Approaches to the Threshold of
Toxicological Concern
Clif McLellan
Director of Toxicology Services
NSF International
March 16, 2010
Overview of Presentation
Who is NSF and how do we use health based risk
assessments ?
Setting Health based criteria when no chemical
specific toxicology data is available.
Threshold of Evaluation
Threshold of Toxicological Concern
Class Based Evaluation Levels
NSF International
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Independent, private, not-for -profit organization
which provides third party services through
programs which focus on public health and
environmental quality
Test & certify products
Inspect production facilities
Register quality systems
Develop and maintain consensus standards; many
of which are related to drinking water and food
NSF Was Established In 1944 To
Develop Standards, And Test And
Certify Food Equipment.
- 3 public health experts
found the National
Sanitation Foundation
(NSF) in the University of
Michigan’s School of Public
Health 66 years ago.
- Initially serviced the food
industry
NSF International in 2010
- Developed more than 72 national consensus standards
- Utilize more that 200,000 square feet of laboratory space
for chemistry, engineering and microbiology
- Client base over 12,000 companies
- Certified more than 225,000 products made in more than
100 countries
Certification Process for Products
Contributing Direct or Indirect
Additives
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Review each material formulation to the individual chemical
level, to identify potential leachates based on material
formulations and manufacturing processes
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Perform material leachate tests based on established protocol
to match end use to potential contaminants
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Normalized test results to determine potential “at the tap”
contaminants for regulated and unregulated chemicals
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Determine whether the “at the tap” concentrations exceeds
health based criteria
What are the results of Material
Extraction Testing?
More than 2,500 different chemicals have been
identified as a result of material leachate tests.
- 41 have MCL’s
- 109 IRIS or Health Advisories
- 300 have sufficient toxicology data
- > 2000 insufficient data for assessment
Process of Setting Acceptance Criteria for
Unregulated Substances With Data
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Perform literature search for compound
Determine the quality of data
Use appropriate data to arrive at an RfD or Cancer
Risk Level, using the EPA guidelines
Internal Peer Review
External Peer Review
Publish on ITER and adoption for use in appropriate
standards
Total Allowable Concentration (TAC)
Total Allowable Concentration (Equivalent to a DWEL) is the
maximum concentration of a nonregulated expressed in mg/L and
calculated as follows:
RfD(mg/kg/day) x BW(70 kg) x Relative Source Contribution
(2 L/day)
Setting Health based criteria when no
chemical specific toxicology data is
available.
The Threshold of Evaluation
The Threshold of Toxicological Concern
Class Based Evaluation Levels
The Threshold of Evaluation (TOE)
The Threshold of Evaluation (TOE) is based on the FDA’s
Threshold of Regulation (TOR).
Prior to 1958, the Food Additives Amendment to the Federal
Food, Drug, and Cosmetic Act (FFDCA) considered all
substances food additives if they were found in food. As
analytical limits of detection improved, FDA had to come up
with a paradigm to address these low-level migrants. Thus
the Threshold of Regulation (TOR) was developed.
– In 1958, an exemption (Delaney Clause) was created which stated
that if a chemical was present at less than 0.5 ppb in food it was not
considered a food additive and would be exempt from the regulation.
To qualify for the exemption
– The substance could not be a known carcinogen
The Threshold of Evaluation (TOE)
The Threshold of Regulation of 0.5 ug/ kg food
or 1.5 ug/person/day was converted to a
drinking water concentration based on the
following conversion.
0.5 ug/ kg food/ day * (3 kg food / day) / (2 L
water / day) = 0.75 ug / L
The Threshold of Evaluation (TOE)
Exclusion to the use of The Threshold of
Evaluation
Not applied to any substance for which
available toxicity data and sound scientific
judgment such as structure activity relationships
indicate that an adverse health effect results at
these exposure concentrations.
Threshold of Toxicological Concern
(TTC)

The TTC approach is used as a substitute for evaluating health
risks in the absence of complete substance-specific health
effects data
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TTC risk assessments are based on an analysis of toxicological
and/or structural data of a broad range of different chemicals
including carcinogenic and non-carcinogenic endpoints

The TTC approach is used in the U.S. and Europe
– FDA allows the use of a TOR when evaluating health risks from food contact
materials (e.g., sandwich bags, retort cups)
– JECFA uses a TTC when evaluating health risks from food additives
“ Threshold of Toxicological
Concern” (TTC)
The Threshold of Toxicological Concern (TTC) is based on a
number of published papers.
Estimation of Toxic Hazard-A Decision Tree Approach (Cramer and Ford,
1978).
Correlation of Structural Class with No-Observed-Effects Levels:
A Proposal for Establishing a Threshold of Concern (Munro et al., 1996)
A Tiered Approach to the Threshold of Regulation (Cheeseman et al.,
1999)
Structure Based Thresholds of Toxicology Concern (TTC): Guidance for
the applications of substances present at low levels in the Diet (Kroes et
al., 2004)
Threshold of Toxicological Concern
(Noncancer)
The first steps is a determination of the structural
classes identified according to the Cramer et al. (1978)
decision tree
– Class I – Simple chemicals, efficient metabolism, low oral
toxicity
– Class II – May contain reactive functional groups, slightly
more toxic than Class I
– Class III – Substances that have structural features that
permit no strong initial presumption of safety or may even
suggest significant toxicity
– Organophoshates (Added Munro et al. (1999))
Step One: TTC Approach (Noncancer)
The Cramer et al. (1978) decision tree comprises 33 questions related to chemical
structure, functional groups, and source of the chemical
Threshold of Toxicological Concern
(Noncancer)
For each group, the 5th percentile of the distribution of NOELs
from the subchronic and chronic animal studies were determined.
The NOELs from the chronic study were divided by a 100-fold
safety factor and the NOELs from the subchronic studies were
divided by a 300-fold safety factor. Body weight of 60 kg was
used.
Group
# of
compounds
Human Exposure Thresholds
(ug/kg/day)
1
137
1800
2
28
540
3
448
90
Organophosphates
31
18
Threshold of Toxicological Concern
(Cancer)
FDA’s TOR was reviewed by Rulis et al. (1986,
1989) and extended by Cheeseman et al. (1999)
– A threshold value of 0.5 ppb in the diet based on
carcinogenic potencies of 500 substances from 3500
experiments of Gold et al.’s (1984, 1989) Carcinogenic
Potency Database
– The distribution of chronic dose rates [mg/kg bw/day] that
would induce tumors in 50% of test animals (TD50s) was
plotted
– This distribution was extrapolated to a Virtually Safe Dose
(10-6 risk of cancer) in humans
Kroes Decision-Tree (Kroes et al., 2004)
TTC
Acceptable Drinking Water Levels Calculation
Group
Total Allowable Concentration (ug/L)
1
200
2
50
3
10
Organophosphates
2
Carcinogens
0.6
[X] µg/person/day x 0.20
2 L/person (60 kg/ 70 kg)
= acceptable level in mg/L
Where:
–
–
–
X = 1800 µg/day for class I compounds, 540 µg/day for class II compounds, and 90 µg/day for class III compounds
Relative Source Contribution = 0.2
Drinking water intake = 2 L/day
–
Human body weight of 70 kg
Analysis of TTC against Previously
Established Risk Levels
Procedure:
NSF evaluated each EPA and NSF established risk level against the TTC
approach to compare the established risk level with what would have been
derived if no information was available for that compound.
Limitations using the TTC approach:
1.
TTC does not address a number of chemical classes. Not all functional groups
are included in the classification scheme.
2.
Naming convention used in scheme does not follow IUPAC nomenclature and
can be ambiguous.
3.
Halogenated compounds may result in underestimated values. The toxicity
class that would allow an acceptance level which exceeds potential health
effects.
4.
It is possible to interpret questions differently and arrive at a different Cramer
class classification. Inconsistencies are possible between reviewers.
Class Based Evaluation Levels (CBEL)
Establishment of the chemical class
The chemical class shall consist of a clearly
defined and closely related group of
substances, and shall be defined according to
chemical structure (e. g., aliphatic or
aromatic), primary chemical functional
group(s) (e. g., alcohol, aldehyde, or ketone),
and molecular weight or weight range.
Class Based Evaluation Levels (CBEL)
Review of all toxicity information for each chemical in the
class including all risk values including:
–
USEPA risk assessments, including MCL’s, Health
Advisories and IRIS entries,
– Health Canada risk assessments,
– risk assessments previously performed to the
requirements of annex A;
– state or provincial drinking water standards and
guidelines; and
– World Health Organization (WHO) or other international
drinking water standards and guidelines.
Class Based Evaluation Levels (CBEL)
Review of chemical class toxicity information
Carcinogenic potential shall be evaluated using
QSAR (e. g., OncoLogic®) and all other non
cancer data shall be evaluated to verify that the
toxicity potential of the chemical without data is no
greater than that of the chemicals being used to
define the class-based evaluation criteria.
Class Based Evaluation Levels (CBEL)
Determination of the class-based evaluation
criteria
The class-based evaluation criteria shall not
exceed the lowest MCL or TAC in the defined
chemical class until such time as sufficient toxicity
data are available to determine chemical-specific
evaluation criteria.
EXAMPLE:
Aliphatic glycol ethers and their acetates
This CBEL class includes aliphatic glycol ethers and
their acetates with constituents of methoxy, ethoxy,
propoxy and butoxy groups as part of the general
identification as a glycol ether also including the
corresponding methyl, ethyl, propyl and butyl
acetates.
This class also includes compounds identified as
ethyl, propyl or butyl isomers or -ethyl, -propyl or –
butyl glycols polymers, oligomers and dimers.
Chemicals Identified to be Included
in This Class
.
107-98-2
Propylene glycol monomethyl ether
24800-44-0
Tripropylene Glycol
108-65-6
Methoxypropylacetate
2516-93-0
2-Butoxyacetic Acid
109-86-4
2-methoxyethanol
110-71-4
Ethylene Glycol Dimethyl Ether
25265-71-8
Dipropylene Glycol
110-80-5
2-ethoxyethanol
25322-68-3
Polyethylene Glycol
111-15-9
Ethylene Glycol Monoethyl Ether Acetate
25322-69-4
Polypropylene Glycol
111-46-6
Diethylene Glycol
2807-30-9
Ethylene Glycol Monopropyl Ether
111-55-7
Ethylene Glycol Diacetate
29387-86-8
Propylene Glycol Monobutyl Ether
111-76-2
Ethylene Glycol Mono-N-Butyl Ether
29911-28-2
Dipropylene Glycol Butyl Ether
111-77-3
Diethylene Glycol Monomethyl Ether
34590-94-8
Dipropylene Glycol Monomethyl Ether
111-90-0
Diethylene Glycol Monoethyl Ether
4792-15-8
Pentaethylene Glycol
111-96-6
Diethylene Glycol Dimethyl Ether
5131-66-8
Propylene Glycol Butyl Ether (a-isomer)
112-27-6
Triethylene Glycol
52125-53-8
Propylene glycol monoethyl ether
112-34-5
Diethylene Glycol Mono-N-Butyl Ether
(butoxyethoxyethanol)
54518-04-6
Dibutoxymethanol
112-35-6
Methoxy Triethylene Glycol
57018-52-7
Propylene Glycol T- Butyl Ether
Polybutyleneoglycol- Multiple CAS#'s
Chemicals Identified to be Included
in This Class
.
112-50-5
Ethoxytriethylene Glycol
57-55-6
Propylene Glycol
112-60-7
Tetraethylene Glycol
60-29-7
Ethyl ether
112-73-2
Diethylene Glycol Dibutyl Ether
629-14-1
Ethylene Glycol Diethyl Ether
12002-25-4
Dipropyleneglycol Methyl Ether
68551-13-3
Alcohols, C12-C15, ethoxylated
propoxylated
Diethylene Glycol Monobutyl Ether
Acetate
6881-94-3
Diethylene Glycol Monopropyl Ether
Dipropylene Glycol Monomethyl Ether
73467-18-2
Tetrapropylene Glycol, Methyl Ester
142-96-1
Dibutyl Ether
74367-33-2
Methyl propanoic acid, dimethyl (hydroxy
methylethyl) propyl ester
143-22-6
Triethylene Glycol Butyl Ether
7580-85-0
Ethylene Glycol, Mono-Tert-Butyl Ether
Polyethylene glycol monobutyl ether
7795-91-7
Ethylene Glycol -Sec Butyl Ether
15764-24-6
Dipropylene Glycol, Ethyl Ether
9003-13-8
Polypropylene Glycol Butyl Ether
15821-83-7
Propylene glycol butyl ether (b-isomer)
9004-74-4
Polyethylene Glycol, Monomethyl Ether
1638-16-0
Tripropylene Glycol
9004-81-3
Polyethylene Glycols Monolaurate
20178-34-1
Tripropylene Glycol Butyl Ether
20324-33-8
Tripropylene Glycol Methyl Ether
124-17-4
13429-07-7
151911-67-0
95-08-9
98516-30-4
Bis (2-Ethylbutyrate) Triethylene Glycol
Propylene Glycol Acetate Ethyl Ether
Surrogates with Quantitative Risk Assessment
Values
.
Key Study Information on the Selected Surrogates
Surrogate
Critical Effect
Departure
Point
mg/kg-day
Dipropylene
A LOAEL was not
1000
glycol n-butyl
identified
(NOAEL)
Propylene glycol n-A LOAEL was not
1000
butyl ether
identified
(NOAEL)
Depressed body
500
weight
(NOAEL)
Ethyl ether
Ethylene glycol Changes in mean
5.1
mono-n-butyl
corpuscular volume
(PBPK and
ether
BMD 05)
Methoxypropyl
A LOAEL was not
1000
acetate
identified
(NOAEL)
UF
Oral RfD Reference
mg/kg-day
3000x
0.3
NSF, 2002
3000x
0.3
NSF, 2002
3000x
0.2
10
0.5
1000
1
USEPA,
1988
NSF, 1998
USEPA,
Total Allowable Concentration (TAC) for
Aliphatic glycol ethers and their acetates
based on ethyl ether
RfD(mg/kg/day) x BW(70 kg) – total contribution of other sources(mg/day)
DWI (2 L/day)
0.2 (mg/kg/day) x BW(70 kg) * 0.2 (RSC)
DWI (2 L/day)
= 1.4 (mg/kg/day) rounded to 1 (mg/kg/day)
Other CBEL’s that have been
developed at NSF
Aliphatic hydrocarbons including alkanes, alkenes, and cyclic compounds.
Aliphatic diols (1,6-hexanediol, etc.)
Aliphatic and alicyclic alcohols (n-butanol, n-heptanol, n-octanol, etc.)
Aliphatic ketones (Decanone, heptanone, hexanone, etc.)
Alkyl substituted phenolics (2-tert-butyl-phenol, 4-nonyl-phenol, 3,5-dimethylphenol,
etc.)
Fatty acid ester (methyl adipate, dimethyl adipate)
Isothiocyanates, alkyl substituted (Isobutyl-isothiocyanate, n-butyl isothiocyanate, etc.)
Naphtha-derived alkylated benzenes, C8-C10 (n-butyl benzene, n-propyl benzene, etc.)
Phthalate esters
Quinolines, alkyl substituted ( Methyl quinoline, dimethyl quinoline, trimethyl quinoline,
etc.)
Questions???