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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
300 mg/kg bw/day
Additional information

Data availability:

Regarding fertility, there is screening-level information on n-BMA (OECD 422 study).Sufficient data to address all reproductive endpoint 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 study, n-BMA in sesame oil was given by oral gavage to 10 male and 10 female rats at doses of 0, 30, 100, 300, or 1000 mg/kg/day (Ito et al., 1998). Male rats were dosed for 44 days and female rats were dosed from 14 days prior to mating through Day 3 of lactation. Treatment-related decreases in body weight and food consumption were observed in high dose (1000 mg/kg/day) animals only. Relative to reproductive performance, there were no treatment-related effects on any endpoint of mating or fertility at any dose level. There were no treatment-related effects on gestation index, gestation length or number of pups per litter. There were no treatment-related deaths during delivery, nor treatment-related effects on offspring viability or the ratio of male to female pups. There were no adverse effects on the reproductive organs at any dose of male (testes, epididymides, prostate, seminal vesicles) and female (ovaries, uterus, cervix, vagina) rats shown by gross and histopathological examination. Observed decreases in numbers of corpora lutea and implantations in parental females in the high dose group were the only effects ascribed to treatment. Thus, based on effects observed in parental females in the 1000 mg/kg/day dose group, the NOAEL for reproductive toxicity is considered to be 1000 mg/kg/day for parental males and 300 mg/kg/day for parental females.

While there is no full reproduction study with n-BMA, Methyl methacrylate has recently been tested in an OECD TG 416 oral two-generation reproduction toxicity study in rats, in which both, parental and F1 animals were dosed with 0; 50; 150 and 400 mg/kg body weight/day (BASF, 2009).

In summary, in mid- and high-dose parental animals (150 and 400 mg/kg bw/d) temporary salivation, presumably due to a bad taste of the test substance and associated dose-related intermittent reductions of food consumption were noted. Less significant changes were noted for the F1 generation animals where the effects were limited to the high-dose group and not associated with effects on histopathology or reproductive performance. 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. There were no signs of systemic toxicity other than reduced body weight gain associated with reduced food consumption, presumably due to bad palatability (NOEL 50 mg/kg bw/day for the P and F1 parental rats and LOEL of 150 mg/kg bw/day in the P parental females).

In detail: methyl methacrylate (MMA) 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. Estrous 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 n-BMA 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 n-BMA.

Metabolites

Since full studies are not available for all members of category and the assessments for the butyl esters rely on read across it is appropriate to gain assurance on the reliability of the assessment by further consideration of the metabolites.

MAA: In a OECD 413 90-day inhalation study for the acid metabolite MAA, 10 male and 10 female Sprague Dawley rats were whole body exposed to target concentrations of 20, 40, 100 and 350 ppm (corresponding to 72, 143, 358 and 1253 mg/m3) MAA for 6 hrs/d, 5 days/wk for 90 days (65 exposures). In addition to examination of the standard organs and tissues, the sexual organs and parameters of fertility were examined. These examinations included weighing of sexual organs in both males and females and sperm mobility, morphology and sperm head count in one testis and one epididymis of each male animal of the high concentration and control group. Substance-related changes of the sexual organs were not noted in any of the exposed animals (males or females), nor were there any changes of sperm mobility and sperm head counts. Under the current test conditions, the NOAEC for fertility related parameters was 350 ppm (1253 mg/m3) for male and female rats.

In the case of the alcohols there is potential for concern for reproductive toxicity because of positive findings observed in some studies that used very high doses/concentrations. The OECD SIAR for n-butanol states: Several studies indicate that BA is not a reproductive toxicant. Female rats exposed to 6000 ppm (18000 mg/m³) BA throughout gestation and male rats exposed to 6000 ppm (18000 mg/m³) BA for six weeks prior to mating showed no effects on fertility or pregnancy rate. Male rats given BA at 533 mg/kg/day for 5 days had no testicular toxicity. BA produced only mild fetotoxicity and developmental alterations at or near the maternally toxic (even lethal) dose of 8000 ppm (24000 mg/m³) throughout gestation”. Therefore in terms of the butyl esters there is no concern for reproductive effects due to the butanol (n- and iso-BMA) metabolites.

Human data

No reliable data available for any members of the category.

Short description of key information:
n-Butyl methacrylate was studied for oral toxicity in rats in an OECD combined repeat dose and reproductive/developmental toxicity screening test. The NOELs for reproductive and developmental toxicity are considered to be 1000 mg/kg/day for the parental males and offspring, and 300 mg/kg/day for the parental females. No 2-generation study has been conducted on n-butyl methacrylate. However, on the basis of the analogy of n-butyl methacrylate with methyl methacrylate and the common, rapid metabolism and clearance of these esters from the body and the results of the 2-generation study performed with methyl methacrylate, it is unlikely that n-butyl methacrylate will represent a reprotoxic risk.

Effects on developmental toxicity

Description of key information
n-butyl methacrylate is not a developmental toxicant. The NOAE(C)L for developmental toxicity was 300 ppm by inhalation in rats and 300 mg/kg bw /d by oral route in rabbits.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
300 mg/kg bw/day
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
1 743 mg/m³
Additional information

Data availability:

Regarding developmental toxicity, there are OECD 414 studies on n-BMA and in rats and rabbits.

Non-human data

In a study comparable to the OECD guideline # 414, groups of 22-25 pregnant female rats were given whole-body inhalation exposures to n-butyl methacrylate at target concentrations of 0, 100, 300, 600 or 1200 ppm (analytical concentrations: 0, 99.6 +/- 5.0, 301.6 +/- 12.2, 602.3 +/-38.0, 1206.4 +/- 46.9 ppm) for 6 hr/day, during days 6 to 20 of gestation (GD). Maternal toxicity (decreased body weight gain) was shown at 300 to 1200 ppm. Feed consumption was decreased at 1200 ppm. No dam died during the test and there were no adverse effects on the average number of implantations and live fetuses, incidence of non-live fetuses, or on resorptions. Foetal body weights of male pups were significantly reduced at 1200 ppm, and females at 600 and 1200 ppm n-butyl methacrylate. There were no significant differences between control and treated groups for external, visceral, or skeletal malformations. A significant increase in the skeletal variations per litter occurred at 1200 ppm n-butyl methacrylate, compared to controls. The authors concluded that NOAEC for developmental toxicity was 300 ppm n-butyl methacrylate. There was no evidence of embryolethality or teratogenicity with n-butyl methacrylate.

In a study performed according to OECD guideline #414 and in compliance with GLP, n-butyl methacrylate was tested for its prenatal developmental toxicity in Himalayan rabbits (BASF SE, 2009). The test substance was administered as an aqueous preparation to 25 time-mated female Himalayan rabbits by stomach tube at doses of 0, 100; 300 and 1000 mg/kg body weight/day on gestation days (GD) 6 through 28. At terminal sacrifice on GD 29, 18-25 females per group had implantation sites. In the does treated at 1000 mg/kg body weight/day, distinct and statistically significant reduction of food consumption (-44%) and gross and net body weight gain (-47% and -54%, respectively) was recorded. Abortions (and subsequent sacrifice) were observed in 7 of 25 animals. Stomach erosions in 7/25 does, no faeces in the small intestine in 5/25 does and watery faeces in the intestines in 3/25 high-dose does (stomach erosions and subsequent massive decrease of individual food consumption particularly affected all does with abortions), complete postimplantation loss in 2 individual does secondary to distinct maternal toxicity and a statistically significant decrease of mean gravid uterine weights were observed at necropsy. A statistically significant decrease of mean weights, a slightly higher rate of malformations per litter (but no specific pattern of malformations), treatment-related adverse findings primarily limited to severely fused sternebrae (bony plate) and a slightly higher rate of variations per litter (skeletal variations such as delayed ossification and supernumerary ribs, commonly associated with decreased foetal weight and maternal stress) were observed in foetuses.

At 300 mg/kg body weight/day, does presented a statistically significant reduction of food consumption (-18%) and net (-37%) body weight gain and no biologically relevant differences between treated and control animals were observed in foetuses. At 100 mg/kg body weight/day, no biologically relevant differences between treated and control animals were observed in does and foetuses.

In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 100 mg/kg bw/d based on reduced food consumption and body weight gain in the does at 300 mg/kg bw/d and above. The no observed adverse effect level (NOAEL) for prenatal developmental toxicity is 300 mg/kg bw/d based on abortions, decreased foetal growth and bone alterations at 1000 mg/kg bw/d. There were no adverse foetal findings evident at a dose not producing maternal toxicity. The compound is no selective teratogen.

Metabolites

Since full studies are not available for all members of category and the assessments for the butyl esters rely on read across it is appropriate to gain assurance on the reliability of the assessment by further consideration of the metabolites.

The OECD SIAR concluded that: “Methacrylic acid (MAA), the common metabolite for all the esters, also was tested in groups of 19-25 pregnant female rats (whole-body inhalation exposure for 6 hr/day, during days 6 to 20 of gestation), at 0, 50, 100, 200, and 300 ppm (0, 179, 358, 716 and 1076 mg/m3) and produced no embryo- or fetal lethality, nor fetal malformations after exposure with MAA at any concentration, despite overt maternal toxicity (decreased body weight and feed consumption) at 300 ppm (1076 mg/m3). The NOAEL for developmental toxicity was considered 300 ppm (1076 mg/m3) MAA (Saillenfait et al., 1999).”

According to the OECD SIAR n-butanol produced only mild fetotoxicity and developmental alterations at or near the maternally toxic (even lethal) dose of 8000 ppm (24000 mg/m3) throughout gestation.. This is consistent and supported by the review on butyl acetate, which like butyl methacrylate is rapidly metabolised to n-butanol and for which a NOAEL of 1500 ppm has been established for developmental effects. Therefore in terms of the n- and iso-butyl ester there is no concern for reproductive effects due to the butanol (n- and iso-BMA) metabolites.

Human data

No reliable data available for any members of the category.

Justification for classification or non-classification

According to the available data and the CLP/GHS criteria for classification as reproductive toxicant, n-BMA did not show specific toxicity to reproduction. Hence, no classification is warranted for n-butyl methacrylate.