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Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

Methyl methacrylate has been tested in a reliable two-generation reproduction toxicity study in rats with oral administration (gavage). The study was performed according to OECD TG 416 in compliance with GLP (REACH Methyacrylate Task Force, 2009). In this study, Methyl Methacrylate was administered to groups of 25 male and 25 female healthy young Wistar rats (P parental generation) as an aqueous preparation by stomach tube at dosages of 0; 50; 150 and 400 mg/kg body weight/day. At least 73 days after the beginning of treatment, P animals were mated to produce a litter (F1). Mating pairs were from the same dose group and F1 animals selected for breeding were continued in the same dose group as their parents.

Groups of 25 males and 25 females, selected from F1 pups to become F1 parental generation, were treated with the test substance at dosages of 0; 50; 150 and 400 mg/kg body weight/day post weaning, and the breeding program was repeated to produce F2 litter. The study was terminated with the terminal sacrifice of the F2 weanlings and F1 adult animals.

Control parental animals were dosed daily with the vehicle (1% Carboxymethylcellulose suspension in drinking water and four drops Cremophor EL and one drop hydrochloric acid).

The mid- and high-dose parental animals (400 mg/kg bw/d) showed clinical signs of systemic toxicity. The only relevant clinical observation was temporary salivation during a short period after dosing, which is considered to be test substance-induced. From the temporary, short appearance immediately after dosing it is likely, that this finding was induced by a bad taste of the test substance or local affection of the upper digestive tract. It is, however, not considered to be an adverse toxicologically relevant finding.

In the mid- and high-dose (150 and 400 mg/kg bw/d) P generation animals, dose-related intermittent reductions of food consumption were noted, either during premating, gestation and lactation phases of this study. Less significant changes were noted for the F1 generation animals where the effects were limited to the high-dose group. High-dose F1 parental males had statistically significant lower body weights during several study segments, which led to a statistically significant reduction of the mean terminal body weight resulting in secondary weight changes of brain. High-dose parental females had statistically significant lower body weights during the first weeks after weaning. This weight decrease during major phases of sexual maturation led to an apparent marginal delay of vaginal patency. This minor delay did, however, not result in any corroborative pathological findings nor did it adversly effect F1 female cyclicity, fertility and reproduction. Thus, an influence of the test substance on female sexual maturation is not assumed. Pathological examinations revealed no test-substance-related changes in organ weights, gross lesions, changes in differential ovarian follicle counts or microscopic findings, apart from an increase in kidney and liver weights in male and female animals in both generations which is presumably related to the treatment. There was no histopathologic lesion observed, that could explain the weight increase. It is regarded to be an adaptive change, most likely caused by an increase in metabolic activity in the two organs, which does not lead to histopathologic findings. It is not regarded to be an adverse effect. There were no indications from clinical examinations as well as gross and histopathology, that the administration of methyl methacrylate via the diet adversely affected the fertility or reproductive performance of the P or F1 parental animals up to and including a dose of 400 mg/kg bw/day. Estrous cycle data, mating behavior, conception, gestation, parturition, lactation and weaning as well as sperm parameters, sexual organ weights and gross and histopathological findings of these organs (including differential ovarian follicle counts in the F1 females) were comparable between the rats of all test groups and ranged within the historical control data of the test facility. All data recorded during gestation and lactation in terms of embryo-/fetal and pup development gave no indications for any developmental toxicity in the F1 and F2 offspring up to a dose level of 400 mg/kg bw/day. Up to this dose level, the test substance did not adversely influence pup viability and pup body weights. Sex ratio and sexual maturation was not directly affected at any dose level, inclusive the high-dose group (400 mg/kg bw/day).

The NOAEL for general, systemic toxicity was determined to be 50 mg/kg bw/day for the P and F1 parental rats, based on adverse effects on food consumption observed at the LOAEL of 150 mg/kg bw/day in the P parental females. The NOAEL for fertility and reproductive performance for the P and F1 parental rats was determined to be 400 mg/kg bw/day, the highest dose tested. The NOAEL for developmental toxicity, in the F1 and F2 progeny, of the test substance was determined to be 400 mg/kg bw/day, the highest dose tested.


Short description of key information:
oral
Two-generation reproduction toxicity study in rats (OECD TG 416): NOAEL general, systemic toxicity: 50 mg/kg bw/day (due to adverse effects on food consumption); NOAEL fertility and reproductive performance: 400 mg/kg bw/ day (REACH Methacrylate Task Force, 2009).

Effects on developmental toxicity

Description of key information
inhalation
rat: LOAEC ca. 0.41 mg/L (corresponding to 99 ppm; due to decreased food consumption and associated reduced body weight gain); NOAEC fetotoxicity, teratogenictiy >= ca. 8.3 mg/L (corresponding to ca. 2028 ppm; Solomon 1991)
oral
rabbit: NOAEL maternal toxicity 50 mg/kg bw (due to decreased food consumption and associated reduced body weight gain); NOAEL developmental toxicity 450 mg/kg bw (REACH Methacrylate Task Force, 2009)
Additional information

Methyl methacrylate has been tested in reliable developmental toxicity studies in rats, rabbits and mice.

 

Inhalation

In a developmental toxicity study according to OECD 414 and conducted in compliance with GLP standards (Solomon et al. 1991), methyl methacrylate (99.9% active ingredient) was administered by inhalation exposure to 5 groups (27 rats/group) of presumed pregnant rats (Crl:CDBR) at concentrations of ca. 0 (control), 0.4, 1.2, 4.8, 8.3 mg/L (corresponding to 99, 304, 1,178, and 2,028 ppm) for 6 hr/day on days 6-15 of gestation (GD) . All doses were administered by a whole-body inhalation exposure under dynamic conditions. Clinical signs were recorded daily on GD 0-20. The dams were weighed on GD 0, 6, 8, 10, 13, 16 and 20. Feed consumption was recorded during gestation. On GD 20, the dams were euthanized and the thoracic and abdominal cavities were examined for gross changes. Each uterus was weighed and corpora lutea, implantation sites and resorptions were counted. Fetuses were weighed, sexed, examined for external alterations and one-half of the fetuses from each litter were examined for visceral alterations.

No treatment-related deaths were noted at any concentration tested. The only clinical sign noted was a minimal increase in the incidence of scant faeces at ca. 8.3 mg/L. At all exposure levels tested losses in maternal body weight or decreases in maternal body weight gain and decreases in maternal feed consumption were noted . Loss in maternal body weight during the first two days of exposure followed by an overall reduced increase in maternal body weight gain during the treatment period was detected for the 4.8 mg/L and 8.3 mg/L groups. Slight effects were observed for the 0.4 and 1.2 mg/L treatment groups as indicated by a transiently (during the first two days of exposure) reduced maternal body weight gain. According to the authors, a maternal no observed effect level (NOEL) could therefore not be demonstrated. No embryo of fetal toxicity was evident and no increase in the incidence in the malformations or variations was noted at exposure levels up to and including 8.3 mg/L. Therefore toxicity to the conceptus was not evident even at exposure levels that resulted in overt maternal toxicity.

Additionally, Tansy et al. (1976) reported no signs of developmental toxicity in a study with mice, which were exposed to ca. 0.48 or 1.64 mg MMA/L (corresponding to 116 and 400 ppm) for 6 hrs/day on GD 4-13.

 

Oral

Methyl Methacrylate was tested for its prenatal developmental toxicity after oral application in Himalayan rabbits according to OECD TG 414 in compliance with GLP (REACH Methacrylate Task Force, 2009). The test substance was administered as an aqueous preparation to 25 inseminated female Himalayan rabbits by stomach tube at doses of 50, 150 and 450 mg/kg body weight/day on GD 6 through GD 28. The control group, consisting of 25 females, was dosed with the vehicle (1% Carboxymethylcellulose CB 30.000 in drinking water and a few drops Cremophor EL and one drop hydrochloric acid [1% CMC]) in parallel. A standard dose volume of 10 mL/kg body weight was used for each test group. At terminal sacrifice on GD 29, 24-25 females per group had implantation sites.

In the mid and high dose group, reduced food consumption (-18% and -13%, resp.) and body weight gain (-31% and -27%, resp.) were noted. No test substance-related adverse effects were observed on gestational parameters or fetuses. In the low dose group, no test substance-related adverse effects on does, gestational parameters or fetuses were observed.

In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 50 mg/kg bw/d. The NOAEL for prenatal developmental toxicity is 450 mg/kg bw/d. No adverse fetal findings of toxicological relevance were evident at any dose.

Toxicity to reproduction: other studies

Additional information

For MMA, based on studies in experimental animals, there is no evidence of selective toxicity to the reproductive system.

Justification for classification or non-classification

In several reliable studies in rats, rabbits and mice, no effects on fertility or developmental toxicity were observed, even in maternal toxic doses. Therefore, methyl methacrylate has not to be classified as developmental toxicant according to 67/548/EEC and UN-GHS requirements, respectively.