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Key value for chemical safety assessment

Effects on fertility

Description of key information

Methacrylates behave as a chemical family when studied for reproductive toxicity potential and, with few exceptions based on alerting chemical structures, new compounds in this family may be considered for waiver from acutal testing based on structure-activity relationships. Therefore the reproductive behaviour of a similar chemical can be predicted with confidence by inclusion within this chemical class, thus avoiding unnessary testing. (Johannsen FR et al.(2008) Regulatory Toxicology and Pharmacology 50: 322 - 335)

There is no study available concerning the reproductive potential for n-Octyl methacrylate. Therefore read-across based on grouping of substances (category approach lower alkyl C1 -C8 methacrylates) was used to cover the endpoint of reproduction.

Effect on fertility: via oral route
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Additional information

Data availability:

Regarding fertility, there is screening-level information on nBMA (OECD 422 study). Sufficient data to address all reproductive endpoints can be obtained by read-across from a 2-generation reproductive toxicity study on MMA by the oral route. No further testing is proposed.

Non-human data

In an OECD Guideline 422 and GLP study, 2-ethylhexyl methacrylate (2-EHMA) in corn oil was administered by oral gavage to 10 male and 10 female rats at 0, 30, 100, 300, or 1000 mg/kg/day. Male rats were dosed for 49 days and female rats were dosed from 14 days prior to mating through Day 3 of lactation (Furuhashi et al., 1998). One high-dose female rat died during the study. Treatment-related decreases in body weight and food consumption were observed in high dose animals only. Relative to reproductive parameters, treatment-related effects observed primarily at 1000 mg/kg/day included: significantly low number of oestrus cycles, prolonged gestation period, decreased number of corpora lutea and implantation sites, and decreased parturition index [77.8%]. Based on effects observed in parental females in the 1000 mg/kg/day dose group (i. e. decreases in the number of corpora lutea and the number of implantation sites), the NOAEL for reproductive toxicity (fertility) is considered to be 300 mg/kg/day 2-EHMA. A 2-generation study is not available on 2-ethylhexyl methacrylate and n-octyl methacrylate.

However, an analogue substance, methyl methacrylate, has been tested in a two-generation reproduction toxicity study in rats (OECD TG 416). 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 (BASF SE, 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 adversely 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 histopathological 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 histopathological 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. Oestrous cycle data, mating behaviour, 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-/foetal 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.

The 2-generation study with MMA provides confidence that the absence of effects seen at 300 mg/kg/d in the screening study with 2-EHMA are a reliable indication for an absence of fertility effects at this concentration in a higher tier study such as a 2 generation study. For the purpose of the risk assessment, a NOAEL for reproductive toxicity (fertility) of 300 mg/kg/d is taken forward for 2-EHMA and n-octyl methacrylate.

Human data

There are no reliable data available.


Short description of key information:
In an OECD Guideline 422 and GLP study with 2-ethylhexyl methacrylate closely related to n-octyl methacrylate, the NOAEL for reproductive toxicity is considered to be 300 mg/kg/day. A 2-generation study is not available on 2-ethylhexyl methacrylate or n-octyl methacrylate. However, an analogue substance, methyl methacrylate, has been tested in a two-generation reproduction toxicity study in rats (OECD TG 416). The NOAEL for general, systemic toxicity was 50 mg/kg bw/day (due to adverse effects on food consumption) and the NOAEL for fertility and reproductive performance was 400 mg/kg bw/ day. Based on these data, 2-ethylhexyl methacrylate nor n-octyl methacrylate are not expected to be reproductive toxicants.

Justification for classification or non-classification

Based on the available data, n-Octyl methacrylate does not need to be classified for toxicity to reproduction, developmental toxicity according to the criteria given in regulation (EC) 1272/2008 or the former European directive on classification and labelling 67/548/EEC. Thus, no labelling is required.

Additional information