methyl acrylate; methyl propenoate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

Toxicity to reproduction (fertility):

In a two-generation study according to OECD TG 416 groups of 27 male and female Crl:CD(SD) rats were whole-body exposed to methyl acrylate vapours at target concentrations of 0, 5, 25, and 75 ppm for six hours/day, seven days/week, resulting in actual average concentrations of 0, 5.3 ± 0.2, 25.7 ± 0.3, and 75.4 ± 0.6 ppm, respectively (corresponding to approx. 0, 0.019, 0.092, and 0.269 mg/L).Rats were exposed daily for approximately ten weeks prior to breeding, and continuing through breeding, gestation and lactation for two generations. Maternal rats were not exposed after GD 20 through LD 4 in order to allow for parturition and initiation of lactation. Exposure of maternal rats continued from LD 5 – LD 28. In-life parameters included clinical observations, feed consumption, body weights, estrous cyclicity, reproductive performance, pup survival, pup body weights, and puberty onset. In addition, post-mortem evaluations included gross pathology, histopathology, organ weights, oocyte quantitation and sperm count, motility and morphology in adults, and gross pathology and organ weights in weanlings (BAMM 2009).

 

Treatment-related effects in parental rats exposed to 75 ppm included decreased body weight and feed consumption in males and females throughout most of the two generation study. There were no effects on body weight or feed consumption at 25 or 5 ppm. Treatment-related, adverse histopathologic effects were present in the nasal tissues of P1 and P2 males and females exposed to 25 or 75 ppm. The incidence and severity of the nasal effects were concentration dependent. Degeneration with regeneration of the olfactory epithelium (very slight to moderate) occurred in all P1 and P2 males and females exposed to 75 ppm. Very slight olfactory epithelial degeneration, without accompanying regenerative hyperplasia, was noted in some of the P1 and P2 females and P2 males exposed to 25 ppm. There were several histopathologic effects that accompanied the degeneration of the olfactory epithelium. Very slight or slight degeneration of the olfactory nerve was present in most of the P1 and P2 males and females exposed to 75 ppm, and one P1 male exposed to 25 ppm. Very slight or slight chronic-active inflammation was present in 16/27 P1 males, 20/27 P1 females, 14/27 P2 males, and 8/27 P2 females exposed to 75 ppm, and in one or two males and females from both generations exposed to 25 ppm. Very slight necrosis of individual olfactory epithelial cells was present in most of the P1 and P2 males and females exposed to 75 ppm, and a few P1 and P2 animals (one to four per sex) exposed to 25 ppm. Very slight mineralization of the olfactory epithelium was present in one or two P1 and P2 animals exposed to 25 ppm, and in 6/27 P1 males, 4/27 P1 females, 16/27 P2 males and 14/27 P2 females exposed to 75 ppm. Other nasal effects consisted of an increase in the incidence of very slight or slight hyperplasia of the transitional epithelium in P1 and P2 males and females exposed to 25 or 75 ppm, and an increase in the incidence of very slight or slight hyperplasia and hypertrophy of the respiratory epithelium in P1 males and females exposed to 25 or 75 ppm, and in P2 males and females exposed to 75 ppm. There were no treatment-related histopathologic effects in P1 or P2 animals exposed to 5 ppm.

No treatment-related effects were seen in reproductive function or pup survival. However, pup body weights of the 75 ppm exposure group were decreased on postnatal day 14-28 in both generations. There were no effects on pup body weight in rats exposed to 25 or 5 ppm. The effects on pup body weight, as well as the changes in parental body weight and feed consumption, likely were secondary changes all stemming from nasal irritation and resultant stress.

 

In summary, the no-observed-adverse-effect concentration (NOAEC) for parental systemic toxicity was determined to be 5 ppm (= ca. 0.018 mg/L) and was based on histologic changes in the nasal tissues seen at higher concentrations. The NOAEC for developmental toxicity was 25 ppm (= ca. 0.089 mg/L), based on decreases in pup body weight at 75 ppm which were secondary to parental toxicity. The NOAEC for reproductive toxicity was 75 ppm (= ca. 0.268 mg/L), the highest concentration tested.

 

 

 

In addition, data on reproductive organ toxicity (testes weights as well as information on gross and microscopic pathology for testes, prostate, ovaries, and uteri) were derived from a 3-month study by the oral route according to a test procedure equivalent to OECD TG 408. F344 rats were administered methyl acrylate via drinking water (0, 1, 5, 20 mg/kg bw/d) for 13 weeks (Dow 1981). Additionally, data on reproductive organ toxicity from subchronic and chronic inhalation studies with Sprague-Dawley rats were taken into account. 10 Sprague Dawley rats per group and sex were exposed to 23, 124, 242 and 626 ppm (corresponding to approx. 0.082, 0.44, 0.86 and 2.24 mg/L) for 12 weeks, 5 day a week, 6 hours per day (BASF AG 1978 & 1980). In a two-year chronic study (equivalent to OECD TG 453), groups of rats were exposed to 15, 45, or 135 ppm (corresponding to approx. 0.058, 0.173, 0.519 mg/L) (BASF AG 1985, Reininghaus et al. 1991). No substance-related effects were found in seminal vesicles prostate, epididymis, uterus, testes, or ovary upon microscopic examinations in any of these studies.

 

Short description of key information:
In a two-generation study in which groups of rats were whole-body exposed to methyl acrylate vapours, no effects on reproductive function (i.e. fertility) were observed. The NOAEC for reproductive function was 75 ppm (= ca. 0.268 mg/L).

Effects on developmental toxicity

Description of key information

No indications of a developmental toxic / teratogenic effect were seen in animal studies.

Additional information

Developmental toxicity:

 

In a study where the developmental toxicity of seven acrylates was investigated, groups of 25 pregnant rats were exposed to 0, 25, 50 or 100 ppm methyl acrylate (corresponding to approx. 0.089, 0.179, 0.358 mg/L) for 6 hrs/day from days 6 through 20 of gestation. Marked maternal toxicity was demonstrated at 50 and 100 ppm as pronounced decreases in maternal body weight gain and food consumption over the entire exposure period. There were no treatment related increases in embryo/fetal mortality and no fetal malformations were observed in any of the treatment groups. Fetal toxicity, indicated by significantly reduced fetal body weight, was observed after exposure to 100 ppm methyl acrylate in the presence of overt signs of maternal toxicity (Saillenfait 1999). The NOAEC for maternal toxicity was 25 ppm (0.089 mg/L), the NOAEC for developmental effects (fetotoxicity) was 50 ppm (0.179 mg/L), and the NOAEC for developmental effects (teratogenicity) was the highest concentration tested of 100 ppm (0.357 mg/L).

 

 

Additionally, a prenatal developmental toxicity study in rabbits as second species was conducted according to OECD TG 414 for the Acrylate Task Force (BAMM 2009). 25 inseminated female Himalayan rabbits per group were whole-body exposed for 6 hrs/day, 5 days/week over a time period of 23 consecutive days (gestation days (GD) 6–28) to methyl acrylate vapours at target concentrations of 0, 5, 15, and 45 ppm. Analytical concentrations of 4.9, 15.7, 44.2 ppm (corresponding to approx. 0.0174, 0.0553, 0.1556 mg/L) were measured. On gestation day 29 the does were sacrificed and submitted to gross and histopathological examination (nasal cavities, larynx, trachea, lungs, mediastinal lymph nodes, all gross lesions). Examinations of ovaries and uterine content of the does included: determination of the weight of the unopened uterus, of the number of corpora lutea, of the number and distribution of implantation sites, and calculations of conception rate and pre- and post-implantation losses. Fetal examinations were performed on all fetuses per litter (external, soft tissue, skeletal) except head examinations that were done on half of the fetuses per litter.

 

There were no test substance-related effects on the does concerning food consumption, gross/net body weight, gestational parameters, uterine, placental and lung weights, as well as necropsy observations up to and including a dose of 45 ppm. The test substance caused a severe degeneration and atrophy of the olfactory epithelium at at least one focal area in the nasal cavity (distal levels III and/or IV) at the high-dose level (45 ppm). Though being local effects, such massive findings in the respiratory tract are likely to cause a considerable amount of distress in the affected maternal animals. Since distress is supposed to influence maternal homeostasis, this is considered to be a significant adverse effect on the maternal organism. The NOAEC for maternal toxicity was 15 ppm (0.0553 mg/L).

 

Fetal examinations revealed no influence of the test compound on sex distribution of the fetuses and fetal body weights. Methyl Acrylate (MA) had no adverse effect on prenatal development of offspring at any of the dose levels tested (5, 15 and 45 ppm). Thus, the NOAEC for developmental effects (fetotoxicity) and the NOAEC for developmental effects (teratogenicity) was the highest concentration tested of 45 ppm (0.1556 mg/L).

Justification for classification or non-classification

EU classification according to Regulation (EC) No. 1272/2008: no classification required