Washington Administrative Code › Title 296 - Labor and Industries, Department of › Chapter 296-901 - Globally harmonized system for hazard communication › Section 296-901-14032 - Appendix F - Guidance for hazard classifications regarding carcinogenicity

Current through Register Vol. 24-14, July 15, 2024
The mandatory criteria for classification of a
				chemical for carcinogenicity under HCS are found in WAC
				296-901-14022 (A.6).
				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
				Guidance1
As noted in Footnote 6 of WAC
				296-901-14022 (A.6).,
				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 WAC
				296-901-14022 (A.6),
				and must 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
				(i) two or more species of animals or (ii) 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.
(a)
Limited evidence of carcinogenicity:
The data suggest a carcinogenic effect but are limited for making a
				definitive evaluation because, e.g. (i) the evidence of
				carcinogenicity is restricted to a single experiment; (ii) there are
				unresolved questions regarding the adequacy of the design, conduct or
				interpretation of the studies; (iii) the agent increases the
				incidence only of benign neoplasms or lesions of uncertain neoplastic
				potential; or (iv) 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 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, must 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/toxico-dynamics 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 WAC
				296-901-14022
				(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 must 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 must 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 must 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-muta-genic 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
				[ALPHA]2u-globu-lin nephropathy (IARC, Scientific Publication N°
				1472). 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)3
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
				Criteria4:
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.
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 (1) in multiple species or at multiple tissue sites, or (2) by
				multiple routes of exposure, or (3) 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. 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.
Approximate Equivalences Among Carcinogen
				Classification Schemes
IARC
GHS
NTP RoC
Group 1
Category 1A
Known.
Group 2A
Category 1B
Reasonably anticipated.
Group 2B
Category 2
(See Note 1).
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:
a.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
b.There is convincing relevant information that the
				agent acts through mechanisms indicating it would likely cause cancer
				in humans.
*References:
Cohen, S.M., J. Klaunig, M.E. Meek, R.N. Hill, T.
				Pastoor, L. Lehman-McKeeman, J. Bucher, D.G. Longfellow, J. Seed, V.
				Dellarco, P. Fenner-Crisp, and D. Patton. 2004. Evaluating the human
				relevance of chemically induced animal tumors.
Toxicol.
				Sci.
78(2):181-186.
Cohen, S.M., M.E. Meek, J.E. Klaunig, D.E. Patton,
				P.A. Fenner-Crisp. 2003. The human relevance of information on
				carcinogenic modes of action: Overview.
Crit. Rev.
				Toxicol.
33(6):581-9.
Meek, M.E., J.R. Bucher, S.M. Cohen, V. Dellarco,
				R.N. Hill, L. Lehman-McKeeman, D.G. Longfellow, T. Pastoor, J. Seed,
				D.E. Patton. 2003. A framework for human relevance analysis of
				information on carcinogenic modes of action.
Crit. Rev.
				Toxicol.
33(6):591-653.
Sonich-Mullin, C., R. Fielder, J. Wiltse, K. Baetcke,
				J. Dempsey, P. Fenner-Crisp, D. Grant, M. Hartley, A. Knapp, D.
				Kroese, I. Mangelsdorf, E. Meek, J.M. Rice, and M. Younes. 2001. The
				conceptual framework for evaluating a mode of action for chemical
				carcinogenesis.
Reg. Toxicol. Pharm.
34:146-152.
International Programme on Chemical Safety
				Harmonization Group. 2004. Report of the First Meeting of the Cancer
				Working Group. World Health Organization. Report IPCS/ HSC-CWG-1/04.
				Geneva.
International Agency for Research on Cancer. IARC
				Monographs on the Evaluation of Carcinogenic Risks to Human.
				Preambles to Volumes. World Health Organization. Lyon, France.
Cohen, S.M., P.A. Fenner-Crisp, and D.E. Patton.
				2003. Special Issue: Cancer Modes of Action and Human Relevance.
				Critical Reviews in Toxicology, R.O. McClellan, ed., Volume 33/Issue
				6. CRC Press.
Capen, C.C., E. Dybing, and J.D. Wilbourn. 1999.
				Species differences in thyroid, kidney and urinary bladder
				carcinogenesis. International Agency for Research on Cancer,
				Scientific Publication N° 147.
Doi, A.M., G. Hill, J. Seely, J.R. Hailey, G.
				Kissling, and J.R. Buchera. 2007. [ALPHA]2u-globulin nephropathy and
				renal tumors in National Toxicology Program studies. Toxicol. Pathol.
				35:533-540
Footnote 1 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.
Footnote 2 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)
Footnote 3 Preamble of the International Agency for
				Research on Cancer (IARC) "Monographs on the Evaluation of
				Carcinogenic Risks to Humans" (2006)
Footnote 4 See:
				http://ntp.niehs.nih.gov/go/15209
Footnote 5 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.
Statutory Authority:
				  RCW  49.17.010,
				  49.17.040,
				  49.17.050,
				  49.17.060 and  29 C.F.R.
				  1910  Subpart Z. 13-06-050, § 296-901-14032, filed 3/5/13,
				  effective 4/15/13.