Allyl 2,3-epoxypropyl ether

Endpoint summary

Additional information

In-vitro studies:

AGE was found to be mutagenic (dose-dependent increase) in S. typhimurium strains TA100 and TA1535 (base-substitution) when tested in the presence and absence of S9 activation. No mutagenic activity was observed in S. typhimurium strains TA98 and TA1537 (frame-shift) with or without S9 metabolic activation (NTP 1990). In another Ames assay (Shell, 1985), a reproducible, dose-related increase (2.5 times background) in revertant colonies were observed in the Salmonella typhimurium TA 1535, TA 100 and Escherichia coli WP2 uvr A pkm 101 both in the presence and absence of metabolic activation, and in TA 1537 only in the absence of metabolic activation.

In a chromosome aberration test (NTP 1990) using chinese hamster ovary cells, AGE was found to cause a significant dose-dependent increase in cells with aberrations with and without metabolic activation. Harvesting was delayed due to chemical-induced cell cycle delay at all concentrations tested, indicating cytotoxicity. These results were supported by positive results in two other chromosomal aberration assays in Chinese hamster lung fibroblasts (JETOC 1996) and rat liver (RL4) cells (Shell 1985).

In a sister chromatid exchange (SCE) assay using Chinese hamster ovary cells, AGE was found to cause a dose-dependent increase in relative SCEs/chromosome with and without metabolic activation (NTP 1990).

In a gene mutation assay (Shell 1985), AGE has shown to induce mitotic gene conversion in the yeast Saccharomyces cerevisiae JDI. AGE also caused increase in the mutation rate of Klebsiella pneumoniae in Luria and Delbrueck's fluctuation test (Voogd et al., 1981), and induced the SOS responses in E.coli PQ37 (Hude et al., 1990).

Additionally, AGE is found to induced formation of DNA adducts in vitro (except at 3-adenine) as detected by the 32P-postlabelling assay (Plna, 1997; Chapter 7.9.3). Two major adducts formed were shown to originate from alkylation at N-7-guanine and N-1-adenine, respectively, while one minor adduct formed was at N-3-cytosine.

 

In vivo studies:

AGE induced dose dependent increase in micronucleated – polychromatic erythrocytes (MN-PCE) and a positive trend in a Micronucleus assay (NTP 1990) performed in mice dosed at rate of 50, 100 and 200 mg/kg bw. In another scarcely documented micronucleus assay (Reliability 4), AGE gave almost identical micronuclei values as the control, and thus did not produce a mutagenic effect in terms of micronuclei at the dosage tested (DOW 1977).

A significant increase in sex-linked recessive lethal mutations was recorded in the germ cells of male D. melanogaster fed a sucrose solution containing AGE, but no increase in reciprocal translocations occurred in these cells (NTP 1990).

In a dominant lethal assay (DOW 1977), male mice were exposed via dermal route 3 times/week for 8 weeks at dose level of 2000 mg/kg bw. Following the exposure period, three untreated virgin females were randomly caged per treated male for one week. At the end of the first week, the females were replaced with three other untreated virgin females for the duration of the second week. All females were sacrificed by cervical dislocation 13-14 days from the mid week of the caging and presumptive mating, without being checked for vaginal plug. At autopsy, females were scored for pregnancy, total number of implants and fetal deaths. No effects attributed to the AGE were observed.

Additionally, DNA adducts (7-AGE-guanine, 1-AGE-adenine and 3-AGE-cytosine) could be detected in the liver and skin in the AGE-treated mice through intraperitoneal or dermal route, respectively. The level of 7-AGE-guanine in skin DNA (after topical application) was found to be 120 per 10E8 normal nucleotides, 57 times higher than in the liver DNA (after i.p application). The results showed formation of DNA adducts in skin DNA after dermal application was observed. However only 3 mice were used and effects on other organs after dermal application was not tested.

Combining all the data, there is enough evidence to classify AGE in Cat 3/R68 based on EU standards and in Cat 2 based on GHS standards.

Short description of key information:
Allyl glycidyl ether (AGE) was found to be genotoxic in vitro (Ames, sister chromatid exchange assay and chromosome aberration test) with and without metabolic activation as well as in vivo (micronucleus assay and drosophila sex-linked recessive lethal test).

Endpoint Conclusion: Adverse effect observed (positive)

Justification for classification or non-classification

EU classification according to Annex VI of Directive 67/548/EEC: Cat 3/R68

GHS classification (EC No 1272/2008): Cat 2