N,N'-methylenediacrylamide

Endpoint summary

Additional information

Studies using bacterial mutagenesis assays have consistently failed to show a mutagenic response for acrylamide. Data from mammalian cell mutagenesis assays have been conflicting, but generally do not provide evidence of mutagenicity of acrylamide. Positive results have been reported in the mouse lymphoma L5178Y cell mutagenesis assay, but the response, consisting almost exclusively of small-colony mutants, is indicative of chromosomal effects rather than being true point mutations. Studies using assays that measure direct damage to DNA have also given negative results.

In vitro tests for induction of sister chromatid exchanges (SCE) have been conflicting, with one lab reporting a positive response with acrylamide and a second one reporting a negative result. Two laboratories have evaluated acrylamide in the rat hepatocyte DNA repair assay. One laboratory reported a positive response for acrylamide, but there were numerous technical problems with the conduct and interpretation of these results. A second study conducted in a well-recognized laboratory reported negative results in this assay.

There have been numerous reports on the cytogenetic effects of acrylamide on bone marrow, spermatogonia, and other cell types. Although some reports are conflicting, the general consensus is that acrylamide is a potent clastogen in bone marrow, but results in spermatogonia are equivocal. Results in other test systems likewise produce conflicting results. Two laboratories reported negative results in cell transformation assays using BALB/3T3 or C3H/10T1/2 cells; a third laboratory reported positive cell transformation results in C3H/10T1/2 and NIH/3T3 cells. Two laboratories reported negative results in the sex-linked recessive lethal assay in Drosophila melanogaster, but one of these laboratories reported a positive result in the somatic mutation and recombination test (SMART) in Drosophila.

The experimental data suggests a mode of action of acrylamide that does not involve binding to DNA. Studies to assess covalent binding of acrylamide to macromolecules have consistently failed to demonstrate significant binding to DNA. In contrast, binding to microtubule proteins is extensive, which could account for many of the chromosomal effects of acrylamide. A study that evaluated binding of acrylamide to spermatogonial cells in mice revealed that significant binding was observed in late-spermatid to early spermatozoa stages, the same stages that are most sensitive to the action of acrylamide. Evaluation of the separate fractions revealed that very little acrylamide is bound to DNA, and the binding of acrylamide to protamine accounts for virtually all of the binding.

Short description of key information:

Acrylamide has been extensively tested in a wide variety of in vitro and in vivo assays for detection of genetic effects. There is no compelling evidence that acrylamide induces point mutations or interacts with DNA in vivo to form DNA adducts. In contrast to point mutation and DNA damage assays, acrylamide induces a variety of chromosomal effects in bone marrow, but studies in spermatogonia are conflicting. Dominant lethal assays have generally produced positive results with acrylamide, which could be explained by chromosomal effects such as deletions. These studies, taken together, provide very strong evidence that acrylamide does not react directly with DNA. Binding to microtubule proteins or proteins associated with chromatin (e.g., histones) could account for nearly all of the reported effects of acrylamide on induction of chromosome aberrations, micronuclei, and dominant lethals.

Endpoint Conclusion: Adverse effect observed (positive)