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The
mandatory criteria for classification of a chemical for carcinogenicity
under HCS (§1910.1200) are found in Appendix A.6 to this
section. This non-mandatory Appendix provides additional guidance
on hazard classification for carcinogenicity. Part A of Appendix
F includes background guidance provided by GHS based on the
Preamble of the International Agency for Research on Cancer
(IARC) “Monographs on the Evaluation of Carcinogenic
Risks to Humans” (2006). Part B provides IARC classification
information. Part C provides background guidance from the
National Toxicology Program (NTP) “Report on Carcinogens”
(RoC), and Part D is a table that compares GHS carcinogen
hazard categories to carcinogen classifications under IARC
and NTP, allowing classifiers to be able to use information
from IARC and NTP Roc carcinogen classifications to complete
their classifications under the GHS, and thus the HCS.
Part
A: Background Guidance (The
text of Appendix F, Part A, on the IARC Monographs, is paraphrased
from the 2006 Preamble to the “Monographs on the Evaluation
of Carcinogenic Risks to Humans”; the Classifier is referred
to the full IARC Preamble for the complete text. The text
is not part of the agreed GHS text on the harmonized system
developed by the OECD Task Force-HCL.)
As noted in Footnote 6 of Appendix
A.6. to this section, the GHS includes as guidance for classifiers
information taken from the Preamble of the International Agency
for Research on Cancer (IARC) “Monographs on the Evaluation
of Carcinogenic Risks to Humans” (2006), providing guidance
on the evaluation of the strength and evidence of carcinogenic
risks to humans. This guidance also discusses some additional
considerations in classification and an approach to analysis,
rather than hard-and-fast rules. Part A is consistent with
Appendix A.6, and should help in evaluating information to
determine carcinogenicity.
Carcinogenicity in humans:
The evidence relevant to carcinogenicity
from studies in humans is classified into one of the following
categories:
(a) Sufficient evidence
of carcinogenicity: A causal relationship has been
established between exposure to the agent and human cancer.
That is, a positive relationship has been observed between
the exposure and cancer in studies in which chance, bias
and confounding could be ruled out with reasonable confidence.
(b) Limited evidence
of carcinogenicity: A positive association has been
observed between exposure to the agent and cancer for which
a causal interpretation is considered by the Working Group
to be credible, but chance, bias or confounding could not
be ruled out with reasonable confidence.
In some instances, the above
categories may be used to classify the degree of evidence
related to carcinogenicity in specific organs or tissues.
Carcinogenicity in experimental
animals:
The evidence relevant to carcinogenicity
in experimental animals is classified into one of the following
categories:
(a) Sufficient evidence
of carcinogenicity: A causal relationship has been
established between the agent and an increased incidence
of malignant neoplasms or of an appropriate combination
of benign and malignant neoplasms in two or more species
of animals or two or more independent studies in one species
carried out at different times or in different laboratories
or under different protocols. An increased incidence of
tumors in both sexes of a single species in a well-conducted
study, ideally conducted under Good Laboratory Practices,
can also provide sufficient evidence. Exceptionally, a single
study in one species and sex might be considered to provide
sufficient evidence of carcinogenicity when malignant neoplasms
occur to an unusual degree with regard to incidence, site,
type of tumor or age at onset, or when there are strong
findings of tumors at multiple sites.
(b) Limited evidence of carcinogenicity: The
data suggest a carcinogenic effect but are limited for making
a definitive evaluation because, e.g. the evidence of carcinogenicity
is restricted to a single experiment; there are unresolved
questions regarding the adequacy of the design, conduct
or interpretation of the studies; the agent increases the
incidence only of benign neoplasms or lesions of uncertain
neoplastic potential; or the evidence of carcinogenicity
is restricted to studies that demonstrate only promoting
activity in a narrow range of tissues or organs.
Guidance on how to consider
important factors in classification of carcinogenicity (See
Reference Section)
The weight of evidence analysis called for in GHS and the
HCS (§1910.1200) is an integrative approach that considers
important factors in determining carcinogenic potential along
with the strength of evidence analysis. The IPCS “Conceptual
Framework for Evaluating a Mode of Action for Chemical Carcinogenesis”
(2001), International Life Sciences Institute (ILSI) “Framework
for Human Relevance Analysis of Information on Carcinogenic
Modes of Action” (Meek, et al., 2003; Cohen et al., 2003,
2004), and Preamble to the IARC Monographs (2006; Section
B.6. (Scientific Review and Evaluation; Evaluation and Rationale))
provide a basis for systematic assessments that may be performed
in a consistent fashion. The IPCS also convened a panel in
2004 to further develop and clarify the human relevance framework.
However, the above documents are not intended to dictate answers,
nor provide lists of criteria to be checked off.
Mode of action
Various documents on carcinogen assessment all note that mode
of action in and of itself, or consideration of comparative
metabolism, should be evaluated on a case-by-case basis and
are part of an analytic evaluative approach. One must look
closely at any mode of action in animal experiments, taking
into consideration comparative toxicokinetics /toxicodynamics
between the animal test species and humans to determine the
relevance of the results to humans. This may lead to the possibility
of discounting very specific effects of certain types of substances.
Life stage-dependent effects on cellular differentiation may
also lead to qualitative differences between animals and humans.
Only if a mode of action of tumor development is conclusively
determined not to be operative in humans may the carcinogenic
evidence for that tumor be discounted. However, a weight of
evidence evaluation for a substance calls for any other tumorigenic
activity to be evaluated, as well.
Responses in multiple animal
experiments
Positive responses in several species add to the weight of
evidence that a substance is a carcinogen. Taking into account
all of the factors listed in A.6.2.5.2 and more, such chemicals
with positive outcomes in two or more species would be provisionally
considered to be classified in GHS Category 1B until human
relevance of animal results are assessed in their entirety.
It should be noted, however, that positive results for one
species in at least two independent studies, or a single positive
study showing unusually strong evidence of malignancy may
also lead to Category 1B.
Responses are in one sex or
both sexes
Any case of gender-specific tumors should be evaluated in
light of the total tumorigenic response to the substance observed
at other sites (multi-site responses or incidence above background)
in determining the carcinogenic potential of the substance.
If tumors are seen only in one sex of an animal species, the
mode of action should be carefully evaluated to see if the
response is consistent with the postulated mode of action.
Effects seen only in one sex in a test species may be less
convincing than effects seen in both sexes, unless there is
a clear patho-physiological difference consistent with the
mode of action to explain the single sex response.
Confounding effects of excessive toxicity or localized
effects
Tumors occurring only at excessive doses associated with severe
toxicity generally have doubtful potential for carcinogenicity
in humans. In addition, tumors occurring only at sites of
contact and/or only at excessive doses need to be carefully
evaluated for human relevance for carcinogenic hazard. For
example, forestomach tumors, following administration by gavage
of an irritating or corrosive, non-mutagenic chemical, may
be of questionable relevance. However, such determinations
must be evaluated carefully in justifying the carcinogenic
potential for humans; any occurrence of other tumors at distant
sites must also be considered.
Tumor type, reduced tumor
latency
Unusual tumor types or tumors occurring with reduced latency
may add to the weight of evidence for the carcinogenic potential
of a substance, even if the tumors are not statistically significant.
Toxicokinetic behavior is normally assumed to be similar in
animals and humans, at least from a qualitative perspective.
On the other hand, certain tumor types in animals may be associated
with toxicokinetics or toxicodynamics that are unique to the
animal species tested and may not be predictive of carcinogenicity
in humans. Very few such examples have been agreed internationally.
However, one example is the lack of human relevance of kidney
tumors in male rats associated with compounds causing á2u-globulin
nephropathy (IARC, Scientific Publication N° 147 - While
most international agencies do not consider kidney tumors
coincident with alpha-2u-globulin nephropathy to be a predictor
of risk in humans, this view is not universally held. (See:
Doi et al., 2007)). Even when a particular tumor type may
be discounted, expert judgment must be used in assessing the
total tumor profile in any animal experiment.
Part
B: International Agency for Research on Cancer (IARC) (Preamble
of the International Agency for Research on Cancer (IARC)
“Monographs on the Evaluation of Carcinogenic Risks to
Humans” (2006)
IARC Carcinogen Classification Categories:
Group 1: The agent is carcinogenic to humans.
This category is used when there is sufficient evidence of
carcinogenicity in humans. Exceptionally, an agent may be
placed in this category when evidence of carcinogenicity in
humans is less than sufficient but there is sufficient evidence
of carcinogenicity in experimental animals and strong evidence
in exposed humans that the agent acts through a relevant mechanism
of carcinogenicity.
Group 2:
This category includes agents for which, at one extreme, the
degree of evidence of carcinogenicity in humans is almost
sufficient, as well as those for which, at the other extreme,
there are no human data but for which there is evidence of
carcinogenicity in experimental animals. Agents are assigned
to either Group 2A (probably carcinogenic to humans) or Group
2B (possibly carcinogenic to humans) on the basis of epidemiological
and experimental evidence of carcinogenicity and mechanistic
and other relevant data. The terms probably carcinogenic and
possibly carcinogenic have no quantitative significance and
are used simply as descriptors of different levels of evidence
of human carcinogenicity, with probably carcinogenic signifying
a higher level of evidence than possibly carcinogenic.
Group 2A: The agent is probably
carcinogenic to humans.
This category is used when there is limited evidence of carcinogenicity
in humans and sufficient evidence of carcinogenicity in experimental
animals. In some cases, an agent may be classified in this
category when there is inadequate evidence of carcinogenicity
in humans and sufficient evidence of carcinogenicity in experimental
animals and strong evidence that the carcinogenesis is mediated
by a mechanism that also operates in humans. Exceptionally,
an agent may be classified in this category solely on the
basis of limited evidence of carcinogenicity in humans. An
agent may be assigned to this category if it clearly belongs,
based on mechanistic considerations, to a class of agents
for which one or more members have been classified in Group
1 or Group 2A.
Group 2B: The agent is possibly carcinogenic to humans.
This category is used for agents for which there is limited
evidence of carcinogenicity in humans and less than sufficient
evidence of carcinogenicity in experimental animals. It may
also be used when there is inadequate evidence of carcinogenicity
in humans but there is sufficient evidence of carcinogenicity
in experimental animals. In some instances, an agent for which
there is inadequate evidence of carcinogenicity in humans
and less than sufficient evidence of carcinogenicity in experimental
animals together with supporting evidence from mechanistic
and other relevant data may be placed in this group. An agent
may be classified in this category solely on the basis of
strong evidence from mechanistic and other relevant data.
Part C: National Toxicology
Program (NTP), “Report on Carcinogens”, Background
Guidance
NTP Listing Criteria (See:
http://ntp.niehs.nih.gov/go/15209)
The criteria for listing an agent,
substance, mixture, or exposure circumstance in the Report
on Carcinogens (Roc) are as follows:
Known To Be A Human Carcinogen: There is sufficient
evidence of carcinogenicity from studies in humans that indicates
a causal relationship between exposure to the agent, substance,
or mixture, and human cancer. (This
evidence can include traditional cancer epidemiology studies,
data from clinical studies, and/or data derived from the study
of tissues or cells from humans exposed to the substance in
question that can be useful for evaluating whether a relevant
cancer mechanism is operating in people).
Reasonably Anticipated To Be A Human Carcinogen: There
is limited evidence of carcinogenicity from studies in humans
that indicates that a causal interpretation is credible, but
that alternative explanations, such as chance, bias, or confounding
factors, could not adequately be excluded,
or,
there is sufficient evidence
of carcinogenicity from studies in experimental animals that
indicates there is an increased incidence of malignant and/or
a combination of malignant and benign tumors in multiple species
or at multiple tissue sites, or by multiple routes of exposure,
or to an unusual degree with regard to incidence, site, or
type of tumor, or age at onset,
or
there is less than sufficient evidence of carcinogenicity
in humans or laboratory animals; however, the agent, substance,
or mixture belongs to a well-defined, structurally-related
class of substances whose members are listed in a previous
Report on Carcinogens as either known to be a human carcinogen
or reasonably anticipated to be a human carcinogen, or there
is convincing relevant information that the agent acts through
mechanisms indicating it would likely cause cancer in humans.
Conclusions regarding carcinogenicity
in humans or experimental animals are based on scientific
judgment, with consideration given to all relevant information.
Relevant information includes, but is not limited to, dose
response, route of exposure, chemical structure, metabolism,
pharmacokinetics, sensitive sub-populations, genetic effects,
or other data relating to mechanism of action or factors that
may be unique to a given substance. For example, there may
be substances for which there is evidence of carcinogenicity
in laboratory animals, but there are compelling data indicating
that the agent acts through mechanisms that do not operate
in humans and would therefore not reasonably be anticipated
to cause cancer in humans.
Part
D. Table Relating Approximate Equivalences among IARC, NTP
Roc, and GHS Carcinogenicity Classifications
The following table may be used to perform hazard classifications
for carcinogenicity under the HCS (§1910.1200). It relates
the approximated GHS hazard categories for carcinogenicity
to the classifications provided by IARC and NTP, as described
in Parts B and C of this Appendix.
Note 1:
1. Limited evidence of carcinogenicity from studies in humans
(corresponding to IARC 2A / GHS 1B);
2. Sufficient evidence of carcinogenicity from studies in
experimental animals (again, essentially corresponding to
IARC 2A / GHS 1B);
3. Less than sufficient evidence of carcinogenicity in humans
or laboratory animals; however:
c. The agent, substance,
or mixture belongs to a well-defined, structurally-related
class of substances whose members are listed in a previous
Roc as either “Known” or “Reasonably Anticipated”
to be a human carcinogen, or
d. There is convincing relevant information that the agent
acts through mechanisms indicating it would likely cause
cancer in humans.
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