

Acute toxicity

Linoleic acid is classed as practically non-toxic, with a probable oral lethal does of >

15 g kg

-1

in humans.

314


Studies of oleic acid, a chemically related compound, are considered relevant for linoleic acid. Oleic acid was found to be negative in a large number of tests for mutagenicity.

315

Linoleic acid is not listed by ACGIH, IARC, NIOSH, NTP or

OSHA.

5. Feverfew

Feverfew, Tanacetum parthenium , is a herbal remedy used in prophylactic treatment of migraine (Sweetman, 1999). The maximum recommended daily dose for Feverfew preparations available in the UK lies between 380 and 760 mg/day. Conventional medications used for migraine prophylaxis include pizotifin, beta-blockers and tricyclic anti-depressants (BMA, 2004).

5.1 Active constituent

The constituent thought to be responsible for the biological activity of Feverfew is parthenolide , for which limited toxicological data are available.

Parthenolide

Toxicokinetics

Pharmacological effects ascribed to parthenolide include decreased prostaglandin synthesis and decreased platelet aggregation and serotonin secretion (Robles et al.

,

1995). These effects serve to relieve inflammatory conditions such as arthritis, and to act as anti-migraine therapy.

Toxicity Profile

Acute toxicity

Contact sensitisation has been reported for Feverfew (Paulsen, 2002), with parthenolide identified as the component responsible.


In vitro tests using mammalian cells have shown mutagenic activity for parthenolide.

316

313 WHO Food additives series viewed online at http://www.inchem.org/documents/jecfa/jecmono/v042je16.htm April 2004

314 Hazardous Substances Databank viewed online at http://toxnet.nlm.nih.gov/ April 2004

315 WHO Food additives series viewed online at http://www.inchem.org/documents/jecfa/jecmono/v042je16.htm April 2004

316 Material Safety Datasheet viewed at http://www.sigmaaldrich.com Apr 04, product number 384283

6. Garlic

Garlic is reported to be of value in lowering blood pressure and blood cholesterol levels.

317

In addition, expectorant, diaphoretic, diuretic and disinfectant properties have been attributed to Garlic (Sweetman, 1999). The maximum recommended dose for Garlic preparations available in the UK is between 170 and 670 mg/day for Garlic extract and 2 and 10 mg/day for Garlic oil. Hypertension and hypercholesterolemia are treated in conventional medicine with anti-hypertensives and statins respectively

(BMA, 2004).

Garlic and Garlic oil are licensed for veterinary use (NOAH, 2004). These preparations are intended for use in dogs and cats for the symptomatic relief of respiratory and digestive complaints, as well as skin infections. The maximum recommended daily dose range between 390 mg/day Garlic extract (equivalent 1.1 mg/day Garlic oil), and 1555 mg/day Garlic extract (equivalent to 4.5 mg/day Garlic oil).

Garlic is considered to be a type I and type IV allergen (Jappe et al.

, 1999). A number of herb-drug interactions have been reported for Garlic (Izzo & Ernst, 2001). Two case reports show an interaction between Garlic and warfarin leading to an increase in

INR (international normalised ratio), and clinical trial data suggest that Garlic can change some of the pharmacokinetic properties of paracetamol via an unknown mechanism. Use of Garlic can increase the risk of post-operative bleeding and can have hypoglycaemic effects.

Adverse effects reported include nausea and gastrointestinal problems (Ernst, 2003a).

Dermatological effects following oral administration of Garlic have been reported to include urticaria and angioedema (Ernst, 2000). Systematic review of Garlic-induced adverse effects showed that causality is well established for allergic reactions, and that the most serious reported adverse effects are those affecting platelet adhesiveness, prothrombin time and partial thromboplastin time (Morbidoni et al.

, 2001).

7. Ginkgo biloba extract

Ginkgo biloba extract is used to improve circulation to the brain and muscles, and also for tinnitus.

318 This herbal remedy is also reputed to be of use in Alzheimer’s disease and multi-infarct dementia (Sweetman, 1999). The maximum recommended dose for Ginkgo biloba preparations available in the UK range between 60 and 120 mg/day and up to 1000 mg/day. Betahistidine is a drug licensed in the UK for the treatment of tinnitus (BMA, 2004).

Toxicokinetics

319

Ginkgo biloba extract (standard extract eGb761) is composed of numerous active constituents, among which are quercetin, Ginkgolides A & B, and bilobalide.

Information available for any of these are of pertinence to the whole extract.

Following oral administration of eGb761 (80mg), the bioavailabilities of Ginkgolides

A & B with plasma half lives of 4 and 6 hours respectively, are approximately 80%.

Bioavailability of Ginkgolide C is very low. The bioavailability of bilobalide is 70% with a plasma half life of 3 hours following oral administration of 120mg 3Gb761.

Excretion is via the urine, accounting for 70%, 50% and 30% for Ginkgolides A & B and bilobalide respectively.



319 The data presented herein is summarised from information obtained from the National Toxicology

Program of the US, viewed online at http://ntpserver.niehs.nih.gov/htdocs/Chem_Background/ExecSumm/Ginkgo.html

Adverse effects of Ginkgo biloba extract include dizziness, palpitations, gastrointestinal disturbances, bleeding disorders and skin hypersensitivity reactions

(Sweetman, 1999).

Toxicity Profile

2

Acute toxicity

Standardised extract eGb761 administered orally to rats shows an LD50 of 7.73 g kg -

1

.


In a 27 week study in rats and mice, no evidence of renal or hepatic damage was observed following oral administration of doses ranging from 100 to 1600 mg kg

-1

.


No carcinogenicity studies have been performed using standardised Ginkgo biloba extract, but studies performed on quercetin are relevant.

320


In general, no teratogenic effects for Ginkgo biloba have been reported (Jurgens,

2003). This article does, however, cite one report of decreased chick viability in a study using a high dose.

Herb-Drug Interactions

Ginkgolides and bilobalides have anti-platelet activity through their action as PAF antagonists (Izzo & Ernst, 2001). Two case reports exist of severe spontaneous bleeding in patients taking warfarin or aspirin following self-medication with Ginkgo biloba at recommended doses. Spontaneous bilateral subdural haematomas have been reported in cases of long-term Ginkgo biloba use. Although Ginkgo biloba is a peripheral vasodilator, it has led to a further increase in blood pressure in a patient prescribed a thiazide diuretic for hypertension. Combination of trazodone and Ginkgo biloba in a patient with Alzheimer’s disease led to coma, due to Ginkgo biloba induced increase in production of an active metabolite of trazodone (MCPP) causing release of the inhibitory neurotransmitter GABA.

Adverse effects following use of Ginkgo biloba include four reported cases of subdural and parietal haematoma and subarachnoid haemorrhage (Ernst, 2003b).


Ginkgo biloba extract contains a number of active constituents, including ginkgolides, bilobalide and quercetin. Of these, the toxicology of quercetin in best characterised.

Quercetin

Toxicokinetics

Following oral administration in rats, quercetin is rapidly excreted into bile and urine within 48 hours as the glucuronide and sulphate conjugates, 3’-O-monomethyl quercetin and 4-monomethyl quercetin.

321

As a glycoside, quercetin is hydrolysed to the corresponding aglycone, which is then metabolised by scission of the heterocyclic ring at the 1,2 and 3,4 bonds to yield homoprotocatechuic acid, which is further metabolised by



-oxidation of the acyl-side chain, O-methylation and demethylation and aromatic dehydroxylation.

Pharmacokinetic studies in man suggest that quercetin is quickly eliminated with a half life of less than 2 hours (Graefe et al.

, 1999). Distribution in a typical 70kg man has been estimated at 0.003-0.012

 molkg

-1

from daily oral administration of 25-50 mg.

322

Oral administration in man of a G inkgo biloba extract dose containing 6.8 mg quercetin, has a mean value of 2.17 hours for half life for elimination and 1.51 hours

320 See below section 7.1

321 Hazardous Substances Databank viewed at http://toxnet.nlm.nih.gov/ Apr 04

322 http://ntp-server.niehs.nih.gov/htdocs/Chem_Background/ExecSumm/Ginkgo.html - chemid

for half life for absorption, demonstrating that the absorption and elimination are rapid (Wang et al.

, 2003). Bioavailability was low, with cumulative urinary excretion was 0.17%, where quercetin was detected as the sulphate and glucuronic acid conjugates. The low bioavailability was thought to be due to the lack of enzymes capable of cleaving glycosidic bonds in the gut. However, reports from randomised clinical trial in ileostomy patients, subsequently confirmed in healthy subjects, suggested that the presence of the glycoside residue facilitated the intestinal absorption (Ross & Kasum, 2002).

The volume of distribution varies among studies, but has important implications for interpreting the pharmacodynamic effects. Due to current technical limitations, there are insufficient data available to determine beyond doubt the mechanism underlying the observed link between consumption of high dietary flavonoids such as quercetin, and decreased risk of coronary heart disease.

Toxicity Profile

Acute toxicity

Acute oral toxicity LD50 value for mice and rats is 160gmg kg -1 323 .


Full details of mutagenicity testing are available on the Chemical Carcinogenesis

Research Information System

324

. Briefly, quercetin has produced positive results in the majority of designs of Salmonella typhimurium tests for mutagenicity. However, quercetin has been extensively tested for carcinogenicity and although it has shown positive results in some studies, it was negative in the majority.

2

The efficient metabolism and excretion of this compound may explain the lack of carcinogenicity in vivo .

8. Ginseng

Ginseng ( Panax ginseng ) is reported to enhance resistance to infection, aid recuperation and to reduce fatigue (Sweetman, 1999). It is used to promote general well-being. Maximum recommended daily dose for Ginseng preparations available in the UK range between 1500 and 3000 mg/day. There is no analogous class of conventional medicines.

Toxicokinetics

325

The chemical constituents responsible for the pharmacological activities of Ginseng extract are the triterpene saponins, termed ginsenosides. These ginsenosides fall into two classes based on the structure of the cognate aglycone, namely protopanaxadiol and protopanaxatriol. The fate of administered ginsenosides is dependant on their class. Ginsenoside Rg

1

(protopanaxatriol) has a half life of 27 minutes following intravenous administration to minipigs. In contrast, the protopanaxadiol ginsenoside

Rb

1

has a half life of 16 hours in the



phase, due to high plasma protein binding.

Information on absorption and metabolism is available for ginsenoside Rg

1

, showing that this constituent is rapidly absorbed and metabolised after oral administration, with very low concentrations of the intact molecule detected in urine or faeces.

Ginsenoside Rg1 is distributed to the blood, liver, bile, subcutis and epithelia of

323 Material Safety Datasheet at https://fscimage.fishersci.com/msds/56284.htm

324 Chemical Carcinogenesis Research Information System viewed at http://toxnet.nlm.nih.gov/ Apr

04

325 Details of the toxicokinetics of Ginseng are included in a document entitled “Getting to the root of ginseng” viewed online at the ACS Publications division http://pubs.acs.org/hotartcl/chemtech/98/apr/get.html

oesophagus and the oral and nasal cavities. The concentrations detected in muscle, endocrine organs and brain are low.

Adverse effects, termed “Ginseng abuse syndrome”, include morning diarrhoea, skin eruptions, sleeplessness, nervousness, hypertension, euphoria and oedema (Sweetman,

1999).

Toxicity Profile

Acute toxicity

326

Oral administration of Ginseng to mice and rats show LD50 of 750 and 200 mg kg

-1 respectively.


Information from subacute/subchronic toxicity studies is available for rats and dogs; no evidence for Ginseng toxicity has been observed in either species.

2


Ginseng has tested negative for mutagenicity in the mouse lymphoma model with and without S9 and aroclor 1254 metabolic activation.

327


Incidences of interaction of Ginseng with prescription drugs are summarised by Izzo and Ernst (2001). Ginseng is reported to interact with the monoamine oxidase inhibitor (MAOI), phenylzine (Ernst, 2003b) and warfarin. Ginsenosides inhibit cAMP phosphodiesterase leading to an increase in cAMP, which may explain in part the psychoactive central effect of Ginseng both alone and in combination with

MAOIs. Use of Ginseng reduces blood alcohol concentration, with induction of the essential components of the microsomal alcohol oxidising system suggested as the underlying mechanism.

Adverse effects following Ginseng ingestion include nausea, vomiting, arteritis, deterioration of schizophrenia and mania (Ernst, 2003b).

9. Glucosamine

Glucosamine supplements have been reported to be of use in the treatment of osteoarthritis.

328

Maximum recommended dose for Glucosamine preparations available in the UK range between 1000 and 2000 mg/day. In conventional medicine, non-steroidal anti-inflammatory drugs (NSAIDs) are routinely prescribed for osteoarthritis (BMA, 2004).


Glucosamine preparations contain the active ingredients Glucosamine hydrochloride and Glucosamine sulphate. The toxicokinetics of Glucosamine sulphate in man are well described (see below).

Glucosamine sulphate

Toxicokinetics

The toxicokinetics of Glucosamine sulphate in man has been reported recently

(Setnikar & Rovati, 2001). Following oral administration, free Glucosamine sulphate in blood was below the limit of quantification. After 1.5 hours, Glucosamine sulphate appeared incorporated in plasma globulins, with a peak at 9 hours, and was eliminated

326 Summarised from information obtained from the National Toxicology Program of the US, viewed online at http://ntp-server.niehs.nih.gov/htdocs/Chem_Background/ExecSumm/Ginseng.html

327 Chemical Carcinogenesis Research Information System (CCRIS) viewed online at http://toxnet.nlm.nih.gov/ , April 2004


with a half life of 58 hours. Gastrointestinal absorption is approximately 90%, but oral bioavailability is only 44% due to the hepatic first pass metabolism effect.

Incorporation into plasma proteins occurs with all routes of administration, with the liver being the site of incorporation. Glucosamine sulphate is covalently bound to plasma globulins (predominantly



-globulins) and is transported to peripheral tissues where it is enzymatically released and made available for local use. Urinary excretion following oral administration is 8% of the administered dose, with faecal excretion

11.4%. Respiratory excretion accounts for the majority (60%), highlighting the effect of hepatic first pass metabolism.

Following oral administration, Glucosamine sulphate is largely distributed to the stomach walls and contents. Concentrations of Glucosamine sulphate in the liver peak at 2 hours and decrease slowly thereafter. There is also rapid uptake in articular cartilage.

In a study of dogs administered Glucosamine sulphate in a mixture of purified chondroitin sulphate and manganese ascorbate, minor but not clinically important changes in haematological and haemostatic variables were observed (McNamara et al.

, 1996). These changes included a decrease in median haematocrit and a decreased neutrophil count.

Toxicity profile

Acute Toxicity

Both Glucosamine sulphate and Glucosamine hydrochloride are in the slightly toxic range, with acute oral toxicity in mice > 5 g kg

-1 329

and 15 g kg

-1 330

respectively.

10. Ma huang

In traditional Chinese Medicine, Ma Huang is used in mild respiratory disorders including asthma.

331,332

Maximum recommended daily dose for the treatment of bronchial asthma range between 45 and 90 mg (Bielory & Lupoli, 1999). In addition, it has been reported to be used as a stimulant and to boost athletic performance and weight loss.

333 The maximum daily dose recommended for Ma huang contained in a training supplement available in the UK is 1000 mg/day (80 mg/day ephedrine).

334

Asthma is treated conventionally using inhaled corticosteroids and selective beta

2 agonists.

335

Three incidences of hepatotoxic events associated with the use of Ma Huang have been reported (Pittler & Ernst, 2003). The adverse effects noted included nausea, vomiting, abdominal discomfort, jaundice, fatigue, cough, chest pain and haemoptysis. Where liver biopsies were performed, diffuse hepatic necrosis, polymorphonuclear neutrophil (PMN) infiltrates and fibrosis were observed.

However, the evidence for hepatotoxicity related to use of Ma huang was said to be anecdotal, therefore it is difficult to define precise incidence figures.

329 http://www.sigmaaldrich.com Glucosamine Hydrochloride, product code G2206, viewed April

2004

330 NTP Glucosamine Data Summary, viewed on-line at http://ntpserver.niehs.nih.gov/htdocs/Chem_Background/ExSumPdf/glucosamine.pdf


332 Merck Index (2001) [Ephedra, entry 3638]

333 Ephedra and Ephedrine for Weight Loss and Athletic Performance Enhancement: Clinical Efficacy and Side Effects. Viewed on-line at http://www.ahrq.gov/clinic/epcsums/ephedsum.htm April 2004

334 Product information for “Thermogen XS” available, May 2004, at http://www.creatinestore.co.uk/products/Thermogen_XS.asp?details=1

335 BNF (2004) British National Formulary 47, viewed online at http://www.bnf.org/ May 2004

One active component of Ma huang, ephedrine, is absorbed more slowly from powdered herbal preparation than from either ephedrine tablet or oral solution forms

(White et al.

, 1997). However, despite this, onset of effect and absorption are the same. Ephedrine content varies between Ephedra species.

Additional adverse effects of Ma huang use include hallucination, stroke, acute dysphoric disorder, and seizures (Ernst, 2003b). Ma huang may interact with other

CNS stimulants,



-blockers, monoamine oxidase inhibitors, phenothiazines and theophylline (Ernst, 2003a). Reports exist of acute autoimmune hepatitis, with massive necrosis (disproportionate severity for clinical picture) observed on biopsy

(Stedman, 2002).

10.1 Active Constituents

The alkaloids L-ephedrine and pseudoephedrine are the constituents of Ma huang that have been identified to have pharmacological activity.

10.1.1 L-Ephedrine

Toxicokinetics

In rats, L-ephedrine is converted to L-norephedrine and 4-hydroxy-L-ephedrine. In rabbits, L-norephedrine is also produced on metabolism of ephedrine, as well as phenylgycol. L-ephedrine is rapidly absorbed after oral, intramuscular and subcutaneous administration (species not specified), with a plasma half life of 6 hours.

Elimination of L-ephedrine is via the urine, where it is detected largely as the unchanged drug.

336

The fraction of ephedrine eliminated by N-demethylation to norephedrine is 8-20% following oral administration. Norephedrine is excreted in urine, largely unchanged, with approximately 4% biotransformation to 4-hydroxynorephedrine and hippuric acid (Haller et al.

, 2002).

Among the most serious adverse effects reported are tachycardia, anxiety, restlessness and insomnia, increased blood pressure and cardiac arrhythmia (Sweetman, 1999). Lephedrine interacts with a number of other drugs including halothane and other general anaesthetics, theophylline and monoamine oxidase inhibitors. L-ephedrine can antagonise anti-hypertensive therapy.

Ephedrine acts as



1-,



1- and



2- adrenergic agonist and promotes release noradrenaline and dopamine. Ephedrine is a more potent vasopressor and cerebral stimulant than pseudoephedrine (Berlin et al.

, 2001).

Toxicity Profile

Acute toxicity

L-ephedrine is classed as extremely toxic, with a probable oral lethal dose between 5 and 50 mg kg

-1

in humans.

337

Acute oral toxicity has been measured with an LD50 of

600 mg kg

-1

and 689 mg kg

-1

for rats

338

and mice

339

respectively. Toxicity is dependant on the route of administration, with LD50 values decreasing with route in the following order: intraperitoneal, parenteral and intravenous.


When tested using four standard strains of Salmonella typhimurium, with or without metabolic activation, no evidence of L-ephedrine mutagenicity was observed. In addition, no evidence of chromosomal aberrations or sister chromatid exchange was

336 Hazardous Substances Databank viewed online at http://toxnet.nlm.nih.gov/ , April 2004.


338 Material Safety Datasheet viewed at http://physchem.ox.ac.uk/MSDS/EP/(-)ephedrine_anhydrous.html, April 2004

339 Material Safety Datasheet viewed at http://www.sigmaaldrich.com, April 2004

detected. In a two year carcinogenicity study, no evidence of carcinogenicity was observed in either F344 rats of B6C3F1 mice.


No animal reproduction studies have been performed,

1 and it is not known whether Lephedrine can have adverse effects on the fetus when administered to pregnant humans.

10.1.2 Pseudoephedrine

Toxicokinetics

340

Following oral administration of pseudoephedrine hydrochloride, the pharmacological effect (nasal decongestion) is observed within 30 minutes, and lasts for 4-6 hours.

Although sufficient evidence is lacking, pseudoephedrine is presumed to cross the placenta and into the CSF. Pseudoephedrine has a short half life, and elimination of the drug is renal, with 55-75% excreted unchanged. In rabbits, D-pseudoephedrine yields D-norpseudoephedrine and L-pseudoephedrine yields L-norpseudoephedrine.

Norpseudoephedrine is classified as a schedule IV controlled substance (Haller et al.

,

2002).

Pseudoephedrine is less potent than ephedrine with respect to pressor, cardiac, mydriatic and CNS stimulant actions.

Adverse effects include tachycardia, anxiety, restlessness, insomnia, skin rashes, urinary retention, and rarely hallucinations especially in children (Sweetman, 1999).

11. St John’s Wort

St John’s Wort is used as a herbal remedy for the treatment of anxiety and mild to moderate depression (Sweetman, 1999). Other reported minor uses include treatment of skin inflammation, wounds and burns.

341

The maximum daily dose recommended for preparations available in the UK (standardised to hypericin content) range between 900 and 2700

 g/day hypericin (450-900 mg/day dried St John’s Wort extract).

342,343

In conventional medicine, tricyclic and SSRI (selective serotonin reuptake inhibitor) antidepressants are used in the treatment of depression, while anxiety is treated with anxiolytics such as benzodiazepines.

344

Toxicokinetics

The pharmacodynamics and kinetics of St John’s Wort have been described recently


, 2003). The absorption of hypericin and pseudohypericin is 14 and 21% respectively following oral administration. The time to peak is between 2 and 6 hours, with a dose-dependant half-life of 24 to 36 hours. Steady state is achieved within 4 days. St John’s Wort exerts multiple effects on the cytochrome

P450 enzyme complex and activates P-glycoprotein.

Numerous pharmacological effects have been described for St John’s Wort that may underlie its anti-depressant action (Hammerness et al.

, 2003). These include inhibition of MAO (monoamine oxidase inhibitor) A &B and COMT (catechol-O-methyl transferase) enzymes, decrease in serotonin, dopamine, and noradrenaline reuptake, and increases in serotonin receptor density. Actions at benzodiazepine, adenosine, inositol trisphosphate, glutamate (NMDA) and cholinergic receptors may contribute to the psychotropic effects.

340 Summarised from information contained in the Hazardous Substances Databank entry for pseudoephedrine viewed at http://toxnet.nlm.nih.gov/ Apr 04


342 Holland and Barrett product information leaflet, available at http://www.hollandandbarrett.co.uk/

343 Lichtwer Pharma UK product information leaflet, available at http://www.lichtwer.co.uk/ May 2004

344 BNF (2004) British National Formulary 47, viewed online at http://www.bnf.org/ May 2004

Although St John’s Wort is generally well tolerated, adverse effects have been documented. These include gastrointestinal symptoms, skin reactions, fatigue and sedation, restlessness and anxiety, dizziness, headache and dry mouth. Phototoxicity has also been reported for St John’s Wort (Mantle et al.

, 2001). A report on a

European drug monitoring study (3250 individuals) showed a 2.4% rate of adverse drug reaction, that were generally mild, transient and similar to placebo (Greeson et al.

, 2001).

Toxicity Profile

Acute toxicity

An acute NOEL value of >5000 mg kg

-1

in mice and rats has been published


, 2003).


A study of long-term effects of St John’s Wort was conducted in dogs, and only nonspecific symptoms were reported (Hammerness et al.

, 2003).


No significant mutagenic properties have been ascribed to St John’s Wort; one study of genotoxicity in Salmonella typhimurium found that the mutagenicity observed was quercetin-mediated (Hammerness et al.

, 2003).


No adverse reproductive effects have been ascribed to use of St John’s Wort (Jurgens,

2003).


St John’s Wort extract interacts with drugs metabolised by cytochrome P450 monoxygenase enzyme system and with selective serotonin reuptake inhibitors

(SSRIs) (Izzo & Ernst, 2001). Four clinical studies showed an increase or a tendency to increase the metabolic capacity of CYP450 enzymes. In addition, St John’s Wort can increase the activity of P-glycoprotein. Due to a combination of these mechanisms, use of St John’s Wort can lead to reduced plasma concentrations of warfarin, phenprocoumon, oral contraceptives, cyclosporin, amitriptyline, theophylline and indinavir. The concentration of digoxin is also likely to be decreased. Concomitant use of St John’s Wort and SSRIs can lead to symptoms of serotonin excess, “serotonin syndrome” (Ernst, 2003b).

An important herb-drug interaction occurs between St John’s Wort and cyclosporin, where concomitant use leads to reduced plasma levels of the anti-rejection drug due to

St John’s Wort-mediated induction of CYP3A/3A4. This has led to severe acute transplant rejection documented in a patient following liver transplantation


, 2003).

St John’s Wort has effects on numerous components of the cytochrome P450 complex, including CYP1A2, CYP2C9, CYP2D6.


The pharmacologically active constituents of St John’s Wort have been identified as quercetin,

345

hypericin, and hyperforin. Limited pharmacological and toxicological information is available for these compounds, described below.

11.1.1 Hypericin

Toxicokinetics

Hypericin is thought to be the constituent of Hypericum extract (St John’s Wort) responsible for the photosensitivity reactions observed in some individuals

(Sweetman, 1999).

345 see Annex 1, section 7.1: Ginkgo biloba extract, active constituent

Investigations of the pharmacodynamics and pharmacokinetics of hypericin, with a view to exploitation of its potential chemotherapeutic effects, have shown a two compartment model for its pharmacokinetics in primates, with a terminal elimination half life of 26 hours (Fox et al.

, 2001). 2 mg kg

-1 was sufficient to maintain an effective cytotoxic plasma concentration for up to 12 hours post-administration.

Metabolism of hypericin is poorly defined, with no free hypericin detected in urine, with or without glucuronidase or sulphatase. However, based on its chemical structure and molecular size, metabolism is predicted to be via glucuronic acid conjugation and biliary excretion (Fox et al.

, 2001).

Toxicity Profile

Acute toxicity

In non-human primates, dose-limiting toxicity was skin reactions at 5 mg kg

-1

, and socalled “hypericinism,” symptoms of which include anorexia, increased liver transaminases and evolution of a skin rash in light-exposed areas (Fox et al.

, 2001).


Hypericin has been found to be negative in mutagenicity tests using two standard strains of Salmonella typhimurium , with and without metabolic activation.

346

11.1.2 Hyperforin

Toxicokinetics

The pharmacodynamics and pharmacokinetics of hyperforin have been reported

(Biber et al.

, 1998). Hyperforin, administered as hypericum extract and therefore in the presence of other active constituents, is orally bioavailable and is not quickly metabolised or decomposed in the gut. Elimination half lives and plasma retention times are long, but it does not accumulate in plasma following once daily administration in human volunteers. After administration of a therapeutic dose, plasma levels increased only after a 1 hour lag, and reached the maximum at 3 hours.

Mean C max

and area under the time concentration curve did not increase with highest doses, but elimination half life was unchanged, implying that loss of bioavailability was due to high lipophilicity of the agent or some other interaction in the gastrointestinal tract. No serious adverse effects were noted, even at the maximum dose administered (5mg hyperforin).

12. Valerian

Valerian has sedative properties and is used for treatment of stress and anxiety

(Sweetman, 1999) and insomnia.

347

The maximum recommended dose for preparations available in the UK ranges between 300 and 900 mg/day. In conventional medicine, stress and anxiety are treated with anxiolytics such as benzodiazepines (BMA, 2004).

Valerian is licensed for veterinary use (NOAH, 2004), in a preparation combining other active ingredients for the treatment of nervous disorders, shyness or overexcitement in dogs and cats. The maximum recommended daily dose ranges between

194 mg/day and 1555 mg/day, dependent on animal size.

Toxicity Profile


No fetotoxicity or external malformations have been observed in rats (Jurgens, 2003).

However, an increase in the number of fetuses with retarded ossification was reported.


346 Chemical Carcinogenesis Research Information System viewed online at http://toxnet.nlm.nih.gov/ April 2004.

347 http://www.pdrhealth.com/drug_info/nmdrugprofiles/herbaldrugs/102830.shtml May 2004

A number of active constituents have been identified in extracts of Valerian root. Of these, toxicological data are available for borneol.

Borneol

Toxicokinetics

Absorption, distribution, metabolism and excretion are as described for Camphor

348

.

Toxicity Profile

Acute toxicity

Acute toxicity of borneol is indistinguishable from Camphor. Laboratory animals are much less susceptible to borneol toxicity than man (as is the case for Camphor).

Borneol is classified as Very Toxic, with a probable oral lethal dose in man of between 50 and 500 mg kg

-1

.

349


Borneol has been shown to be non-mutagenic in the Ames test, using three strains of

Salmonella typhimurium , with and without metabolic activation.

350

348 see Annex 2, section 2: Camphor

349 Hazardous Substances Databank viewed at http://toxnet.nlm.nih.gov April 2004

350 Chemical Carcinogenesis Research Information System viewed at http://toxnet.nlm.nih.gov April

2004

Appendix 1.4

– Summary of Findings for Individual

Essential Oils

1. Lavender Oil

Lavender oil is used as a carminative and as a flavouring ingredient. In addition, it is occasionally topically applied as an insect repellant (Sweetman, 1999). Additional suggested uses include aromatherapy for appetite loss, insomnia and nervousness.

351

Recommended quantities range from 1-4 drops of essential oil in a carrier

1

, to topical application of neat oil.

352

Topical administration of Lavender oil has been reported to cause allergic contact dermatitis (Ernst, 2000). Traces of linalool and linalyl acetate are detected in the blood within 5 minutes of dermal application of Lavender oil (Bickers et al.

, 2003), with the maximum concentration reached at 19 minutes.


Active constituents identified in Lavender essential oil include



-pinene and linalool and its ester linalyl acetate.

1.1.1



-Pinene

Toxicokinetics

The toxicokinetics of



-pinene have been studied in man and are summarised in the

Hazardous Substances Databank.

353 Exposure was by inhalation, and uptake was 59% of the exposure concentration. The concentration of



-pinene in the blood rose sharply, then tapered off, and was linearly related to the exposure concentration.

Elimination from blood was shown to be triphasic, with half lives of 4.8, 39 and 695 minutes for each phase.



-pinene is absorbed from skin, lungs and intestines, and is readily metabolised with elimination of unchanged



-pinene very low. Urinary excretion of verbenols after



pinene inhalation is complete 20 hours following a 2 hour exposure. In primary cultures of chick embryo liver cells,



-pinene was shown to be porphyrogenic.

Toxicity Profile

Acute toxicity

The fatal dose in man is approximately 180g as turpentine (58-65%



-pinene). Acute oral toxicity LD50 value is 3700 mg kg

-1 in rats. By inhalation, LC

LO

(lowest published lethal concentration) values for rats, mice and guinea pigs are 625, 364 and

572

 gm -3 respectively.

354




-pinene is not listed by IARC, but there is a documented increased risk of developing respiratory cancer if duration of occupational exposure to turpentine is greater than five years.

1

No evidence of mutagenicity was observed using four standard strains of Salmonella typhimurium , with or without metabolic activation.

355

1.1.2 Linalool and Linalyl acetate

Toxicokinetics


352 http://hcd2.bupa.co.uk/fact_sheets/html/aromatherapy.html May 2004

353 Viewed at http://toxnet.nlm.nih.gov/ Apr 04



04

Linalool is representative of a number of tertiary alcohols and their related esters used as flavouring agents, and therefore its metabolism in mammals is well characterised.

356 In rats, following a single oral dose of radioactively labelled linalool,

55% of the radioactivity was excreted in the urine as the glucuronic acid conjugate and 23% as expired CO

2

. Of the remainder, 15% was excreted within 72 hours in the faeces, with minor amounts (0.5, 0.6, 0.8 and 1.2%) in the liver, gut, skin and skeletal muscle respectively.

Linalyl acetate, an ester of linalool, is metabolised by hydrolysis to yield linalool and the corresponding aliphatic carboxylic acid (acetic acid).

357

Metabolism proceeds as for linalool.

The biological half-life for both linalool and linalyl acetate is 14 minutes (Bickers et al.

, 2003).

Toxicity Profile

Acute toxicity

Acute oral toxicity LD50 values for linalool are 3000 mg kg

-1

for mice and 2790 mg kg -1 for rats.

358 LD50 value following application to skin in rabbits and rats is

5610 mg kg

-1

in both species.

Acute oral toxicity LD50 values are 14.55 g kg

-1

and 13.36 g kg

-1

for rats and mice respectively.

359


A 20 day study

1 in rats showed that cytochrome P450 (CYP450)-induced allylic oxidation becomes important on repeated dosing, yielding urinary metabolites such as

8-hydroxylinalool and 8-carboxylinalool. A transient rise in liver microsome CYP450 activity was observed.

A 29 day study of dermal application of linalool has been conducted in rats (Bickers et al.

, 2003). Lethargy, ataxia and moderate to severe erythema were observed at all doses. The toxic signs and dermal irritation were dose-related. At necropsy, abnormalities were detected in the treated skin area, as well as gross liver, kidney and intestinal abnormalities. Histopathology revealed very slight to slight changes in liver and kidneys, but these were not related to treatment. In a 90 day study, linalool treatment led to a decrease in body weight and increased in liver and kidney weight.

Haematology, clinical chemistry and urinalysis were normal.


Linalool has been tested for mutagenicity in a series of standard tests,

360,361

and was not found be mutagenic in the majority. However, weak positive results were detected one design of the mouse lymphoma and Bacillus subtilis H17 (rec

+

) and M45 (rec

-

) tests.

Linalyl acetate was negative for mutagenicity in five strains of Salmonella typhimurium , with and without metabolic activation. Neither linalool nor linalyl acetate caused chromosomal aberrations or unscheduled DNA synthesis (Bickers et al.

, 2003).


356 WHO Food Additives series viewed online at http://www.inchem.org/documents/jecfa/jecmono/v042je17.htm, April 2004


358 Material Safety Datasheet viewed online at http://www.fisher.co.uk/ Product number 12515-1000


360 WHO Food Additives series viewed online at http://www.inchem.org/documents/jecfa/jecmono/v042je17.htm, April 2004

361 Chemical Carcinogenesis Research Information System viewed online at http://toxnet.nlm.nih.gov/,

April 2004

Studies of coriander oil in rats in mice have concluded that linalool does not affect reproductive performance or subsequent growth and survival of offspring except where there is maternal toxicity (Bickers et al.

, 2003). No developmental toxicity data were available.

2. Orange Essential Oil

Orange essential oil is used as a flavour and in perfumery (Sweetman, 1999).


The natural oil contains a number of active constituents, including linalool and its ester linalyl acetate

362

, citral, and d-limonene.

2.1.1 Citral

Toxicokinetics

Detailed information on the absorption, distribution, metabolism and excretion are contained in the Hazardous Substances Databank entry for citral.

363

Citral is a naturally occurring aliphatic aldehyde, and undergoes detoxification in a manner expected for aldehydes. Two routes for aldehyde detoxification exist, firstly oxidation to yield readily metabolised acids (fatty acid oxidation pathways and the Krebs cycle), and secondly, inactivation by reaction with sulphydryl groups e.g., glutathione. In experimental animals, citral is converted in part to the “Hildebrandt acid”, where a double omega oxidation reaction has taken place. In rats and mice, absorption from the gastrointestinal tract is rapid, and excretion is via the urine, with no evidence for long-term storage. Metabolism is rapid; urinary metabolites include several acids and a biliary glucuronide.

Toxicity Profile

Acute toxicity

Acute toxicity data are summarised in a Material Safety Datasheet

364

. Acute oral toxicity studies in rats showed an LD50 value of 4960 mg kg

-1

, while the value in mice was 6000 mg kg -1 . Citral was more toxic when administered via intraperitoneally in rats, with an LD50 460 mg kg

-1

for this route. No human toxic dose has been established.

365

Citral is an irritant, causing contact or allergic dermatitis and irritation of the membranes of the nose and throat.


A repeated dose toxicity test in mice showed that on percutaneous absorption, citral caused an increase in lymph node weight compared to untreated controls 366


Citral showed no evidence of mutagenicity when tested using 4 strains of Salmonella typhymurium, with and without S9 metabolic inactivation.

367


Citral has been shown to be teratogenic in animals but not in humans,

368

causing craniofacial abnormalities in chick embryos. In rats, citral caused a decrease in both

362 see section 1.1.2 linalool and linalyl acetate

363 Hazardous Substances Databank viewed online at http://toxnet.nlm.nih.gov/ , April 2004

364 Material Safety Datasheet viewed http://physchem.ox.ac.uk/MSDS/CI/citral.html April 2004

365 Hazardous Substances Databank viewed online at http://toxnet.nlm.nih.gov/ , April 2004

366 Beilstein database, viewed May 2004

367 Chemical Carcinogenesis Research Information System viewed online at http://toxnet.nlm.nih.gov/


the number of follicles per section and in implantation number and litter size. In addition, an increase in post-implantation fetal death was observed. The no observed adverse effect level (NOAEL) for embryofetotoxicity was < 60 mg kg -1 by oral administration in rats. However, no developmental toxicity was observed in rats following inhalation of citral up to the maternally toxic dose.

2.1.2 D-limonene

Toxicokinetics

Data for absorption and metabolism of D-limonene is available for humans.

3

In humans following oral administration, 75-95% was excreted in urine and <10% excreted in faeces within 2-3 days. A relative pulmonary uptake for D-limonene was determined to be 70% of the amount supplied. D-limonene is readily metabolised and accumulates in adipose tissue (long half life in blood in the slow elimination phase).

The major metabolite in urine following oral administration is perillic acid 8,-9 diol in rats and rabbits, perillyl-



-D-glucopyranosiduronic acid in hamster, P-menth-1-ene-

8,-9 diol in dogs, and 8-hydroxy-P-menth-1-en-9-yl-



-D-glucopyranosiduronic acid in guinea pigs and man.

Toxicity Profile

Acute toxicity

Orally administered D-limonene has an LD50 of 4400 mg kg

-1

in rats and

5600 mg kg

-1

in mice.

369

Intravenous administration in rats results in a much lower

LD50 value of 110 mg kg

-1

.


The IARC classification

370

of D-limonene is Group 3 ( not classifiable as to its carcinogenicity to humans) . National Toxicology Program studies

371

in rats and mice showed no evidence for carcinogenicity of D-limonene. D-limonene has been tested in a number of short-term tests and has been shown to be non-genotoxic.

The nephropathy and renal tumour-induction observed in male rats is due to



2microglobulin, a male rat specific protein, and is not relevant to human carcinogenesis. When combined, the lack of evidence for a genotoxic mechanism and the demonstration of a plausible epigenetic mechanism (accumulation of



2microglobulin) implies a species-specific mechanism for d-limonene carcinogenesis

(Whysner & Williams, 1996).


No evidence for embryotoxicity or teratogenicity has been observed in the absence of maternal toxicity.

372

3. Peppermint Essential Oil

Peppermint essential oil is used as a carminative and relaxes gastric smooth muscle, and is used in the management of irritable bowel syndrome (IBS) (Sweetman, 1999).

Recommended dose for Peppermint essential oil is 0.6-1.2 ml/day for up to 3 months

(Sweetman, 1999). Conventional treatments for IBS symptoms include antispasmodics, anti-motility drugs and laxatives. However, Peppermint oil is also prescribed for IBS in conventional medicine.

369 Material Safety Datasheet viewed online at http://ptcl.chem.ox.ac.uk/MSDS/LI/(R)-(+)limonene.html, April 2004

370 IARC classification viewed online at http://www.inchem.org/documents/iarc/vol73/73-11.html,

April 2004

371 http://ntp-server.niehs.nih.gov/htdocs/Results_Status/Resstatl/10071-T.Html

372 Hazardous Substances Databank viewed online at http://toxnet.nlm.nih.gov/ April 2004.

Peppermint oil is licensed for veterinary use (NOAH, 2004), for the treatment of digestive disorders and motion sickness in cats and dogs. The maximum recommended daily dose ranges between 0.001 ml/day and 0.004 ml/day, dependent on animal size.


Menthol and the related compound menthyl acetate are the active constituents of

Peppermint essential oil.

Menthol & Menthyl acetate

Toxicokinetics

Adverse effects include hypersensitivity, abdominal pain, nausea, vomiting, vertigo, ataxia, drowsiness and coma (Sweetman, 1999). Application of decongestants containing menthol to the nostrils of infants and children may lead to acute respiratory distress with cyanosis and respiratory arrest.

In humans, menthol is readily absorbed (100%) and metabolised, with approximately

80% of an oral dose eliminated as the glucuronic acid conjugate in the urine within 6 hours.

373 Menthol ingestion in animals has been shown to have a number of enzyme effects. Elevation of glucuronidase activity was observed in mice. Menthol caused elevation of hepatic microsomal cytochrome c and NADPH-cytochrome P450 reductase in rats while two other CYP450 complexes were unchanged.

As an ester of menthol, menthyl acetate is presumed to be hydrolysed in the gastrointestinal tract to yield menthol and acetic acid, and metabolism is assumed to proceed as for menthol.

Toxicity Profile

Acute toxicity

Menthol is classed as very toxic, with a probable oral lethal dose of between 50 and

500 mg kg -1 in humans.

374 However, the published oral toxicity LD50 values are of the order 3000 mg kg

-1

for rats and mice.

2


Menthol produced no toxicity in either mice or rats in a 103 week study.

2


Long-term studies of menthol in mice and rats produced no evidence for carcinogenicity.

2,375

Neither menthol nor its metabolites have been shown to be genotoxic in vitro or in vivo .


No developmental toxicity or teratogenicity have been noted for menthol.

2

373 WHO Food Additives series, viewed at http://www.inchem.org/documents/jecfa/jecmono/v042je04.htm Apr 04



04

4. Tea Tree oil

Tea Tree oil is used as an antiseptic and disinfectant.

376

It can be applied neat to the skin.

377


Cineole has been identified as an active constituent of Tea Tree oil, and for which toxicological data are available.

Cineole

Toxicokinetics

Oral administration of cineole (also known as Eucalyptol) to bushtailed possums led to the detection of 19 metabolites in urine and faeces,

378

among which were p-cresol,

9-hydroxycineole and cineol-9-oic acid.

Following oral administration in Swiss albino mice, cineole was found to reduce significantly the hepatic necrosis caused by GalN/LPS. In vitro tests have shown cineole to act as an inhibitor of cyclooxygenase 2, and to reduce lipid peroxidation.

Investigation of the effects of cineole on cytochrome P450 enzymes, measured in rat liver microsomes, showed no effect on total CYP450 content, with elevation of the levels of 2B1 and 3A2 isoforms.

Toxicity Profile

Acute toxicity

Cineole is listed as Very Toxic, that is, the probable lethal dose in humans is between

50 and 500 mg kg -1 . 379 Adverse effects such as nausea, vomiting, vertigo, ataxia, muscle weakness, stupor, pallor and sometimes cyanosis have been reported. Acute toxicity data are summarised in a Material Safety Datasheet.

380

Acute oral toxicity measured in rats gave LD50 of 2480 mg kg

-1

. Behavioural effects observed were somnolence and coma. LD50 values measured in mice were 1000 mg kg

-1

for the intramuscular route and 1070 mg kg

-1

for subcutaneous administration.


Subcutaneous cineole (2450mg kg -1 , cumulative in 10 days) showed no evidence of effects on liver regeneration.


Cineole (12 g kg

-1

for 8 weeks) was not positive for tumour induction in a mouse primary lung tumour model.

381

In mutagenicity tests, cineole gave negative results in tests using four standard strains of Salmonella typhimurium , with and without S9 metabolic activation.

1

5. Thyme essential oil

Thyme essential oil has carminative, antiseptic, antitussive and expectorant properties and is used chiefly in preparations for respiratory-tract disorders (Sweetman, 1999).

Thyme EO is recommended for use at no more than 2% in a suitable carrier.

382



377 http://hcd2.bupa.co.uk/fact_sheets/html/aromatherapy.html May 2004

378 Beilstein Database [cineole] accessed May 2004

379 Hazardous Substances Databank record viewed at http://toxnet.nlm.nih.gov/ April 2004

380 Material Safety Datasheet viewed at http://www.sigmaaldrich.com product number C8144, April

2004

381 Beilstein Database [cineole] accessed May 2004

382 http://www.naturedirect2u.com/Essential%20oils/thyme.htm May 2004

Thyme EO has been shown to contain a number of compounds for which biological activity has been shown. Of these, toxicological data are available for borneol,

383 carvacrol and thymol.

5.1.1 Carvacrol

Toxicokinetics

Carvacrol 384 is slowly absorbed from the gastrointestinal tract in rabbits, with 30% of the administered dose remaining in the intestine 22 hours post administration. It is metabolised by conjugation to glucuronic acid and sulphate. No absorption of carvacrol applied to intact mouse skin was observed after 2 hours.

Toxicity Profile

Acute toxicity

Carvacrol is listed as very toxic, with probable oral lethal dose between 50 and 500 mg kg -1 in humans.

4 When applied to intact or abraded rabbit skin, neat carvacrol was shown to be a severe irritant. Acute toxicity values are summarised in a Material

Safety Datasheet.

385

The oral LD50 was shown to be 810 mg kg

-1

in rats, and a number of behavioural effects were also observed; these included somnolence and convulsions or effect on seizure threshold. Additional acute toxicity data are available for mice, where intraperitoneal injection of carvacrol resulted in LD50 of 73.3 mg kg

-

1

, intravenous administration gave an LD50 value of 80 mg kg

-1

, and subcutaneous administration gave an LD50 of 680 mg kg

-1

. The behavioural effects observed in mice were similar to those observed in rats.


Carvacrol was negative in Ames tests for mutagenicity.

386

5.1.2 Thymol

Applied topically, thymol is used as an antiseptic and as an antihelmintic. Veterinary uses as an antihelmintic, and as an external and internal antiseptic, have also been described .

387

Toxicokinetics

Substituted monophenols such as thymol are conjugated with glucuronic acid and sulphate.

388

The systematic availability following oral administration of thymol in humans has been studied (Kohlert et al.

, 2002). The sulphate conjugate of thymol but not free thymol was detected in plasma. The glucuronic acid and sulphate conjugates of thymol but not free thymol were detected in urine. Thymol was quickly absorbed, with significant plasma levels observed at 20 minutes and C max achieved at 2 hours.

The bioavailability was 16%.

Toxicity Profile

Acute toxicity

Thymol is a mild local irritant and its toxicity is classified as borderline between moderately and very toxic. Ingestion can cause gastric pain, nausea, vomiting, central hyperactivity, occasional convulsions, and cardiac and respiratory collapse. Acute oral

383 See Annex 2, section 12.1: Valerian, active constituent Borneol

384 Hazardous Substances Databank viewed at http://toxnet.nlm.nih.gov/ April 2004.

385 Material Safety Datasheet downloaded from https://www.sigmaaldrich.com Product number 282197,

Apr 04

386 Chemical Carcinogenesis Research Information System (CCRIS) database viewed at http://toxnet.nlm.nih.gov/ Apr 04.

387 O’Neil MJ, Smith A, Heckelman PE et al. (2001) The Merck Index. An Encyclopedia of Chemicals,

Drugs, and Biologicals. Thirteenth Edition . New Jersey, USA, Merck & Co., Inc. [Thymol, entry 89-

93-8]


toxicity LD50 values for mice, rats and guinea pigs are 1800, 980 and 880 mg kg

-1 respectively.


The IARC classification

389

for thymol is Group 3, that is, not classifiable as to its carcinogenicity to humans. Thymol gave negative results in Salmonella typhimurium tests for mutagenicity 390 , and was also negative for the induction of chromosome aberration.

391

6. Wormwood

The essential oil of Artemisia absinthium , Wormwood EO, has been used as flavouring in alcoholic beverages (e.g. vermouth)

2

, as a bitter and in homoeopathic medicine (Sweetman, 1999). Acute toxicity data for Wormwood EO shows an LD50 value of 960 mg kg

-1

by oral administration in rats.

392

Details on the use of

Wormwood (among other plants) as de-worming preparations in Nordic countries are available (Waller et al.

, 2001). However, this information is historical and/or anecdotal in nature, and serves to detail the plants used, the target organism and the livestock species.


Wormwood EO contains a number of active constituents, including absinthin,



santonin, and



- and



- thujone. Significant toxicological data is available only for



- and



- thujone.

6.1.1



-santonin

Acute toxicity testing of



-santonin shows LD50 value of 900 mg kg

-1

following oral administration in mice.

393

In addition, anti-helminthic activity has been ascribed to



santonin.

394



6.1.2



-/



- thujone

Toxicokinetics

Data on metabolism of



or



- thujone is lacking, as is information on long-term and/or reproductive effects.

395

Thujone administration can lead to convulsions that are epileptiform in nature and are preceded by vasodilation, fall in blood pressure and slowing of cardiac rhythm.

Toxicity Profile

Acute toxicity

Acute oral toxicity for thujone isomers is complicated by the use of mixtures of isomers, or the isomer is not specified in some acute tests. However, it is clear that the acute oral LD50 value of



-thujone in rats and mice is 250 and 500

396

mg kg

-1 respectively.



-thujone has LD50 for oral toxicity of 250 mg kg

-1

in dogs.

389 http://www.inchem.org/documents/iarc/vol71/027-phenol.html


04

391 Genetox database viewed at http://toxnet.nlm.nih.gov/ Apr 04

392 WHO Food Additives Series viewed online at http://www.inchem.org/documents/jecfa/jecmono/v16je25.htm , May 2004

393 Material Safety Datasheet viewed online at http://www.sigmaaldrich.com Product number 223085,

May 2004

394 O’Neil MJ, Smith A, Heckelman PE et al. (2001) The Merck Index. An Encyclopedia of Chemicals,

Drugs, and Biologicals. Thirteenth Edition . New Jersey, USA, Merck & Co., Inc.

395 WHO food additives series viewed online at http://www.inchem.org/documents/jecfa/jecmono/v16je25.htm, May 2004.

396 Material Safety Datasheet viewed online at http://www.sigmaaldrich.com Product number 89231,

May 2004


A 14 week study in rats demonstrated no significant differences in weight gain, haematology, or heart, liver, kidney, spleen or adrenal gland weights following thujone treatment (isomer not specified). NOEL values for female and male rats were calculated to be 5 mg kg

-1

per day and 10 mg kg

-1

per day respectively.




-thujone was found to be negative for mutagenicity using five standard strains of

Salmonella typhimurium .

397

397 Chemical Carcinogenesis Research Information System viewed online at http://toxnet.nlm.nih.gov/ , May 2004

Appendix 1.5 Glossary and list of abbreviations

Glossary

398

Antitussive a drug that suppresses coughing

Carminative a drug that relieves flatulence, used to treat gastric discomfort and colic

Diaphoretic a drug that causes an increase in sweating which stimulates the sweat glands directly

Dysphoria (dysphoric) a feeling of uneasiness, discomfort, anxiety, or anguish in vitro taking place in a living organism in vivo taking place in a test tube, culture dish, or elsewhere outside a living organism

Rubefacient an agent that causes reddening and warming of the skin. Rubefacients are often used as counterirritants for the relief of muscular pain

Statin any one of a class of drugs that inhibit the action of hydroxymethylglutaryl coenzyme

A reductase (HMG-CoA reductase), an enzyme that is involved in the liver's production of cholesterol.

Abbreviations

ACGIH: American Conference of Governmental Industrial Hygienists

CAM: Complementary and Alternative Medicine

CCRIS: Chemical Carcinogenesis Research Information System

COMT: Catechol-O-methyl transferase

CYP450: Cytochrome P450

EO: Essential Oil

HRT: Hormone Replacement Therapy

HSDB: Hazardous Substances Databank

IARC: International Agency for Research on Cancer

LCLO: Lowest published Lethal Concentration

LD50: Dose estimated to kill 50% of the animals dosed

MAOI: Monoamine Oxidase Inhibitor

MSDS: Material Safety Datasheet

NIOSH: National Institute for Occupational Safety and Health

NOEL/NOAEL: No Obseved (Adverse) Effect Level

NSAID: Non-Steroidal Anti-Inflammatory Drug

NTP: National Toxicology Program

OSHA: Occupational Safety and Health Administration

PAF: Platelet Activating Factor

QSAR: Quantitative Structure-Activity Relationships

QSDR: Quantitative Structure-Degradability Relationships

QSPR: Quantitative Structure-Property Relationships

SSRI: Selective Serotonin Re-Uptake Inhibitor

TCM: Traditional Chinese Medicine

398 definitions obtained from The Oxford Concise Medical Dictionary, available at Oxford Reference

Online

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Appendix 1 CAM data

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