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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

A reverse gene mutation assay was conducted in line with Guidelines for Screening Mutagenicity Testing of Chemicals (Japan) and OECD Test Guidelines 471 and 472, using the pre-incubation method. Trimethyl phosphate showed negative results in Salmonella typhimurium TA100, TA1535, TA98, TA1537 and Escherichia coli WP2 uvrA at concentrations up to 5 mg/plate with or without a metabolic activation system (MHW, 1993).

In a supporting gene mutation assay conducted by Zeiger et al. 1992 comparable to the guideline OECD 471 with acceptable restictions only Salmonella typhimurium TA 98 and TA100 were used. The test was positive with Salmonella typhimurium strain TA100 after metabolic activation.

A chromosomal aberration test in line with Guidelines for Screening Mutagenicity Testing of Chemicals (Japan) and OECD Test Guideline 473 was conducted using cultured Chinese Hamster lung (CHL/IU) cells. Cytotoxic effects were seen at 1.4 mg/ml. In the short term treatment, it was set to 3.5 mg/ml because the concentration was equivalent to ca. 10 mM as required in test guidelines.

Cytogenetic effects were not seen under the conditions of this experiment. Neither structural chromosomal aberrations nor polyploidy were induced up to the limit concentration of 10 mM, in the absence or presence of an exogenous metabolic activation system in CHL/IU cells. (MHW, Japan, 1994).

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

In the micronuclei test of Weber et al. (1975) 5 B6D2F1/j mice per group were exposed for 5 consecutive days to 0, 500, 750, 1000 or 2000 mg/kg bw/day. Under the experimental conditions of this study, in metaphase analysis, trimethyl phosphate was found to increase the break frequency between 0.5 and 0.75 g/kg. No other aberreation other than chromatid breaks was observed.

In micronuclei test an increasing response was found at doses between 0.5 and 1 g/kg. The highest dose of 2 g/kg was lethal.

In intreperitoneal dominant lethal and heritable translocation studies mice were exposed to 1000, 1250 and 1500 mg/kg bw/day.

In the dominant lethal assay, each male was mated with 2 virgin females for 1 week from day 7. Females were checked for the presence of vaginal plugs every morning. They were sacrificed 12 - 15 days after conception to analyze uterine contents.

No significant differences were found between control and test groups in the number of corpora lutea. Significant decreases in the number of implants and living embryos were however found, and the number of early fetal deaths in the TMP test groups increased with the dose.

In the heritable translocation study, seven days after the injection, each male was mated with 2 untreated females for a period of 1 week. Litter sizes were determined at birth and at weaning. No significant differences were found in the frequency of fertile females between the control and TMP groups but a marked decrease was observed in the MMS group. There were significant decreases in the number of live young at birth in all test groups compared with the control. These results suggest that there would be marked increases in the frequency of pre- and post-implantation losses in these test groups.

The frequency of dominant lethal mutations estimated from the mean litter size at birth in each test group was 13.0% (lower TMP dose), 51.2% (higher TMP dose) or 57.6% (MMS). The difference between the frequency from the lower dose in this study and that in the dominant lethal assay might be due to the small number of matings in the dominant lethal test. Based upon male progeny only a slight but significant reduction in the number of young weaned was observed in the TMP high dose group. Since litter sizes were adjusted to 4 or more at the time of birth, any loss of young due to insufficient stimulus of lactation of the female could be avoided. Thus the result suggests that TMP treatment of males using a dose of 1 500 mg/kg resulted in a decrease in viability of their male offspring. After weaning, 4 animals in the higher TMP dose group and 3 in the MMS group died because of weakness or by accident.

The present data clearly show that TMP is capable of inducing chromosomal breakage in mouse post-meiotic germ cells (spermatids). The breakage induced includes heritable translocations. The incidence of translocations observed in the higher TMP dose group was comparable to that in the MMS group (50 mg/kg dose). A clear-cut and dose-dependent increase in translocation induction was observed with TMP exposure.

In a comet assay CD-1 mice were exposed to 0, 125, 250 or 500 mg/kg bw/day per gavage. Testicular cells were examined using the alkaline version of the Comet assay and the DNA damage was quantified as % tail DNA using a fully automatic scoring system. There were five animals in each dose group and 200 cells were scored for each mouse. Data were analyzed by means of a linear mixed-effects model with Dunnett’s test to compare the dose groups to their corresponding control. The results show significant DNA strand breaking effects (% tail DNA after administration) in the dose group of 500 mg/kg bw/day. (Hansen et al., 2004).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (positive)

Additional information

Studies on in vitro genotoxicity showed heterogenous effects (Ames-Tests, Chromosome aberration test) while the in vivo genetic toxicity tests (Comet Assay, Dominant Lethal Assay and Heritable translocation study, Micronucleus Test) were consistently positive.

Justification for classification or non-classification