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GHS Classification Criteria for Germ Cell Mutagenicity

Little Pro on 2018-03-07

Mutagenicity refers to the induction of permanent transmissible changes in the amount or structure of the genetic material (i.e, gene, DNA) of cells or organisms. A germ cell mutagen is a chemical that may cause mutations in the germ cells of humans that can be transmitted to the progeny. 

Genotoxicity is a broader term and refers to processes which alter the structure, information content or segregation of DNA and are not necessarily associated with mutagenicity. All mutagens are genotoxic. Not all genotoxic substances are mutagenic.

Mutations can either occur in germ cells or somatic cells. Under GHS, only germ cell mutagens are classified. However, both test results from in vitro/in vivo germ cell and somatic cell mutagenicity tests should be considered

  • Germ cells are those cells that are involved in the reproductive process and can give rise to a new organism. Male germ cells give rise to sperm and female germ cells develop into ova. Toxicity to germ cells can cause effects on the developing fetus (such as birth defects, abortions).
  • Somatic cells are all body cells except the reproductive germ cells. They have two sets (or pairs) of chromosomes. Toxicity to somatic cells causes a variety of toxic effects to the exposed individual (such as dermatitis, death, and cancer).
  • In vitro (latin: "in the glass") test is a study that is performed outside of a living organism (i.e, glass, petri dishes). The test usually involves the use of isolated tissues, organs or cells.
  • In vivo(latin: "in the living") test is a study that is performed in living organisms (i.e, rat, rabbit).

Hazard Categories for Germ Cell Mutagenicity and GHS Classification Criteria

There are 3 hazard categories for germ cell mutagenicity depending on whether there is sufficient human evidence or animal test data. The table below summarizes GHS classification criteria for tested substances. 

Category GHS Classification Criteria
Category 1A Chemicals known to induce or regarded as if they induce heritable mutations in human germ cells

Known to induce heritable mutations –positive evidence from human epidemiological studies.

Category 1B Chemicals known to induce or regarded as if they induce heritable mutations in human germ cells
  • Positive result(s) from in vivo heritable germ cell mutagenicity tests in mammals; or
  • Positive result(s) from in vivo somatic cell mutagenicity tests in mammals, in combination with some evidence that the substance has potential to cause mutations to germ cells. This supporting evidence may, for example, be derived from mutagenicity/genotoxic tests in germ cells in vivo, or by demonstrating the ability of the substance or its metabolite(s) to interact with the genetic material of germ cells; or
  • Positive results from tests showing mutagenic effects in the germ cells of humans, without demonstration of transmission to progeny; for example, an increase in the frequency of aneuploidy in sperm cells of exposed people.
Category 2 Chemicals that may induce heritable mutations in human germ cells

Positive evidence obtained from experiments in mammals and/or in some cases from in vitro experiments, obtained from:

  • Somatic cell mutagenicity tests in vivo, in mammals; or
  • Other in vivo somatic cell genotoxicity tests which are to be supported by positive results from in vitro mutagenicity assays

Note: Chemicals which are positive in in vitro mammalian mutagenicity assays, and which also show chemical structure activity relationship to known germ cell mutagens should be classified as category 2.

List of Validated Mutagenicity/genotoxicity Tests

The table below summarizes a list of mutagenicity tests and genotoxicity tests that could be used for GHS classification. They are grouped by somatic cells/germ cells and in vitro/in vivo. 

Test Type Validated Methods
Germ cell mutagenicity tests in vivo
  • Rodent dominant lethal mutation test (OECD 478)
  • Mouse heritable translocation assay (OECD 485)
  • Transgenic rodent (TGR) somatic and germ cell gene mutation assays (OECD 488) 
  • Mouse specific locus test
Germ cell genotoxicity tests in vivo
  • Sister chromatid exchange analysis in spermatogonia
  • Unscheduled DNA synthesis test (UDS) in testicular cells
Somatic cell mutagenicity tests in vivo
  • Mammalian bone marrow micronucleus test (OECD 474)
  • Mammalian bone marrow chromosome aberration test (OECD 475)
  • Mouse spot test (OECD 484)
  • Mammalian erythrocyte micronucleus test (OECD 474)
  • Transgenic rodent (TGR) somatic and germ cell gene mutation assays (OECD 488)
Somatic cell genotoxicity tests in vivo
  • Liver Unscheduled DNA Synthesis (UDS) in vivo (OECD 486)
  • Mammalian bone marrow sister chromatid exchanges (SCE)
In vitro mutagenicity tests 
  • In vitro mammalian chromosome aberration test (OECD 473)
  • In vitro mammalian cell gene mutation test (OECD 476)
  • Bacterial reverse mutation tests (OECD 471)
  • In vitro micronucleus test (OECD 487)

Note:The classification of individual substances should be based on the total weight of evidence available, using expert judgement.

All known germ cell mutagens are also mutagenic in somatic cells in vivo. Substances that are mutagenic in somatic cells may produce heritable effects if they, or their active metabolites, have the capability of interacting with the genetic material of germ cells. Substances that do not induce mutations in somatic cells in vivo would not be expected to be germ cell mutagens.

Examples of Germ Cell Mutagen Classification

Test Result Proposed Classification
Positive result in a human epidemiological study
  • Category 1A
1 positive result in germ cell mutagencity study in vivo
  • Category 1B
1 positive result in somatic cell mutagencity study in vivo evidence of exposure of the substance showing activity or metabolite to germ cells
  • Category 1B
1 positive result in somatic cell mutagencity study in vivo
  • Category 2
1 positive result in somatic cell genotoxicity study in vivo +  1 positive result in in vitro mutagenicity study
  • Category 2
Only negative results in in vivo mutagenicity tests
  • Not classified
Only 1 postive result in in vitro mutagenicity test data available
  • Classification not possible
Negative result in the in vivo genotoxicity test. However, in vivo mutagenicity data is not available.
  • Classification not possible

Mutagen Classification for Mixture

For a mixture containing mutagens, the mixtures may be classified using the table below:

GHS Classification Mutagen

Read more: comparison fo GHS concentration limits for mutagenicity

References and More Reading

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