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In the key bacterial reverse mutation assay (according to OECD guideline 471),ametryn technical was tested in a GLP compliant study at doses of 0, 50, 150, 500, 1,500, or 5,000 µg/plate in Salmonella typhimurium strains TA 98, TA 100, TA 1535, and TA 1537 both in the absence and presence of exogenous metabolic activation (Aroclor 1254-induced rat liver S9) (Jones, 1994).  The experiment was conducted in triplicate and an independent repeat experiment was performed. Dimethyl sulfoxide (DMSO) was used as the vehicle and positive controls were included in all incubations. No cytotoxicity was observed and no increase in the reverse mutation rate was observed at any ametryn technical concentration either in the presence or absence of metabolic activation. Incubation with positive control substances in the absence or presence of metabolic activation resulted in anticipated increases in reverse mutation rates.

 

Similar negative results were seen in the supportive, GLP compliant bacterial reverse mutation assay (Deparade, 1984). Ametryn technical was tested at doses of 0, 20, 80, 320, 1,280, or 5,120 µg/0.1 mL in S. typhimurium strains TA 98, TA 100, TA 1535, and TA 1537 both in the absence and presence of exogenous metabolic activation (Aroclor 1254-induced rat liver S9).  Incubation with positive control substances in the absence or presence of metabolic activation resulted in anticipated increases in reverse mutation rates.

 

In a key, GLP compliant mammalian gene mutation assay (according to OECD guideline 476),ametryn technical was tested at doses of 0, 28.1, 37.5, 56.3, 75, 112.5, 150, 225, 281, or 300 µg/mL in the absence of exogenous metabolic activation (Aroclor 1254-induced rat liver S9)and at doses of 0, 9.4, 12.5, 18.8, 25, 37.5, 50, 75, 90, or 112.5 µg/mL in the presence of exogenous metabolic activation in mouse lymphoma L5178Y cells (Wollny, 2008).  The experiment was conducted in duplicate and an independent repeat experiment was performed. Acetone was used as the vehicle and methyl methane sulfonate and cyclophosphamide were used as the positive control compounds in the absence or presence of metabolic activation, respectively. No cytotoxicity was observed and no increase in the mutant frequency was noted at any ametryn technical concentration either in the absence or presence of metabolic activation. Incubation with the positive control compounds in the absence or presence of metabolic activation resulted in anticipated increases in the mutation frequencies.

 

Similar negative results were seen in a supportive, GLP compliant mammalian gene mutation assay (Dollonmeier, 1986). In this study, ametryn technical was tested at doses of 0, 30, 46, 60, 92, 120, 180, 184, 240, 270, 276, 300, 368, 414, or 460 µg/mL in the absence of exogenous metabolic activation (Aroclor 1254-induced rat liver S9) and at doses of 0, 25, 50, 100, 150, 200, 225, or 250 µg/mL in the presence of exogenous metabolic activation in mouse lymphoma L5178Y cells.  No cytotoxicity was observed either in the absence or presence of metabolic activation and incubation with the positive control substances ethylmethane sulfonate and dimethylnitrosamine in the absence or presence of metabolic activation, respectively, resulted in anticipated increases in the mutation frequencies.

 

In another supportive, GLP compliant mammalian gene mutation assay (according to OECD guideline 476), ametryn technical was tested at doses of 0, 1.5, 10, 20, 25, 50, 100, 150, 200, 250, or 300 µg/mL in the absence of exogenous metabolic activation (Aroclor 1254-induced rat liver S9) and at doses of 0, 1, 5, 10, 20, 25, 30, 40, 50, 60, 70, or 80 µg/mL in the presence of exogenous metabolic activation in mouse lymphoma L5178Y cells (Adams, 1995).  No cytotoxicity was observed either in the absence or presence of metabolic activation and no increase in the mutant frequency was observed at any ametryn technical concentration in the absence of metabolic activation. In the presence of metabolic activation, genotoxicity (defined as a two-fold increase in the mutation frequency over solvent control levels) was noted at a concentration of 50 µg/mL in one experiment and at concentrations of 70 and 80 µg/mL in the second experiment. Incubation with the positive control substances ethylmethane sulfonate and 20-methyl cholanthrene in the absence or presence of metabolic activation, respectively, resulted in anticipated increases in the mutation frequencies.

 

In a key, GLP compliant mammalian chromosome aberration test (according to OECD guideline 473), ametryn technical was tested at doses of 0, 37.5, 75, 100, 150, or 200 µg/mL in the absence of exogenous metabolic activation (Aroclor 1254-induced rat liver S9) and at doses of 0, 9.8, 37.5, 39.1, 75, 78, or 150 µg/mL in the presence of exogenous metabolic activation in cultured human lymphocytes (Adams, 1995).  Incubations at each concentration were done in duplicate and an independent repeat experiment was performed.  DMSO was used as the vehicle and ethyl methanesulphonate and cyclophosphamide were used as the positive control compounds in the absence and presence of metabolic activation, respectively. No cytotoxicity was observed either in the absence or presence of metabolic activation and no chromosome damage was observed at any ametryn technical concentration in the absence of metabolic activation. In the presence of metabolic activation, chromosome damage was noted at concentrations of 9.8 µg/mL and above. Incubations with the positive control compounds resulted in anticipated increases in chromatid damage both in the absence and presence of metabolic activation.

 

In a supportive, GLP compliant mammalian chromosome aberration test (according to OECD guideline 473), ametryn technical did not induce chromosome damage when tested at doses of 0, 37.5, 75, 150, or 300 µg/mL in the absence of exogenous metabolic activation (Aroclor 1254-induced rat liver S9) and when tested at doses of 0, 37.5, 75, or 150 µg/mL in the presence of exogenous metabolic activation in Chinese hamster ovary cells (Strasser, 1989). No cytotoxicity was observed either in the absence or presence of metabolic activation and incubations with the positive control compounds mitomycin C and cyclophosphamide resulted in anticipated increases in chromatid damage both in the absence and presence of metabolic activation.

 

Three supportive cytogenicity studies (i.e., unscheduled DNA synthesis assays) also were conducted with ametryn technical (Puri, 1984; Puri, 1984; Hertmner, 1989). In these studies, ametryn technical was tested at doses ranging from 0.41 to 156.25 µg/mL in rat hepatocytes or cultured human fibroblasts. No cytotoxicity was noted and no increases in the average nuclear grain count were observed at any ametryn technical concentration in any study.  Incubation with the positive control substance resulted in an anticipated increase in the average nuclear grain count in all studies.

 

In a GLP compliant in vivo micronucleus assay (equivalent to OECD guideline 474), ametryn technical was administered via intraperitoneal (IP) injection to male and female CD-1 mice at a dose of 245 mg/kg body weight (Proudlock, 1995).  Aqueous methylcellulose was used as the vehicle and mitomycin C, the positive control compound, was administered via oral gavage. Mice were sacrificed at 24 or 48 hours following injection of test article or control (5 to 15 mice/sex/time point). Two male mice died following test article administration and toxicity (i.e., lethargy, ptosis, and piloerection) was noted in animals receiving ametryn technical. No statistically significant increases in the number of micronucleated polychromatic erythrocytes were noted at any time point. Injection of the positive control caused the anticipated increase in micronucleated polychromatic erythrocytes. The use of only 1 dose level instead of the recommended 3 rendered this study reliable with restrictions.

Similar negative results were noted in 2 supportive studies in which ametryn technical was orally (i.e., gavage) administered at doses of 200, 400, or 800 mg/kg body weight and 625, 1,250, or 2,500 mg/kg body weight to male and female NMRI mice and male and female Chinese hamsters, respectively (Hertner, 1989; Strasser, 1984).  Administration of the positive control compound caused the anticipated increase in micronucleated polychromatic erythrocytes in both studies. 

 

In a GLP compliant in vivo unscheduled DNA synthesis assay (equivalent to OECD guideline 486), ametryn technical was orally administered to male Sprague Dawley rats at single doses of 0, 480, or 1600 mg/kg body weight (Proudlock, 1995).  Aqueous methyl cellulose was used as the vehicle and N-dimethylnitrosamine and 2-acetylaminofluorene were used as the positive control compounds at the 2- and 14-hour time-points, respectively. Following a post-exposure period of 2 or 14 hours, toxicity (i.e., piloerection, lethargy, ptosis, and hunched position) was noted in some of the animals; however, no mortalities occurred and no increases in the average nuclear grain count were observed at any ametryn technical concentration.  Administration of the positive control substances resulted in an anticipated increase in the average nuclear grain count.


Short description of key information:
The genetic toxicity of ametryn technical has been assessed in 10 in vitro studies (including 2 bacterial reverse mutation assays, 2 mammalian chromosome aberration tests, and 3 mammalian gene mutation assays) as well as in 5 in vivo studies (including 3 micronucleus assays). Negative results were reported in all studies, with the exception of 2 in vitro studies (a mammalian chromosome aberration test and a mammalian gene mutation assay) in which positive responses were observed only in the presence of exogenous metabolic activation.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification