[Code of Federal Regulations]
[Title 16, Volume 2]
[Revised as of January 1, 2007]
From the U.S. Government Printing Office via GPO Access
[CITE: 16CFR1500.135]

[Page 489-495]
 
                     TITLE 16--COMMERCIAL PRACTICES
 
             CHAPTER II--CONSUMER PRODUCT SAFETY COMMISSION
 
PART 1500_HAZARDOUS SUBSTANCES AND ARTICLES; ADMINISTRATION AND 
ENFORCEMENT REGULATIONS--Table of Contents
 
Sec.  1500.135  Summary of guidelines for determining chronic toxicity.

    A substance may be toxic due to a risk of a chronic hazard. (A 
regulatory definition of ``toxic'' that pertains to chronic toxicity may 
be found at 16 CFR 1500.3(c)(2).) The following discussions are intended 
to help clarify the complex issues involved in assessing risk from 
substances that may potentially cause chronic hazards and, where 
possible, to describe conditions under which substances should be 
considered toxic due to a risk of the specified chronic hazards. The 
guidelines are not intended to be a static classification system, but 
should be considered along with available data and with expert judgment. 
They are not mandatory. Rather, the guidelines are intended as an aid to 
manufacturers in determining whether a product subject to the FHSA 
presents a chronic hazard. All default assumptions contained in the 
guidelines on hazard and risk determination are subject to replacement 
when alternatives which are supported by appropriate data become 
available. The following are brief summaries of more extensive 
discussions contained in the guidelines. Thus, the guidelines should be 
consulted in conjunction with these summaries. Copies of the guidelines 
may be obtained from the Office of Compliance and Enforcement, Consumer 
Product Safety Commission, Washington, DC 20207. (In addition to the 
chronic hazards discussed below, issues relating to the chronic hazard 
of

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sensitization are discussed in 16 CFR 1500.3(c)(5).)
    (a) Carcinogenicity. Substances are toxic by reason of their 
potential carcinogenicity in humans when they are known or probable 
human carcinogenic substances as defined below. Substances that are 
possible human carcinogenic substances or for which there is no evidence 
of carcinogenic effect under the following categories lack sufficient 
evidence to be considered toxic by virtue of their potential 
carcinogenicity.
    (1) Known Human carcinogenic Substances (``sufficient evidence'' in 
humans). Substances are toxic by reason of their carcinogenicity when 
they meet the ``sufficient evidence'' criteria of carcinogenicity from 
studies in humans, which require that a causal relationship between 
exposure to an agent and cancer be established. This category is similar 
to the Environmental Protection Agency's (EPA) Group A, the 
International Agency for Research on Cancer's (IARC) Group 1, or the 
American National Standards Institute's (ANSI) Category 1. A causal 
relationship is established if one or more epidemiological 
investigations that meet the following criteria show an association 
between cancer and exposure to the agent.
    (i) No identified bias that can account for the observed association 
has been found on evaluation of the evidence.
    (ii) All possible confounding factors which could account for the 
observed association can be ruled out with reasonable confidence.
    (iii) Based on statistical analysis, the association has been shown 
unlikely to be due to chance.
    (2) Probable Human Carcinogenic Substances. Substances are also 
toxic by reason of their probable carcinogenicity when they meet the 
``limited evidence'' criteria of carcinogenicity in humans or the 
``sufficient evidence'' criteria of carcinogenicity in animals described 
below. This category is similar to EPA's Group B, IARC's Group 2, or 
ANSI's Categories 2 and 3. Evidence derived from animal studies that has 
been shown not to be relevant to humans is not included. For example, 
such evidence would result when there was an identified mechanism of 
action for a chemical that causes cancer in animals that has been shown 
not to apply to the human situation. It is reasonable, for practical 
purposes, to regard an agent for which there is ``sufficient'' evidence 
of carcinogenicity in animals as if it presented a carcinogenic risk to 
humans.
    (i) ``Limited evidence'' of carcinogenicity in humans. The evidence 
is considered limited for establishing a causal relationship between 
exposure to the agent and cancer when a causal interpretation is 
credible, but chance, bias, or other confounding factors could not be 
ruled out with reasonable confidence.
    (ii) ``Sufficient evidence'' of carcinogenicity in animals. 
Sufficient evidence of carcinogenicity requires that the substance has 
been tested in well-designed and -conducted studies (e.g., as conducted 
by National Toxicology Program (NTP), or consistent with the Office of 
Science Technology Assessment and Policy (OSTP) guidelines) and has been 
found to elicit a statistically significant (p <0.05) exposure-related 
increase in the incidence of malignant tumors, combined malignant and 
benign tumors, or benign tumors if there is an indication of the ability 
of such benign tumors to progress to malignancy:
    (A) In one or both sexes of multiple species, strains, or sites of 
independent origin; or experiments using different routes of 
administration or dose levels; or
    (B) To an unusual degree in a single experiment (one species/strain/
sex) with regard to unusual tumor type, unusual tumor site, or early age 
at onset of the tumor.

The presence of positive effects in short-term tests, dose-response 
effects data, or structure-activity relationship are considered 
additional evidence.
    (3) Possible Human Carcinogenic Substance (``limited evidence'' 
animal carcinogen). In the absence of ``sufficient'' or ``limited'' 
human data, agents with ``limited'' evidence of carcinogenicity from 
animal studies fall into this category. Such substances, and those that 
do not fall into any other group, are not considered ``toxic.'' This 
does not imply that the substances are or are

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not carcinogens, only that the evidence is too uncertain to provide for 
a determination. This category is similar to EPA's Group C, IARC's Group 
3, or ANSI's category 4.
    (b) Neurotoxicity. Substances are toxic by reason of their potential 
neurotoxicity in humans when they meet the ``sufficient evidence'' or 
``limited evidence'' criteria of neurotoxicity in humans, or when they 
meet the ``sufficient evidence'' criteria of neurotoxicity in animals.
    (1) Known Neurotoxic Substances (``sufficient evidence in humans''). 
Substances are toxic by reason of their neurotoxicity and are considered 
``known neurotoxic substances'' when they meet the ``sufficient 
evidence'' criteria of neurotoxicity derived from studies in humans 
which require that a causal association between exposure to an agent and 
neurotoxicity be established with a reasonable degree of certainty. 
Substances in this category meet the definition of ``neurotoxic'' as 
stated above. ``Sufficient evidence,'' derived from human studies, for a 
causal association between exposure to a chemical and neurotoxicity is 
considered to exist if the studies meet the following criteria.
    (i) A consistent pattern of neurological dysfunction is observed.
    (ii) The adverse effects/lesions account for the neurobehavioral 
dysfunction with reasonable certainty.
    (iii) All identifiable bias and confounding factors are reasonably 
discounted after consideration.
    (iv) The association has been shown unlikely to be due to chance, 
based on statistical analysis.
    (2) Probable Neurotoxic Substances. Substances are also toxic by 
reason of their probable neurotoxicity when they meet the ``limited 
evidence'' criteria of neurotoxicity in humans, or the ``sufficient 
evidence'' criteria derived from animal studies. Evidence derived from 
animal studies that has been shown not to be relevant to humans is not 
included. Such evidence would result, for example, when there was an 
identified mechanism of action for a chemical that causes neurotoxicity 
in animals that has been shown not to apply to the human situation.
    (i) ``Limited evidence'' of neurotoxicity in humans. The evidence 
derived from human studies is considered limited for neurotoxicity when 
the evidence is less than convincing, i.e., one of the criteria of 
``sufficient evidence'' of neurotoxicity for establishing a causal 
association between exposure to the agent and neurotoxicity is not met, 
leaving some uncertainties in establishing a causal association.
    (ii) ``Sufficient evidence'' of neurotoxicity in animals. Sufficient 
evidence of neurotoxicity derived from animal studies for a causal 
association between exposure to a chemical and neurotoxicity requires 
that:
    (A) The substance has been tested in well-designed and -conducted 
studies (e.g., NTP's neurobehavioral battery, or conforming to EPA's 
neurotoxicity test guidelines); and
    (B) The substance has been found to elicit a statistically 
significant (p <0.05) increase in any neurotoxic effect in one or both 
sexes of multiple species, strains, or experiments using different 
routes of administration and dose-levels.
    (3) Possible Neurotoxic Substances. ``Possible neurotoxic 
substances'' are the substances which meet the ``limited evidence'' 
criteria of neurotoxicity evidence derived from animal studies in the 
absence of human data, or in the presence of inadequate human data, or 
data which do not fall into any other group. Substances in this category 
are not considered ``toxic.''
    (c) Developmental and Reproductive Toxicity--(1) Definitions of 
``Sufficient'' and ``Limited'' Evidence. The following definitions apply 
to all categories stated below.
    (i) ``Sufficient evidence'' from human studies for a causal 
association between human exposure and the subsequent occurrence of 
developmental or reproductive toxicity is considered to exist if the 
studies meet the following criteria:
    (A) No identified bias that can account for the observed association 
has been found on evaluation of the evidence.
    (B) All possible confounding factors which could account for the 
observed association can be ruled out with reasonable confidence.

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    (C) Based on statistical analysis, the association has been shown 
unlikely to be due to chance.
    (ii) ``Limited evidence'' from human studies exists when the human 
epidemiology meets all but one of the criteria for ``sufficient 
evidence''; i.e., the statistical evidence is borderline as opposed to 
clear-cut, there is a source of bias, or there are confounding factors 
that have not been and cannot be accounted for.
    (iii) ``Sufficient evidence'' from animal studies exists when
    (A) Obtained from a good quality animal study; and
    (B) The substance has been found to elicit a statistically 
significant (p<0.05) treatment-related increase in multiple endpoints in 
a single species/strain, or in the incidence of a single endpoint at 
multiple dose levels or with multiple routes of administration in a 
single species/strain, or increase in the incidence of a single endpoint 
in multiple species/strains/ experiments.
    (iv) ``Limited evidence'' from animal studies exists when:
    (A) Obtained from a good quality study and there is a statistically 
significant (p<0.05) treatment-related increase in the incidence of a 
single endpoint in a single species/strain/experiment at a single dose 
level administered through only one route and such evidence otherwise 
does not meet the criteria for ``sufficient evidence''; or
    (B) The evidence is derived from studies which can be interpreted to 
show positive effects but have some qualitative or quantitative 
limitations with respect to experimental procedures (e.g., doses, 
exposure, follow-up, number of animals/group, reporting of the data, 
etc.) which would prevent classification of the evidence in the group of 
``sufficient evidence.''
    (2) Developmental Toxicants. Substances are toxic by reason of their 
potential developmental or reproductive toxicity when they meet the 
``sufficient evidence'' or ``limited evidence'' criteria of 
developmental or reproductive toxicity in humans, or when they meet the 
``sufficient evidence'' criteria of developmental or reproductive 
toxicity in animals. The Food and Drug Administration (FDA) and the 
European Economic Community (EEC) have developed categories for 
teratogens but not other developmental toxicants. The teratogen 
guidelines limit the information only to structural birth defects and do 
not include other hazards of developmental toxicity such as embryonal 
death, fetal death, or functional deficiencies which are also important 
in assessing the overall toxicity of a substance when administered 
during pregnancy. Recently, EPA has proposed a system for classifying 
developmental toxicity. The Occupational Safety and Health 
Administration (OSHA) has not yet developed any classification for 
developmental toxicity. The commission has established the following 
categories for determination of developmental toxicity according to the 
available evidence.
    (i) Known Human Developmental Toxicant (``sufficient evidence in 
humans''). A substance is considered a ``known human developmental 
toxicant'' if there is ``sufficient'' human evidence to establish a 
causal association between human exposure and the subsequent occurrence 
of developmental toxicity manifested by death of the conceptus (embryo 
or fetus), or structural or functional birth defects. This category 
(Human Developmental Toxicant) is comparable to category 1 of the EEC 
and categories D and X of FDA, except that these guidelines are limited 
to teratogens. This category is also comparable to the category 
``definitive evidence for human developmental toxicity'' proposed by 
EPA.
    (ii) Probable Human Developmental Toxicant. A substance is 
considered a ``probable human developmental toxicant'' if there is 
``limited'' human evidence or ``sufficient'' animal evidence to 
establish a causal association between human exposure and subsequent 
occurrence of developmental toxicity. This group (Probable Human 
Developmental Toxicant) is comparable to the category ``adequate 
evidence for human developmental toxicity'' proposed by EPA. This 
category is also comparable to category 2 of the EEC and category A1 of 
FDA, except that these guidelines are limited to teratogens.
    (iii) Possible Human Developmental Toxicant. A substance is 
considered a

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``possible human developmental toxicant'' if there is ``limited'' animal 
evidence, in the absence of human data, or in the presence of inadequate 
human data, or which does not fall into any other group, to establish a 
causal association between human exposure and subsequent occurrence of 
developmental toxicity. EEC, FDA, and EPA have not developed a category 
comparable to this group. The Commission believes that data from well 
planned animal studies are important to consider even though they may 
provide only limited evidence of developmental toxicity.
    (3) Male Reproductive Toxicants. Male reproductive toxicants can be 
grouped into the following different categories based on evidence 
obtained from human or animal studies.
    (i) Known Human Male Reproductive Toxicant. A substance is 
considered a ``known human male reproductive toxicant'' if there is 
``sufficient'' human evidence to establish a causal association between 
human exposure and the adverse effects on male reproductive main 
endpoints which are mating ability, fertility, and prenatal and 
postnatal development of the conceptus. This category is comparable to 
the one termed ``Known Positive'' in the EPA guidelines on male 
reproductive risk assessment.
    (ii) Probable Human Male Reproductive Toxicant. A substance is 
considered a ``probable human male reproductive toxicant'' if there is 
``limited'' human evidence or ``sufficient'' animal evidence to 
establish a causal association between human exposure and the adverse 
effects on male reproductive main endpoints. This category is comparable 
to the one termed ``Probable Positive'' in the EPA guidelines on male 
reproductive risk assessment. However, the EPA category is based only on 
sufficient animal evidence. CPSC believes that limited human evidence is 
also sufficient for a chemical to be placed in this category.
    (iii) Possible Human Male Reproductive Toxicant. A substance is 
considered a ``possible human male reproductive toxicant'' if there is 
limited animal evidence, in the absence of human data, or in the 
presence of inadequate human data, or which does not fall into any other 
group, to establish a causal association between human exposure and 
adverse effects on male reproductive main endpoints. This category is 
comparable to the one termed ``Possible Positive A'' in the EPA 
guidelines on male reproductive risk assessment. EPA proposes to use 
either limited human or limited animal evidence data to classify a 
toxicant as a ``Possible Positive A'' toxicant. As described above, CPSC 
would elevate limited human evidence to the category ``Probable Human 
Male Reproductive Toxicant.''
    (4) Female Reproductive Toxicants. Female reproductive toxicants can 
be grouped into the following different categories based on evidence 
obtained from human or animal studies. EPA has proposed guidelines for 
assessing female reproductive risk but has not yet proposed a specific 
system for categorization of female reproductive toxicants.
    (i) Known Human Female Reproductive Toxicant. A substance is 
considered a ``known human female reproductive toxicant'' if there is 
``sufficient'' human evidence to establish a causal association between 
human exposure and adverse effects on female reproductive function such 
as mating ability, fertility, and prenatal and postnatal development of 
the conceptus.
    (ii) Probable Human Female Reproductive Toxicant. A substance is 
considered a ``probable human female reproductive toxicant'' if there is 
``limited'' human evidence or ``sufficient'' animal evidence to 
establish a causal association between human exposure and adverse 
effects on female reproductive function.
    (iii) Possible Human Female Reproductive Toxicant. A substance is 
considered a ``possible human female reproductive toxicant'' if there is 
``limited'' animal evidence, in the absence of human data, or in the 
presence of inadequate human data, or which does not fall into any other 
group, to establish a causal association between human exposure and 
adverse effects on female reproductive function.
    (d) Other Subjects Related to the Determination that a Substance is 
Toxic. Under the FHSA, for a toxic substance to be considered hazardous, 
it must not

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only have the potential to be hazardous but there must also be the 
potential that persons are exposed to the substance, that the substance 
can enter the body, and that there is a significant risk of an adverse 
health effect associated with the customary handling and use of the 
substance. Under these guidelines, existence of an adverse health effect 
means that such exposure is above the ``acceptable daily intake'' 
(``ADI''). The ADI is based on the risks posed by the substance, and 
whether they are acceptable under the FHSA. This section addresses those 
issues by providing guidelines concerning assessment of exposure, 
assessment of bioavailability, determination of acceptable risks and the 
ADI to children and adults, and assessment of risk.
    (1) Assessment of Exposure. An exposure assessment may comprise a 
single exposure scenario or a distribution of exposures. Reasonably 
foreseeable use, as well as accidental exposure, should be taken into 
consideration when designing exposure studies. The following guidelines 
should be used in the assessment of exposure.
    (i) Inhalation. Inhalation studies to assess exposure should be 
reliable studies using direct monitoring of populations, predictions of 
exposure through modeling, or surrogate data.
    (A) Direct Monitoring. Populations to be monitored should be 
selected randomly to be representative of the general population, unless 
the exposure of a particular subset population is the desired goal of 
the assessment. The monitoring technique should be appropriate for the 
health effect of interest.
    (B) Modeling. Predictions of exposure to a chemical using 
mathematical models can be based on physical and chemical principles, 
such as mass balance principles. Mass balance models should consider the 
source strength of the product of interest, housing characteristics, and 
ambient conditions likely to be encountered by the studied population.
    (C) Surrogate Data. Surrogate data should only be used when data 
concerning the chemical of interest are sparse or unavailable and when 
there is a reasonable assurance that the surrogate data will accurately 
represent the chemical of interest.
    (ii) Oral Ingestion. Oral ingestion studies may involve direct 
monitoring of sources of chemicals as well as laboratory simulations. 
The estimation of exposure from ingestion of chemicals present in 
consumer products is predicted based upon estimates of use of the 
product and absorption of the chemical from the gastrointestinal tract. 
The following criteria should be established for laboratory simulations 
to estimate exposure:
    (A) A simulant or range of simulants should be carefully selected to 
mimic the possible range of conditions which occur in humans, such as 
full and empty stomachs, or various saliva compositions at different 
times of the day.
    (B) The mechanical action to which a product is submitted must be 
chosen to represent some range of realistic conditions to which a human 
may subject the product.
    (iii) Dermal Exposure. (A) Dermal exposure involves estimating the 
amount of substance contacting the skin. This may involve experiments 
measuring the amount of material leached from a product contacting a 
liquid layer which interfaces with the skin, or the amount of substance 
which migrates from a product (in solid or liquid form) which is in 
contact with the skin.
    (B) Parameters to be considered include: Surface area of the skin 
contacted, duration of contact, frequency of contact, and thickness of a 
liquid interfacial layer.
    (2) Assessment of Bioavailability. (i) The need to consider 
bioavailability in estimating the risk from use of a product containing 
a toxic substance only arises when it is anticipated that the absorption 
characteristics of a substance to which there is human exposure will 
differ from those characteristics for the substance tested in the 
studies used to define the dose-response relationship.
    (ii) In determining the need to assess bioavailability, the factors 
to be examined include:
    (A) The physical or chemical form of the substance,
    (B) The route of exposure (inhalation, ingestion, or through the 
skin),
    (C) The presence of other constituents in the product which 
interfere

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with or alter absorption of the toxic substance, and
    (D) Dose.
    (3) Assessment of Risk. This section on quantitative risk assessment 
applies to estimates of risk for substances that are toxic by reason of 
their carcinogenicity.
    (i) Generally, the study leading to the highest risk should be used 
in the risk assessment; however, other factors may influence the choice 
of study.
    (ii) Risk should be based on the maximum likelihood estimate from a 
multistage model (such as Global83 or later version) unless the maximum 
likelihood estimate is not linear at low dose, in which case the 95% 
upper confidence limit on risk should be used.
    (iii) For systemic carcinogens, if estimates of human risk are made 
based on animal data, a factor derived from dividing the assumed human 
weight (70 kg) by the average animal weight during the study and taking 
that to the \1/3\ power should be used. There is the possibility that 
this factor may be changed, using the \1/4\ power instead of the \1/3\ 
power, as part of a unified Federal regulatory approach. If such an 
approach is adopted, it will apply here.
    (iv) When dose is expressed as parts per million, and the carcinogen 
acts at the site of contact, humans and animals exposed to the same 
amount for the same proportion of lifetime should be assumed to be 
equally sensitive.
    (v) If no experimental study having the same route of exposure as 
that anticipated for human use of a substance is available, a study by 
another route of exposure may be used. Pharmacokinetic methods may be 
used if sufficient data are available.
    (vi) When exposure scenarios are different from those used in the 
underlying study upon which estimates of risk are based, proportionality 
should be applied. If pharmacokinetic methods are used to adjust for 
risks at high versus low exposure levels, level-time measures should not 
be combined without taking the non-linearity into account.
    (4) Acceptable Risks--(i) ADI for Carcinogens. The maximum 
acceptable daily intake (``ADI'') is that exposure of a toxic (by virtue 
of its carcinogenicity) substance that is estimated to lead to a 
lifetime excess risk of one in a million. Exposure refers to the 
anticipated exposure from normal lifetime use of the product, including 
use as a child as well as use as an adult.
    (ii) ADI for Neurotoxicological and Developmental/Reproductive 
Agents. Due to the difficulties in using a numerical risk assessment 
method to determine risk for neurotoxicological or developmental/
reproductive toxicants, the Commission is using a safety factor 
approach, as explained below.
    (A) Human Data. If the hazard is ascertained from human data, a 
safety factor of ten will be applied to the lowest No Observed Effect 
Level (``NOEL'') seen among the relevant studies. If no NOEL can be 
determined, a safety factor of 100 will be applied to the Lowest 
Observed Effect Level (``LOEL''). Both the NOEL and LOEL are defined in 
terms of daily dose level.
    (B) Animal Data. If the hazard is ascertained from animal data, a 
safety factor of one hundred will be applied to the lowest NOEL. If no 
NOEL can be determined, a safety factor of one thousand will be applied 
to the lowest LOEL. Both the NOEL and LOEL are defined in terms of daily 
dose level.

[57 FR 46665, Oct. 9, 1992]