DfE Genetic Toxicity





Chemicals considered genotoxicants according to the authoritative lists below (see Table 4) shall not pass the Criteria. Chemicals not on those authoritative lists, but which are classifiable as to their potential to cause genotoxicity according to GHS [31] shall not pass the Criteria. Effects to be considered include heritable germ cell mutagenicity (including gene mutation and chromosome mutation), germ cell genetic toxicity, and somatic cell mutagenicity or genetic toxicity.



Table 4 – Authoritative Lists and GHS Criteria


Authoritative Body

Does not pass DfE Criteria

EU CMR List [16]

Category 1 – “Substances known to be mutagenic to man”

Category 2 – “Substances which should be regarded as if they are mutagenic to man”

Category 3 – “Substances which cause concern for man owing to possible mutagenic effects”

EU Risk Phrases [16]

R46: “May cause heritable genetic damage”

R68: “Possible risk of irreversible effects”

And all combination risk phrases containing one or more of the above.

Globally Harmonized System (GHS) [31]

Category 1A – Chemicals known to induce heritable mutations in germ cells of humans

Category 1B – Chemicals which should be regarded as if they induce heritable mutations in the germ cells of humans

Category 2 – Chemicals which cause concern for humans owing to the possibility that they may induce heritable mutations in the germ cells of humans


Data Requirements


All available data, measured and/or estimated, for the chemical and/or a suitable analog will be reviewed against the criteria using a weight-of-evidence approach. 


All available data, including in vivo, in vitro, and epidemiological studies, will be evaluated. GHS Criteria, cited in Table 4, will be applied.


Test Methods for GHS Review


Per GHS [31], results from multiple acceptable test methods must be used in conjunction for evaluation of genetic toxicity. 


 OECD Test Guideline 471 (OPPTS 870.5100):  Bacterial Reverse Mutation Test [32, 33];

 OECD Test Guideline 473 (OPPTS 870.5375): In vitro Mammalian Chromosome Aberration Test [34, 35];

 OECD Test Guideline 474 (OPPTS 870.5395):  Mammalian Erythrocyte Micronucleus Test [36, 37];

 OECD Test Guideline 475 (OPPTS 870.5385): Mammalian Bone Marrow Chromosome Aberration Test [38, 39];

 OECD Test Guideline 476 (OPPTS 870.5300): In vitro Mammalian Cell Gene Mutation Test [40, 41]; and

 OECD Test Guideline 483 (OPPTS 870.5380): Mammalian Spermatogonial Chromosome Aberration Test [42, 43];

 OECD Test Guideline 486: Unscheduled DNA Synthesis (UDS) Test with Mammalian Liver Cells in vivo [44]. This guideline does NOT substitute in the necessary minimum set for either the gene mutation or the chromosome aberration test.


Data Interpretation 


The following sources should be consulted for additional information:


 EU Dangerous Substances Directive, http://ecb.jrc.ec.europa.eu/documentation/. To access the list of substances carrying Risk Phrases, click on “CLASSIFICATION-LABELLING”, then “DIRECTIVE 67-548-EEC”, then “ANNEX I OF DIRECTIVE 67-548-EEC”, and then either of the files listed as: “Annex I of Directive 67548EEC”. [25]

 EU Dangerous Preparations Directive Article 6 and Annex II (1999/45/EC and subsequent updates/amendments) [26-28]; and

 GHS Ch 3.5 Germ Cell Mutagenicity [31].

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