Article

The EFSA Journal (2008) 746, 1-22

Flavouring Group Evaluation 87, (FGE.87)

1

Consideration of bicyclic secondary alcohols, ketones and related esters evaluated by JECFA (63

rd

meeting) structurally related to bicyclic secondary alcohols, ketones and related esters evaluated by EFSA in

FGE.47 (2008)

Scientific Opinion of the Panel on Food Additives,

Flavourings, Processing Aids and Materials in Contact with Food

(EFSA-Q-2008-071)

Adopted on 22 May 2008

P

ANEL

M

EMBERS

Fernando Aguilar, Herman Nybro Autrup, Susan Barlow, Laurence Castle, Riccardo Crebelli,

Wolfgang Dekant, Karl-Heinz Engel, Nathalie Gontard, David Michael Gott, Sandro Grilli,

Rainer Gürtler, John Christian Larsen, Jean-Charles Leblanc, Catherine Leclercq, F. Xavier

Malcata, Wim Mennes, Maria Rosaria Milana, Iona Pratt, Ivonne Magdalena Catharina Maria

Rietjens, Paul P. Tobback, Fidel Toldrá.

S

UMMARY

The Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in

Contact with Food (the Panel) is asked to advise the Commission on the implications for human health of chemically defined flavouring substances used in or on foodstuffs in the

Member States. In particular the Scientific Panel is requested to consider the Joint FAO/WHO

Expert Committee on Food Additives (the JECFA) evaluations of flavouring substances assessed since 2000, and to decide whether no further evaluation is necessary, as laid down in

Commission Regulation (EC) No 1565/2000. These flavouring substances are listed in the

Register, which was adopted by Commission Decision 1999/217/EC, and its consecutive amendments.

The present consideration concerns a group of 15 bicyclic secondary alcohols, ketones and related esters evaluated by the JECFA (63 rd meeting) and will be considered in relation to the

European Food Safety Authority (EFSA) evaluation of four bicyclic secondary alcohols, ketones and related esters in the Flavouring Group Evaluation 47 (FGE.47).

The Panel agrees with the application of the Procedure as performed by JECFA for the 15 bicyclic secondary alcohols, ketones and related esters. However, for two substances [FL-no:

1 For citation purposes: Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in

Contact with Food on a request from Commission on Flavouring Group Evaluation 87, (FGE.87) bicyclic secondary alcohols, ketones and related esters. The EFSA Journal (2008) 746, 1-22

© European Food Safety Authority, 2008

Flavouring Group Evaluation 87, (FGE.87) bicyclic secondary alcohols, ketones and related esters

09.153 and 09.319] the JECFA evaluation is only based on MSDI values derived from production figures from the USA. EU production figures are needed in order to finalise the evaluation of these substances.

For all 15 substances evaluated through the Procedure use levels are needed to calculate the mTAMDIs in order to identify those flavouring substances that need more refined exposure assessments and to finalise the evaluation.

In order to determine whether the conclusion for the 15 JECFA evaluated substances can be applied to the materials of commerce, it is necessary to consider the available specifications:

Specifications are available for the 15 materials of commerce. Information on composition of mixture is lacking for eight substances [FL-no: 02.016, 02.038, 07.159, 09.017, 09.131,

09.153, 09.176 and 09.218].

Thus, for nine of the 15 JECFA evaluated bicyclic secondary alcohols, ketones and related esters [FL-no: 02.016, 02.038, 07.159, 09.017, 09.131, 09.153, 09.176, 09.218 and 09.319] the Panel has reservations (no European production volumes available, preventing them from being evaluated using the Procedure, and/or information on the composition of mixture is lacking).

For the remaining six of the 15 JECFA evaluated bicyclic secondary alcohols, ketones and related esters [FL-no: 02.059, 07.153, 09.082, 09.269, 09.456 and 09.457] the Panel agrees with the JECFA conclusion “no safety concern at estimated levels of intake as flavouring substances” based on the MSDI approach.

FGE.47: Flavouring Group Evaluation 47, (FGE.47)

JECFA evaluation: http://whqlibdoc.who.int/publications/2006/9241660546_eng.pdf

K EYWORDS

Bicyclic secondary alcohols, ketones and related esters, JECFA, secondary alicyclic saturated alcohols, secondary alicyclic unsaturated alcohols, FGE.47.

The EFSA Journal (2008) 746, 2-22


Table of Contents

Panel Members ..........................................................................................................................................1

Summary ....................................................................................................................................................1

Keywords....................................................................................................................................................2

Background................................................................................................................................................4

Terms of Reference ...................................................................................................................................4

Acknowledgements ....................................................................................................................................4

Assessment .................................................................................................................................................5

1.

Presentation of the Substances in the JECFA Flavouring Group................................................6

1.1.

Description.................................................................................................................................6

1.1.1.

JECFA Status.........................................................................................................................6

1.1.2.

EFSA Considerations ............................................................................................................6

1.2.

Isomers.......................................................................................................................................7

1.2.1.

JECFA Status.........................................................................................................................7

1.2.2.


1.3.

Specifications.............................................................................................................................7

1.3.1.

JECFA Status.........................................................................................................................7

1.3.2.


2.

Intake Estimations ............................................................................................................................7

2.1.

JECFA Status .............................................................................................................................7

2.2.

EFSA Considerations.................................................................................................................7

3.

Genotoxicity Data .............................................................................................................................8

3.1.

Genotoxicity Studies – Text Taken from JECFA (JECFA, 2006a) ...........................................8

3.2.

Genotoxicity Studies - Text Taken from EFSA.........................................................................8

3.3.


4.

Application of the Procedure ...........................................................................................................9

4.1.

Application of the Procedure to to 15 Bicyclic Secondary Alcohols, Ketones and related

Esters by the JECFA (JECFA, 2006a) ....................................................................................................9

4.2.

Application of the Procedure to Four Bicyclic Secondary Alcohols, Ketones and Related

Esters by EFSA (FGE.47).......................................................................................................................9

4.3.


Conclusion................................................................................................................................................10

Table 1: Specification Summary for JECFA Evaluated Substances in the Present Group .............11

Table 2: Genotoxicity Data .....................................................................................................................15

Table 3: Summary of Safety Evaluation Tables ...................................................................................17

References ................................................................................................................................................21

The EFSA Journal (2008) 746, 3-22


B

ACKGROUND

Regulation (EC) No 2232/96 of the European Parliament and the Council (EC, 1996) lays down a Procedure for the establishment of a list of flavouring substances, the use of which will be authorised to the exclusion of all other substances in the EU. In application of that

Regulation, a Register of flavouring substances used in or on foodstuffs in the Member States was adopted by Commission Decision 1999/217/EC (EC, 1999a), as last amended by

Commission Decision 2006/252/EC (EC, 2006). Each flavouring substance is attributed a

FLAVIS-number (FL-number) and all substances are divided into 34 chemical groups.

Substances within a group should have some metabolic and biological behaviour in common.

Substances which are listed in the Register are to be evaluated according to the evaluation programme laid down in Commission Regulation (EC) No 1565/2000 (EC, 2000a), which is broadly based on the Opinion of the Scientific Committee on Food (SCF, 1999).

Commission Regulation (EC) No 1565/2000 lays down that substances that are contained in the Register and will be classified in the future by the Joint FAO/WHO Expert Committee on

Food Additives (the JECFA) so as to present no safety concern at current levels of intake will be considered by the European Food Safety Authority (EFSA), who may then decide that no further evaluation is necessary.

In the period 2000 – 2006, during its 55 th , 57 th , 59 th , 61 st , 63 evaluated about 900 substances which are in the EU Register. rd and 65 th meetings, the JECFA

T ERMS OF R EFERENCE

EFSA is requested to consider the JECFA evaluations of flavouring substances assessed since

2000, and to decide whether no further evaluation is necessary, as laid down in Commission

Regulation (EC) No 1565/2000 (EC, 2000a). These flavouring substances are listed in the

Register, which was adopted by Commission Decision 1999/217/EC (EC, 1999a), and its consecutive amendments.

A CKNOWLEDGEMENTS

The Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials in

Contact with Food wishes to thank Jørn Gry, Vibe Beltoft, Frederikke Bentzen, Pia Lund and

Karin Nørby for their contribution to the draft opinion.

The EFSA Journal (2008) 746, 4-22


A

SSESSMENT

The approach used by EFSA for safety evaluation of flavouring substances is referred to in

Commission Regulation (EC) No 1565/2000 (EC, 2000a), hereafter named the “EFSA

Procedure”. This Procedure is based on the Opinion of the Scientific Committee on Food

(SCF, 1999), which has been derived from the evaluation procedure developed by the Joint

FAO/WHO Expert Committee on Food Additives (JECFA, 1995; JECFA, 1996a; JECFA,

1997a; JECFA, 1999b), hereafter named the “JECFA Procedure”. The Panel compares the

JECFA evaluation of structurally related substances with the result of a corresponding EFSA evaluation, focussing on specifications, intake estimations and toxicity data, especially genotoxicity data. The evaluations by EFSA will conclude whether the flavouring substances are of no safety concern at their estimated levels of intake, whether additional data are required or whether certain substances should not be evaluated through the EFSA Procedure.

The following issues are of special importance.

Intake

In its evaluation, the Panel as a default uses the Maximised Survey-derived Daily Intake

(MSDI) approach to estimate the per capita intakes of the flavouring substances in Europe.

In its evaluation, the JECFA includes intake estimates based on the MSDI approach derived from both European and USA production figures. The highest of the two MSDI figures is used in the evaluation by the JECFA. It is noted that in several cases, only the MSDI figures from the USA were available, meaning that certain flavouring substances have been evaluated by the JECFA only on the basis of these figures. For Register substances for which this is the case the Panel will need EU production figures in order to finalise the evaluation.

When the Panel examined the information provided by the European Flavour Industry on the use levels in various foods, it appeared obvious that the MSDI approach in a number of cases would grossly underestimate the intake by regular consumers of products flavoured at the use level reported by the Industry, especially in those cases where the annual production values were reported to be small. In consequence, the Panel had reservations about the data on use and use levels provided and the intake estimates obtained by the MSDI approach. It is noted that the JECFA, at its 65 th meeting considered ”how to improve the identification and assessment of flavouring agents, for which the MSDI estimates may be substantially lower than the dietary exposures that would be estimated from the anticipated average use levels in foods” (JECFA, 2006c).

In the absence of more accurate information that would enable the Panel to make a more realistic estimate of the intakes of the flavouring substances, the Panel has decided also to perform an estimate of the daily intakes per person using a modified Theoretical Added

Maximum Daily Intake (mTAMDI) approach based on the normal use levels reported by

Industry.

As information on use levels for the flavouring substances has not been requested by the

JECFA or has not otherwise been provided to the Panel, it is not possible to estimate the daily intakes using the mTAMDI approach for the substances evaluated by the JECFA. The Panel will need information on use levels in order to finalise the evaluation.

The EFSA Journal (2008) 746, 5-22


Threshold of 1.5 Microgram/Person/Day (Step B5) Used by the JECFA

The JECFA uses the threshold of concern of 1.5 microgram/person/day as part of the evaluation procedure:

“The Committee noted that this value was based on a risk analysis of known carcinogens which involved several conservative assumptions. The use of this value was supported by additional information on developmental toxicity, neurotoxicity and immunotoxicity. In the judgement of the Committee, flavouring substances for which insufficient data are available for them to be evaluated using earlier steps in the Procedure, but for which the intake would not exceed 1.5 microgram per person per day would not be expected to present a safety concern. The Committee recommended that the Procedure for the Safety Evaluation of

Flavouring Agents used at the forty-sixth meeting be amended to include the last step on the right-hand side of the original procedure (“Do the condition of use result in an intake greater than 1.5 microgram per day?”)” (JECFA, 1999b).

In line with the Opinion expressed by the Scientific Committee on Food (SCF, 1999), the

Panel does not make use of this threshold of 1.5 microgram per person per day.

Genotoxicity

As reflected in the Opinion of SCF (SCF, 1999), the Panel has in its evaluation focussed on a possible genotoxic potential of the flavouring substances or of structurally related substances.

Generally, substances for which the Panel has concluded that there is an indication of genotoxic potential in vitro, will not be evaluated using the EFSA Procedure until further genotoxicity data are provided. Substances for which a genotoxic potential in vivo has been concluded, will not be evaluated through the Procedure.

Specifications

Regarding specifications, the evaluation by the Panel could lead to a different opinion than that of the JECFA, since the Panel requests information on e.g. isomerism.

Structural Relationship

In the consideration of the JECFA evaluated substances, the Panel will examine the structural relationship and metabolism features of the substances within the flavouring group and compare this with the corresponding FGE.

1.

Presentation of the Substances in the JECFA Flavouring Group

1.1.

Description

1.1.1.

JECFA Status

The JECFA has evaluated a group of 32 flavouring substances consisting of monocyclic and bicyclic secondary alcohols, ketones and related esters.

1.1.2.

EFSA Considerations

Three of the 32 JECFA evaluated substances are not included in the Register, alphaisomethylionyl acetate (JECFA-no: 1410), d,l-menthol-(±)-propylene glycol carbonate

(JECFA-no: 1413), l-monomenthyl glutarate (JECFA-no: 1414).

Six of the 32 JECFA evaluated substances are alpha,beta-unsaturated [FL-no: 02.100, 02.101,

07.089, 07.136, 07.140 and 09.305] and will be evaluated together with other alpha,betaunsaturated aldehydes and ketones (EFSA, 2008b). One of the JECFA evaluated substances is

The EFSA Journal (2008) 746, 6-22

Flavouring Group Evaluation 87, (FGE.87) bicyclic secondary alcohols, ketones and related esters an ether [FL-no: 16.088], which will be considered together with other ethers in a revision of

FGE.59 (FGE.59Rev1).

Six of the 32 JECFA evaluated substances are monocyclic secondary alcohols, ketones and related esters and will considered in FGE.56.

Finally, the JECFA evaluated substance, (1R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one

(camphor [FL-no: 07.215], which the Panel has evaluated in a separate Opinion (EFSA,

2008l), will not be further considered in this FGE.

This consideration will therefore only deal with 15 bicyclic secondary alcohols, ketones and related esters. The Panel concluded that all 15 substances in the JECFA flavouring group of bicyclic secondary alcohols, ketones and related esters are structurally related to the group of four bicyclic secondary alcohols, ketones and related esters evaluated by EFSA in FGE.47.

1.2.

Isomers

1.2.1.

JECFA Status

All 15 Register substances have one or more chiral centres. Ten of the substances are mixtures of positional isomers. See Table 1 for details.

1.2.2.


For the substance [FL-no: 09.561] having a double bond, the geometrical isomer is specified.

For the two substances [FL-no: 09.721 and 09.724] having a chiral centre the stereoisomeric composition has not been specified.

1.3.

Specifications

1.3.1.

JECFA Status

JECFA specifications are available for all 15 substances (JECFA, 2005b).

1.3.2.


The composition of the mixture has not been specified for eight substances (see Section

1.2.2). For two substances [FL-no: 02.059 and 07.153] the minimum assay is below 95 %, but information on secondary components is available in the specifications (see Table 1).

2.

Intake Estimations

2.1.

JECFA Status

For 13 substances evaluated through the JECFA Procedure production figures are available for the EU. For the two remaining substances [FL-no: 09.153 and 09.319] production figures are only available for the USA.

2.2.


As production figures are only available for the USA for two substances MSDI values for the

EU cannot be calculated for these [FL-no: 09.153 and 09.319].

The EFSA Journal (2008) 746, 7-22

3.

Genotoxicity Data


3.1.

Genotoxicity Studies – Text Taken from JECFA (JECFA, 2006a)

Tests for genotoxicity in vitro

and in vivo

using standardized protocols have been used to study two representative members [FL-no: 02.016 and 09.131] of the bicyclic secondary alcohols, ketones and related esters group used as flavouring agents.

In vitro

Two members of this group (borneol [FL-no: 02.016] and isobornyl propionate [FL-no:

09.131]) consistently gave negative results in the Ames assay when incubated at a concentration of up to 5000 µg/plate with a variety of

Salmonella typhimurium strains including TA97, TA98, TA100, TA1535, TA1537 and TA1538 with or without metabolic activation (Simmon et al., 1977; Wild et al., 1983; Azizan & Blevins, 1995).

Borneol [FL-no: 02.016] showed no mutagenic activity when tested in

Escherichia coli

WP2 uvrA at concentrations of up to 3200 µg/plate (Yoo, 1986).

In the Rec-assay, borneol [FL-no: 02.016] was reported to induce growth inhibition in

Bacillus subtilis strain M45- when tested at concentrations of up to 10 mg/disc (Yoo, 1986).

This test has very limited relevance for the genotoxicity evaluation.

In vivo

The potential of isobornyl propionate [FL-no: 09.131] to induce sex-linked recessive lethal mutations in adult Drosophila melanogaster was studied in a Basc test. No increased frequency of mutation was observed in flies fed with isobornyl propionate [FL-no: 09.131] in a 10 mmol/l solution for 3 days (Wild et al., 1983).

In the test for micronucleus formation, groups of NMRI mice given isobornyl propionate (FLno: 09.131) at a dose of 841, 1893 or 2944 mg/kg bw by intraperitoneal administration showed no increase in micronucleated erythrocytes in samples of bone marrow, 30 h after administration (Wild et al., 1983).

Conclusion on genotoxicity

The testing of these representative bicyclic secondary alcohols, ketones and related esters in bacterial (Ames assay) and mammalian (micronucleus formation) in vivo

systems showed no evidence of genotoxic potential, and these results are further supported by the lack of positive findings in the

Drosophila

Basc test.

For a summary of in vitro/in vivo

genotoxicity data considered by JECFA, see Table 2.1.

3.2.

Genotoxicity Studies - Text Taken from EFSA

No in vitro/in vivo

genotoxicity data are available for the candidate substances in FGE.47.

3.3.


Genotoxicity data are available only for a limited number of structurally related substances, and the genotoxicity could not be assessed adequately. However, the data available do not preclude the evaluation of the candidate substances using the Procedure.

The EFSA Journal (2008) 746, 8-22


4.

Application of the Procedure

4.1.

Application of the Procedure to to 15 Bicyclic Secondary Alcohols, Ketones and related Esters by the JECFA (JECFA, 2006a)

According to the JECFA, 13 of the 15 substances belong to structural class I and two to structural class II using the decision tree approach presented by Cramer et al. (1978).

The JECFA concluded the 15 bicyclic secondary alcohols, ketones and related esters at step

A3 in the JECFA Procedure, i.e. the substances are expected to be metabolised to innocuous products (step 2) and concluded that the intakes for all substances are below the thresholds for their structural classes I and II (step A3).

In conclusion, the JECFA considered that the 15 bicyclic secondary alcohols, ketones and related esters, evaluated through the Procedure, were of no safety concern at the estimated levels of intakes based on the MSDI approach.

The evaluations of the 15 bicyclic secondary alcohols, ketones and related esters are summarised in Table 3.1: Summary of Safety Evaluation of 15 bicyclic secondary alcohols, ketones and related esters (JECFA, 2005c).

4.2.

Application of the Procedure to Four Bicyclic Secondary Alcohols, Ketones and

Related Esters by EFSA (FGE.47)

For the safety evaluation of the four candidate substances from chemical group 8 the

Procedure was applied.

Step 1

Three of the four candidate substances are classified in structural class I and one in structural class II according to the decision tree approach as presented by Cramer et al. (1978).

Step 2:

All four candidate substances in this group are expected to be metabolised to innocuous products. The evaluation of these substances therefore proceeded via the A-side of the evaluation scheme

Step A3:

The estimated per capita daily intakes for all four candidate substances classified in structural classes I and II are below the human intake threshold of concern (i.e. 1800 μ g/person per day for class I and 540 μ g/person per day for class II).

Based on results of the safety evaluation sequence of the Procedure, these four candidate substances proceeding via the A-side of the Procedure do not pose a safety concern when used as flavouring substances at the estimated levels of intake, based on the MSDI approach.

4.3.


The Panel agrees with the application of the Procedure as performed by the JECFA for the 15 bicyclic secondary alcohols, ketones and related esters. However, for two substances [FL-no:

09.153 and 09.319] no European production figures were available and consequently no

European exposure estimates could be calculated. Accordingly, the safety in use could not be assessed using the Procedure for these two substances.

The EFSA Journal (2008) 746, 9-22


C

ONCLUSION

The Panel concluded that all the 15 substances in the JECFA flavouring group of bicyclic secondary alcohols, ketones and related esters are structurally related to the group of four bicyclic secondary alcohols, ketones and related evaluated by EFSA in the Flavouring Group

Evaluation 47 (FGE.47).

The Panel agrees with the application of the Procedure as performed by JECFA for the 15 bicyclic secondary alcohols, ketones and related esters. However, for two substances [FL-no:

09.153 and 09.319] the JECFA evaluation is only based on MSDI values derived from production figures from the USA. EU production figures are needed in order to finalise the evaluation of these substances.

For all 15 substances evaluated through the Procedure use levels are needed to calculate the mTAMDIs in order to identify those flavouring substances that need more refined exposure assessments and to finalise the evaluation.

In order to determine whether the conclusion for the 15 JECFA evaluated substances can be applied to the materials of commerce, it is necessary to consider the available specifications:

Specifications are available for the 15 materials of commerce. Information on composition of mixture is lacking for eight substances [FL-no: 02.016, 02.038, 07.159, 09.017, 09.131,

09.153, 09.176 and 09.218].

Thus, for nine of the 15 JECFA evaluated bicyclic secondary alcohols, ketones and related esters [FL-no: 02.016, 02.038, 07.159, 09.017, 09.131, 09.153, 09.176, 09.218 and 09.319] the Panel has reservations (no European production volumes available, preventing them from being evaluated using the Procedure, and/or information on the composition of mixture is lacking).

For the remaining six of the 15 JECFA evaluated bicyclic secondary alcohols, ketones and related esters [FL-no: 02.059, 07.153, 09.082, 09.269, 09.456 and 09.457] the Panel agrees with the JECFA conclusion “no safety concern at estimated levels of intake as flavouring substances” based on the MSDI approach.

The EFSA Journal (2008) 746, 10-22


T

ABLE

1: S

PECIFICATION

S

UMMARY FOR

JECFA E

VALUATED

S

UBSTANCES IN THE

P

RESENT

G

ROUP

Table 1: Specification Summary of 15 Bicyclic Secondary Alcohols, Ketones and Related Esters Evaluated by the JECFA

FL-no

JECFA-no

EU Register name

02.016

1385

02.038

1397

02.059

1386

Borneol

Fenchyl alcohol

Isoborneol

Structural formula FEMA no

CoE no

CAS no

2157

64

507-70-0

OH

_____

HO

OH

_____

2480

87

1632-73-1

2158

2020

124-76-5

Phys. form

Mol. formula

Mol. weight

Solid

C

10

H

18

154.25

O

Solid

C

10

H

18

O

154.25

Solid

C

10

H

18

O

154.25

Solubility 1)

Solubility in ethanol 2)

Very slightly soluble

Soluble


Soluble


Soluble

Boiling point, °C 3)

Melting point, °C

ID test

Assay minimum

Refrac. Index 4)

Spec. gravity 5) n.a.

202

IR

97 % n.a. n.a. n.a.

35-40

IR

97 % n.a.

212-214

IR

92 % n.a. n.a. n.a. n.a.

EFSA comments

CASnr refers to

(1R,2S,4R)-stereoisomer.

JECFA: "Min. assay value may incl. isoborneol, other isomers of borneol, trace amounts of fenchyl alcohol

& other C10H18O compounds".

Compositon of mixture not specified.

CASrn in Register refers to the racemate.

According to JECFA: Min. assay value is "97% of

C10H18O" which may include small amounts of borneol and isoborneol.

Mixture of fenchyl alcohol, borneol and isoborneol not specified.

CASrn in Register refers to

(1R,2R,4R)-stereoisomer.

According to JECFA: Min. assay value is "92%" and secondary components "3-5

% borneol".

The EFSA Journal (2008) 746, 11-22



FL-no

JECFA-no

07.153

1407


1,10-

Dihydronootkatone

O


CoE no

CAS no

3776

20489-53-6

07.159

1396

09.017

1387

09.082

1389 d-Fenchone

Bornyl acetate

Bornyl formate

O

O

O

O

O

_____

2479

551

4695-62-9

2159

207

76-49-3

2161

349

7492-41-3

Phys. form

Mol. formula

Mol. weight

Liquid

C

15

H

24

220.36

O

Liquid

C

10

H

16

O

152.24

Liquid

C

12

H

20

O

2

196.29

Liquid

C

11

H

18

O

2

182.26

Solubility 1)



Soluble

Insoluble

Soluble

Slightly soluble

Soluble

Slightly soluble

Soluble



ID test

Assay minimum


Spec. gravity 5)

100-104(0.09hPa

NMR

90 %

1.502-1.508

0.975-0.988

192

IR

97 %

226

25

IR

98 %

106-108 (27hPa)

NMR

95 %

1.460-1.467

0.940-0.948

1.462-1.466

0.981-0.985

1.466-1.472

1.007-1.013 (20°)

EFSA comments


(4R,4aS,6R,8aS)stereoisomer.

According to JECFA: Min. assay value is "90%" and secondary components "5-

6% nootkatone".

CASrn in the Register refers to (1S,4R)-isomer.

According to JECFA: Min. assay value is "97% of

C10H16O" which may include small amounts of d-camphor.

Composition of mixture not specified.

CASrn in the Register refers to (1R,2S,4R)isomer.

According to JECFA: Min. assay value is "98 % and may include isobornyl acetate and other bornyl acetate isomers".




The EFSA Journal (2008) 746, 12-22



FL-no

JECFA-no

09.131

1391


Isobornyl propionate


CoE no

CAS no

2163

412

2756-56-1

O

O

_____

09.153

1392

09.176

1390

Bornyl valerate

Isobornyl formate

O

O

_____

O

O

_____

2164

471

7549-41-9

2162

565

1200-67-5

Phys. form

Mol. formula

Mol. weight

Liquid

C

13

H

22

O

2

210.32

Liquid

C

15

H

26

O

2

238.37

Liquid

C

11

H

18

O

2

182.26

Solubility 1)


Soluble

Soluble

Insoluble

Soluble

Slightly soluble

Soluble



ID test

Assay minimum



245

NMR

97 %

1.461-1.465

0.968-0.971

136-137 (16hPa)

NMR

96 %

94-95 (20 hPa)

NMR

96 %

1.459-1.465

0.957-0.963

1.469-1.473

1.011-1.017

EFSA comments



According to JECFA: Min. assay value "may include small amounts of bornyl propionate".




According to JECFA: Min. assay value "may include small amounts of isobornyl valerate".




According to JECFA: Min. assay value "may include small amounts of bornyl formate".


The EFSA Journal (2008) 746, 13-22



FL-no

JECFA-no

09.218

1388


Isobornyl acetate


CoE no

CAS no

2160

2066

125-12-2

O

O

_____

09.269

1399

Fenchyl acetate

O

O

09.319

1412

Bornyl butyrate

O

O

_____

09.456

1393

Bornyl isovalerate

O

O

_____

09.457

1394

Isobornyl isovalerate

O

O

1)

Solubility in water, if not otherwise stated.

2)

Solubility in 95% ethanol, if not otherwise stated.

_____

3)

At 1013.25 hPa, if not otherwise stated.

4)

At 20°C, if not otherwise stated.

5)

At 25°C, if not otherwise stated.

3390

11769

13851-11-1

3907

13109-70-1

2165

451

76-50-6

2166

452

7779-73-9

Phys. form

Mol. formula

Mol. weight

Liquid

C

12

H

20

O

2

196.29

Liquid

C

12

H

20

O

2

196.29

Liquid

C

14

H

24

O

2

224.34

Liquid

C

15

H

26

O

2

238.37

Liquid

C

15

H

26

O

2

238.37

Solubility 1)


Insoluble

Soluble

Slightly soluble

Soluble

Slightly soluble

Soluble

Insoluble

Soluble

Insoluble

Soluble

220

NMR

98 %

247

MS

97 %

260

NMR

97 %

266-269

NMR

96 %



ID test

Assay minimum



227

IR

97 %

1.462-1.465

0.979-0.984

1.456-1.462

0.973-0.979

1.462-1.469

0.981-0.991

1.458-1.461

0.944-0.947

1.463-1.469

0.900-0.906

EFSA comments



According to JECFA: Min. assay value "may include small amounts of bornyl acetate".


CASrn in Register refers to the racemate.







The EFSA Journal (2008) 746, 14-22


T

ABLE

2: G

ENOTOXICITY

D

ATA

Table 2.1: Genotoxicity Data (in vitro/in vivo) for 15 Bicyclic Secondary Alcohols, Ketones and Related Esters (JECFA, 2006a)

Table 2.1: Summary of genotoxicity data for 15 Bicyclic Secondary Alcohols, Ketones and Related Esters Evaluated by JECFA

FL-no

JECFA-no

In vitro


JECFA name

Structural formula End-point

02.016

1385

Borneol

OH

_____

09.131

1391


O

O

_____

In vivo

09.131

1391


1)

2)

O

O

_____

Tested with and without metabolic activation.

Dose calculated based on the relative molecular mass of substance = 210.32.

Reverse mutation

Reverse mutation

DNA repair

Mutation test

Reverse mutation

S. typhimurium

TA97, TA98,

TA100

1 mg/ml (1000 µg/ml) Negative 1

S. typhimurium

TA1538

TA98,

TA100, TA1535, TA1537,

B. subtilis

M45 and H17 +

≤ 5 mg/plate

(5000µg/plate)

≤ 10 mg/disc

Negative 1

Positive

E. coli

WP2 uvrA (trp-)

S. typhimurium

TA98,

TA100, TA1535, TA1537,

TA1538

0.4-3.2 mg/plate

≤ 3.6 mg/plate (3600

µg/plate)

Negative

Negative 1

Somatic mutation and recombination

Micronucleus formation

D. melanogaster

10 mmol/l (2103

µg/ml)

Mouse bone marrow cells 841, 1893 and 2944 mg/kg bw

Negative 2

Negative 3

(Azizan & Blevins, 1995)

(Simmon et al., 1977)

(Yoo, 1986)

(Yoo, 1986)

(Wild et al., 1983)

(Wild et al., 1983)

(Wild et al., 1983)

The EFSA Journal (2008) 746, 15-22


T ABLE 2.2: G ENOTOXICITY ( IN VITRO ) EFSA / FGE.47

No in vitro genotoxicity data are available for the candidate substances in FGE.47. Data for supporting substances are presented in Table 2.1.

T ABLE 2.3: G ENOTOXICITY ( IN VIVO ) EFSA / FGE.47

No in vivo

genotoxicity data are available for the candidate substances in FGE.47. Data for supporting substances are presented in Table 2.1.

The EFSA Journal (2008) 746, 16-22


T

ABLE

3: S

UMMARY OF

S

AFETY

E

VALUATION

T

ABLES

Table 3.1: Summary of Safety Evaluation of 15 Bicyclic Secondary Alcohols, Ketones and Related Esters evaluated by JECFA (JECFA, 2005c)

Table 3.1: Summary of Safety Evaluation of 15 JECFA-Evaluated Cyclic Secondary Alcohols, Ketones and Related Esters (JECFA, 2005c)

FL-no

JECFA-no


02.016

1385

02.038

1397

02.059

1386

09.017

1387

Borneol

Fenchyl alcohol

Isoborneol

Bornyl acetate

Structural formula EU MSDI 1)

US MSDI

(

μ g/ capita /day)

OH

HO

O

_____

OH

_____

O

130

23

55

17

21

0.07

18

3

Class 2)

Evaluation procedure path 3)

Outcome on the named compound

[4) or 5)]

Class I

A3: Intake below threshold

Class I


Class I


Class I


4)

4)

4)

4)

EFSA conclusion on the named compound

(Procedure steps, intake estimates, NOAEL,

EFSA conclusion on the material of commerce genotoxicity)

No safety concern at estimated level of intake as flavouring substance.

CASnr refers to (1R,2S,4R)-stereoisomer,

Register name to be changed accordingly.

JECFA: "Min. assay value may incl. isoborneol, other isomers of borneol, trace amounts of fenchyl alcohol & other C10H18O compounds".

Compositon of mixture to be specified.




CASrn refers to the racemate.

According to JECFA: Min. assay value is "97% of C10H18O" which may include small amounts of borneol and isoborneol.

Composition of mixture to be specified.

CASrn refers to (1R,2R,4R)-stereoisomer.


According to JECFA: Min. assay value is "92%" and secondary components "3-5 % borneol".


CASrn in the Register refers to (1R,2S,4R)isomer. Register name to be changed accordingly.

According to JECFA: Min. assay value is "98 % and may include isobornyl acetate and other bornyl acetate isomers".


The EFSA Journal (2008) 746, 17-22



FL-no

JECFA-no

09.082

1389

09.131

1391

09.153

1392

09.176

1390

09.218

1388

09.269

1399

09.319

1412


Bornyl formate


Bornyl valerate

Isobornyl formate

Isobornyl acetate

Fenchyl acetate

Bornyl butyrate

O

O

Structural formula EU MSDI 1)

US MSDI

(


O

O

O

O

O

O

_____

O

_____

O

_____

_____

O

O

O

O

_____

_____

1.2

0.09

2.6

0.007

ND

5

0.61

0.4

890

236

2.9

0.07

ND

9

Class 2)


Class I


Class I


Class I


Class I


Class I


Class I


Class I



[4) or 5)]

4)

4)

4)

4)

4)

4)

4)

EFSA conclusion on the EFSA conclusion on the material of named compound

(Procedure steps, intake commerce estimates, NOAEL, genotoxicity)


CASrn refers to (1R,2S,4R)-stereoisomer.




MSDI based on USA production figure.







According to JECFA: Min. assay value "may include small amounts of bornyl propionate".




According to JECFA: Min. assay value "may include small amounts of isobornyl valerate".





According to JECFA: Min. assay value "may include small amounts of bornyl formate".




According to JECFA: Min. assay value "may include small amounts of bornyl acetate".


CASrn refers to the racemate.





The EFSA Journal (2008) 746, 18-22



FL-no

JECFA-no

09.456

1393

09.457

1394

07.153

1407

07.159

1396


Bornyl isovalerate

Isobornyl isovalerate

1,10-

Dihydronootkaton e d-Fenchone

O

Structural formula

O

O

O

O

O

_____

_____

EU MSDI 1)

US MSDI

(


0.12

0.5

0.012

0.08

0.6

0.9

6

5

Class 2)


Class I


Class I


Class II


Class II



[4) or 5)]

4)

4)

4)

4)

EFSA conclusion on the EFSA conclusion on the material of named compound

(Procedure steps, intake commerce estimates, NOAEL, genotoxicity)









Registername to be changed accordingly.


CASrn refers to (4R,4aS,6R,8aS)-stereoisomer.


According to JECFA: Min. assay value is "90%" and secondary components "5-6% nootkatone".


CASrn in the Register refers to (1S,4R)-isomer.

According to JECFA: Min. assay value is "97% of C10H16O" which may include small amounts of d-camphor.


1)

EU MSDI: Amount added to food as flavour in (kg / year) x 10E9 / (0.1 x population in Europe (= 375 x 10E6) x 0.6 x 365) = µg/capita/day.

2)

Thresholds of concern: Class I = 1800, Class II = 540, Class III = 90 µg/person/day.

3)

Procedure path A substances can be predicted to be metabolised to innocuous products. Procedure path B substances cannot.

4)

No safety concern based on intake calculated by the MSDI approach of the named compound.

5)

Data must be available on the substance or closely related substances to perform a safety evaluation.

ND: not determined

The EFSA Journal (2008) 746, 19-22


Table 3.1: Summary of Safety Evaluation Applying the Procedure (EFSA / FGE.47)

Table 2a: Summary of Safety Evaluation Applying the Procedure (based on intakes calculated by the MSDI approach)

FL-no EU Register name Structural formula

(

MSDI 1)

μ g/capita/day)

Class 2)



[4) or 5)]

Outcome on the material of commerce

[6), 7), or 8)]

Evaluation remarks

09.584 Isobornyl isobutyrate

O

O

O

O

0.085 Class I


4) 7)

09.848 (1S-endo)-1,7,7-

Trimethylbicyclo[2.2.1]heptan-2-ol acetate

O

O

_____

0.011 Class I


4) 7)

09.888 Isobornyl 2-methylbutyrate

O

O

_____

0.061 Class I


4) 7)

07.171 Isopinocamphone

O

0.024 Class II


4) 7)

1)

MSDI: Amount added to food as flavouring substance in (kg / year) x 10E9 / (0.1 x population in Europe (= 375 x 10E6) x 0.6 x 365) = µg/capita/day.

2)

Thresholds of concern: Class I = 1800, Class II = 540, Class III = 90 µg/person/day.

3)

Procedure path A substances can be predicted to be metabolised to innocuous products. Procedure path B substances cannot.

4) No safety concern based on intake calculated by the MSDI approach of the named compound.

5)

Data must be available on the substance or closely related substances to perform a safety evaluation.

6)

No safety concern at estimated level of intake of the material of commerce meeting the specification of Table 1 (based on intake calculated by the MSDI approach).

7)

Tentatively regarded as presenting no safety concern (based on intake calculated by the MSDI approach) pending further information on the purity of the material of commerce.

8)

No conclusion can be drawn due to lack of information on the purity of the material of commerce.

The EFSA Journal (2008) 746, 20-22


R

EFERENCES

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28, 248-258.

Cramer, G.M., Ford, R.A., Hall, R.L., 1978. Estimation of toxic hazard - a decision tree approach. Food Cosmet.

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EC, 1999a. Commission Decision 1999/217/EC of 23 February 1999 adopting a register of flavouring substances used in or on foodstuffs. Official Journal of the European Communities 27.3.1999, L 84, 1-137.

EC, 2000a. Commission Regulation No 1565/2000 of 18 July 2000 laying down the measures necessary for the adoption of an evaluation programme in application of Regulation (EC) No. 2232/96. Official Journal of the

European Communities 19.7.2000, L 180, 8-16.

EC, 2006. Commission Decision 2006/252/EC of 27 March 2006 amending Decision 1999/217/EC as regards the register of flavouring substances used in or on foodstuffs. Official Journal of the European Union 29.3.2006, L 91,

48.

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[Online]. Available: http://www.efsa.europa.eu/EFSA/Event_Meeting/afc_minutes_26thplen_en.pdf

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Committee on Food Additives. Geneva, 6-15 February 1996. WHO Technical Report Series, no. 868. Geneva.

JECFA, 1999b. Evaluation of certain food additives and contaminants. Forty-ninth report of the Joint FAO/WHO

Expert Committee on Food Additives. Rome, 17-26 June 1997. WHO Technical Report Series, no. 884. Geneva.

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Food Additives 63 rd session. Rome, 8-17 June 2004. FAO Food and Nutrition paper 52 Add. 12.

JECFA, 2005c. Evaluation of certain food additives. Sixty-third report of the Joint FAO/WHO Expert Committee on

Food Additives. WHO Technical Report Series, no. 928. Geneva, 8-17 June 2004.

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JECFA, 2006a. Safety evaluation of certain food additives and contaminants. Sixty-third meeting of the Joint

FAO/WHO Expert Committee on Food Additives, WHO Food Additives Series: 54. IPCS, WHO, Geneva.

JECFA, 2006b. Evaluation of certain food additives. Sixty-fifth report of the Joint FAO/WHO Expert Committee on

Food Additives. WHO Technical Report Series, no. 934. Geneva, 7-16 June 2005.

JECFA, 2006c. Joint FAO/WHO Expert Committee on Food Additives. Sixty-seventh meeting Rome, 20-29 June 2006,

Summary and Conclusions. Issued 7 July 2006.

SCF, 1999. Opinion on a programme for the evaluation of flavouring substances (expressed on 2 December 1999).

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34(3-4), 267-288. (In Japanese)

The EFSA Journal (2008) 746, 22-22

Article

Flavouring Group Evaluation 87, (FGE.87)

Consideration of bicyclic secondary alcohols, ketones and related esters evaluated by JECFA (63

meeting) structurally related to bicyclic secondary alcohols, ketones and related esters evaluated by EFSA in

FGE.47 (2008)

Scientific Opinion of the Panel on Food Additives,

Flavourings, Processing Aids and Materials in Contact with Food

Adopted on 22 May 2008

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Article

Flavouring Group Evaluation 87, (FGE.87)

Consideration of bicyclic secondary alcohols, ketones and related esters evaluated by JECFA (63

meeting) structurally related to bicyclic secondary alcohols, ketones and related esters evaluated by EFSA in

FGE.47 (2008)

Scientific Opinion of the Panel on Food Additives,

Flavourings, Processing Aids and Materials in Contact with Food

Adopted on 22 May 2008

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