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Key value for chemical safety assessment

Effects on fertility

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

One combined repeated dose toxicity study with the reproduction/developmental toxicity screening test report by MHW Japan (1997) was available for evaluation. This study was conducted according to OECD TG 422 in compliance with GLP and was identified as the key study.

SD (Crj:CD) rats (12 animals/group/sex) were administered doses of 0(vehicle; corn oil), 4, 20, and 100 mg/kg/day by gavage. The dosing period for males was 43 days, and females were dosed from 14 days before mating to day 3 of lactation. Two dams died at 100 mg/kg/day. Investigations of the parent animals revealed, that reproductive parameters as the mating index, the fertility index, number of corpora lutea or implantations, the implantation index, the gestation index, the delivery index, gestation length, parturition or maternal behavior were not affected by the treatment with the test substance. Investigations of neonates revealed, that there were no changes related to the test substance in the number of offspring, the sex ratio, the live birth index, the viability index or the body weight. No abnormal findings were observed in external features, in clinical signs or in necropsy. According to these results, the test substance is considered to have no effects on reproductive and developmental parameters. The NOAEL for reproduction/developmental toxicity is considered to be 100 mg/kg/day, the highest dose tested.

In addition, a two-generation reproduction toxicity study in rats according to OECD TG 416 in compliance with GLP with the structural analogue methyl acrylate (CAS 96-33-3) was used to assess the reproduction toxicity of the test substance (BAMM, 2009). In this study, methyl acrylate was administered to groups of 27 male and 27 female Crl:CD(SD) rats by whole-body inhalation exposure to target concentrations of 0, 5, 25, or 75 ppm vaporized methyl acrylate 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 (corresponding to approx. 0, 0.019, 0.092, and 0.269 mg/L), respectively. 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.

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, 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, very slight squamous metaplasia of the transitional epithelium in 5/27 P1 males exposed to 75 ppm, and ulceration of the olfactory epithelium in four P1 males, one P1 female, and one P2 female 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 PND 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 NOEC for parental systemic toxicity was determined to be 5 ppm (corresponding to approx. 0.019 mg/L) and was based on histologic changes in the nasal tissues seen at higher concentrations. The NOEC for developmental toxicity was 25 ppm (corresponding to approx. 0.092 mg/L), based on decreases in pup body weight at 75 ppm which were secondary to parental toxicity. The NOEC for reproductive toxicity was 75 ppm (corresponding to approx. 0.269 mg/L), the highest concentration tested.


Short description of key information:
The NOAEL for reproduction/developmental toxicity in rats was determined in an OECD TG 422 study to be 100 mg/kg/day, the highest dose tested (MHW Japan, 1997). According to this study, the test substance is considered to have no effects on reproductive and developmental parameters.

Supportingly, in a two-generation reproduction toxicity study in rats with the structural analogue methyl acrylate (CAS 96-33-3) no adverse findings on the fertility and reproductive performance were evident at any of the tested doses. In summary, the NOEC of the structural analogue methyl acrylate for parental systemic toxicity was determined to be 5 ppm (corresponding to approx. 0.019 mg/L) and was based on histologic changes in the nasal tissues seen at higher concentrations. The NOEC for developmental toxicity was 25 ppm (correponding to approx. 0.092 mg/L), based on decreases in pup body weight at 75 ppm which were secondary to parental toxicity. The NOEC for reproductive toxicity was 75 ppm (corresponding to approx. 0.269 mg/L), the highest concentration tested.

Effects on developmental toxicity

Description of key information
In a study according to OECD TG 414, the NOAEL for maternal toxicity in rats was 10 mg/kg. Prenatal developmental toxicity was only observed at doses which produced signs of maternal toxicity and mortality (100 mg/kg/day). The NOAELs for reproduction/developmental toxicity and teratogenicity are considered to be 10 and 30 mg/kg/day, respectively (Atochem, 1997). A developmental toxicity study in rabbits conducted with the structural analogue methyl acrylate did not give any indication for a developmental toxic or teratogenic effect.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
10 mg/kg bw/day
Additional information

There was one teratogenicity test report by Atochem (1997) available for evaluation. This study was conducted according to OECD TG 414 in compliance with GLP and was identified as the key study.

Mated female SD (Crl:CD) rats were administered the doses of 0 (vehicle; peanut oil), 10, 30 and 100 mg/kg/day (25 animals/group) by gavage. The animals were dosed from day 6 to day 15 after mating.

Maternal effects: One female was killed moribund at 100 mg/kg/day, two females died at 30 mg/kg/day. Some clinical signs (principally loud breathing, piloerection, chromorhinorrhea, round back and dyspnea) were observed in 17/25 females at 100 mg/kg/day and in 8/25 females at 30 mg/kg/day. No abortions occurred in any female. No total resorptions occurred in any female except one at 100 mg/kg/day. The food consumption and body weight gain at 100 mg/kg/day were lower than those of the control. In macroscopic examinations, at 30 and 100 mg/kg/day, gaseous dilatation or thickening of mucosa in gastrointestinal tracts were observed in 3/25 and 6/25 females, respectively. These findings were principally observed in the decedent animals. There were no effects at 10 mg/kg/day. This substance was maternally toxic at 30 mg/kg/day.

Developmental effects: The post-implantation loss was increased and the body weight of the fetuses was decreased at 100 mg/kg/day. The number of live fetuses and sex-ratio were not affected. No effect was observed at 10 and 30 mg/kg/day. In external examination, 27/299 fetuses showed anomalies (14 fetuses from the same litter were dwarf, 13 other fetuses from another litter had adactyly) at 100 mg/kg/day. In internal examination, 2/144 fetuses showed anomalies (one fetus had a cleft palate, other fetuses presented hydrocephaly, and six dwarf fetuses suffered testicular ectopia). The absence of ossification of various bones (vertebrae, sternebrae) were found in many individuals. As fetal variations, reduced ossification of many bones (head, vertebrae, sternebrae, limbs) were found and the incidence for the reduced ossification of the 6th sternebra was increased at 100 mg/kg/day. At 30 mg/kg/day, reduced ossification of head and vertebrae were found. The NOAEL for teratogenicity is delineated at 30 mg/kg/day.

 

Additionally, a prenatal developmental toxicity study in rabbits as second species was conducted with the structural analogue methyl acrylate 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).

 

In summary, the NOAEL for maternal toxicity in rats was 10 mg/kg. Prenatal developmental toxicity was only observed at doses which produced signs of maternal toxicity and mortality (100 mg/kg/day). The NOAELs for reproduction/developmental toxicity and teratogenicity are considered to be 10 and 30 mg/kg/day, respectively.

A developmental toxicity study in rabbits conducted with the structural analogue methyl acrylate did not give any indication for a developmental toxic or teratogenic effect.

 

Justification for classification or non-classification

The result of an animal study gave no indication of a fertility impairing effect. The test substance causes developmental effects in animals only at high, maternally toxic doses.

EU classification according to Annex VI of the Directive 67/548/EEC:

- No classification required.

GHS classification according toAnnex I 1272/2008 CLP (EU GHS):

- No classification required.

Additional information