Mutagenicity germ cell

1 This hazard class is primarily concerned with chemicals that may cause mutations in the germ cells of humans that can be transmitted to the progeny. However, mutagenicity/genotoxicity tests in vitro and in mammalian somatic cells in vivo are also considered in classifying substances and mixtures within this hazard class. 

2 In the present context, commonly found definitions of the terms mutagenic, mutagen, mutations and genotoxic are used. A mutation is defined as a permanent change in the amount or structure of the genetic material in a cell. 

1 The classification system provides for two different categories of germ cell mutagens to accommodate the weight of evidence available. The two-category system is described in the following. 

2 To arrive at a classification, test results are considered from experiments determining mutagenic and/or genotoxic effects in germ and/or somatic cells of exposed animals. Mutagenic and/or genotoxic effects determined in in vitro tests may also be considered. 

3 The system is hazard based, classifying chemicals on the basis of their intrinsic ability to induce mutations in germ cells. The scheme is, therefore, not meant for the (quantitative) risk assessment of chemical substances. 

---

Waters MD, Stack HF, Jackson MA, et al. 1994. The performance of short-term tests in identifying potential germ cell mutagens A qualitative and quantitative analysis. Mutat Res 341 109-131. 

Adler, I.D. and Ashby, J. (1989). The present lack of evidence for unique rodent germ-cell mutagens. Mutation Res. 212 55-66. 

ICEMC (1983). Committee Final Report screening strategy for chemicals that are potential germ-cell mutagens in mammals. Mutation Res. 114 117-177. 

Bentley KS, Working PK. 1988. Activity of germ-cell mutagens and nonmutagens in the rat spermatocyte UDS assay. Mutat Res 203 135-142. 

OECD. 1999b. Detailed review document on classification systems for germ cell mutagenicity in OECD member countries. OECD Series on Testing and Assessment No. 12. Environment Directorate, Joint Meeting of the Chemicals Committee and the Working Party on Chemicals. ENV/JM/MONO(99)2. Paris OECD. 

Studies are not needed if the substance is a known genotoxic carcinogen and/or a germ cell mutagen and appropriate risk management measures are implemented. Also, the studies are not needed if the substance has no evidence of toxicity, there is no systemic absorption (from toxicokinetic data) and there is no significant human exposure. 

The basic idea of the CLH process is the transfer of responsibility for classification and labeling from industrial companies to authorities on a European Community level. In case of active substances in biocidal or plant protection products, all intrinsic properties including physicochemical properties, human health hazards, and environmental hazards are subject to the harmonization. By contrast, in the case of chemicals which are used in other application fields only some specific hazard classes are considered in the CLH procedure. According to Article 36 of the CLP Regulation, these are respiratory sensitization, carcinogenicity, germ cell mutagenicity, and reproductive toxicity. Consequently, these provisions have... 

Lahdetie, J., Peltonen, K. Sjoblom, T. (1997) Germ cell mutagenicity of tlirce metabolites of 1,3-butadiene in the rat induction of spermatid micronuclei by butadiene mono-, di-, and diol-epoxides in vivo. Environ, mol. Mutag., 29, 230-239... 

Any adverse effects can then be attributed to specific cell populations by back-calculation on the basis of the well-known kinetics of spermatogenesis (Chapin et al. 1985). The test was originally designed for detection of germ cell mutagenicity, and it requires a large number of female animals (e.g., an 8-wk trial would use 160-480 females), which is a disadvantage. 

Examples of in vivo heritable germ cell mutagenicity tests are ... 

Figure 3.5.1 Hazard categories for germ cell mutagens... 

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 considered for classification as Category 2 mutagens. 

If a mixture is diluted with a diluent which is not expected to affect the germ cell mutagenicity of other ingredients, then the new mixture may be classified as equivalent to the original mixture. 

The germ cell mutagenic potential of one production batch of a complex mixture can be assumed to be substantially equivalent to that of another production batch of the same commercial product produced by and under the control of the same manufacturer unless there is reason to believe there is significant variation in composition such that the germ cell mutagenic potential of the batch has changed. If the latter occurs, a new classification is necessary. 

Table 3.5.1 Cut-off values/concentration limits of ingredients of a mixture classified as germ cell mutagens that would trigger classification of the mixture...

Table 3.5.2 Label elements of germ cell mutagenicity...

Decision logic 3.5.1 for germ cell mutagenicity substances... 

Decision logic 3.5.2 for germ cell mutagenicity mixtures... 

Are the test results on the mixture conclusive taking into account dose and other factors such as duration, observations and analysis (e.g. statistical analysis, test sensitivity) of germ cell mutagenicity test systems ... 

---