Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

No experimental data on the potential of isobutyl acrylate to impair reproduction are available. However, data from the structural analogue n-butyl acrylate are available. In addition, a 2-generation study in rats according to OECD TG 416 with the structurally-related methyl acrylate was conducted for The Acrylate Task Force (BAMM 2009).

Fertility:

 

There are no one- or two-generation studies on n-Butyl acrylate available.

 

In a subchronic inhalation study with rats (BASF AG, 1978) extensive pathological and histopathological examinations of the gonads were performed. Sprague-Dawley rats were exposed to 0, 21, 108, 211 and 546 ppm (0, 0.11, 0.57, 1.11, 2.86 mg/L) n-butyl acrylate 6 hours per day, 5 days per week for 13 weeks. In males of the high dose group, severe toxicity was observed; the relative testes weight was increased, which was related to body weight reduction. No effects were found in the seminal vesicles, prostate, epididymis, uterus, testes, or ovary upon microscopic examination.

 

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. 0.269 mg/L), the highest concentration tested.

 

 

 

Conclusion:

 

Based on the data derived from the structural analogues n-butyl acrylate and methyl acrylate, isobutyl acrylate is not expected to impair fertility.


Short description of key information:
Based on the data derived from the structural analogues n-butyl acrylate and methyl acrylate, isobutyl acrylate is not expected to impair fertility.

Effects on developmental toxicity

Description of key information
Based on the data derived from the structural analogue n-butyl acrylate, isobutyl acrylate is not expected to cause fetotoxic, developmental or teratogenic effects at doses below the maternally toxic dose levels. 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.
Additional information

No experimental data on the potential developmental toxicity of isobutyl acrylate are available. However, data from the structural analogue n-butyl acrylate are available. In addition, a prenatal developmental toxicity study in rabbits as second species according to OECD TG 414 with the structurally-related methyl acrylate was conducted for The Acrylate Task Force (BAMM 2009).

 

 

Developmental toxicity:

 

Sprague Dawley rats were exposed to n-butyl acrylate vapour concentrations of 25, 135 and 250 ppm (corresponding to approx. 0.13; 0.71; 1.31 mg/L) for 6 hours per day on days 6 to 15 of gestations (BASF AG, 1979). Inhalation of 135 and 250 ppm of the test substance caused a significant reduction in maternal body weight gain, as well as irritation to the nose and eyes. At the end of the exposure period, the weight gain was comparable to the controls. The two highest exposure concentrations caused embryo lethality, as evidenced by a dose-dependent increase in post-implantation loss. The 25-ppm dose did not lead to any signs of maternal toxicity or embryo lethality. No signs of organ changes or skeletal abnormalities were observed in the fetuses at any concentration.

The NOAEC for maternal and developmental toxicity was 25 ppm (0.13 mg/L), and the NOAEC for teratogenicity was 250 ppm (1.31 mg/L).

 

 

In a study where the developmental toxicity of seven acrylates was investigated, groups of 25 pregnant rats were exposed to 0, 100, 200 and 300 ppm n-Butyl acrylate (corresponding to approx.0.52, 1.05, and 1.57 mg/L) for 6 hrs/day from days 6 through 20 of gestation. A NOAEC for maternal toxicity could not be determined since the absolute weight gain was significantly reduced in all dose groups in a concentration-related manner. No treatment-related effects were reported in terms of numbers of implantation sites, live fetuses, non-live implants or resorptions. Fetal body weight was significantly reduced at 200 and at 300 ppm. A few sporadic malformations were seen in the 300 ppm and the control group. There was no evidence of treatment-related effects on the incidence of external and visceral variations. The incidence of individual skeletal variations (mainly incomplete ossification of sternebrae and of vertebral centra) was similar in the control and treated groups (Saillenfait 1999).

No NOAEC could be derived for maternal toxicity. The LOAEC for maternal toxicity was 100 ppm (0.52 mg/L), the NOAEC for developmental effects (fetotoxicity) was 100 ppm (0.52 mg/L), and the NOAEC for developmental effects (teratogenicity) was the highest concentration tested of 300 ppm (1.57 mg/L).

 

In a gavage study, pregnant CD-1 mice were administered n-butyl acrylate dissolved in cottonseed oil. Concentrations of 0, 100, 1000, 1500, 2000, 2500, 3000 and 4000 mg n-butyl acrylate/kg bw were administered from gestation day 6 to 15. No animals survived in the high dose group. At 3000 and 2500 mg/kg bw 2 of 30 animals died; at 2000 mg/kg bw 1 of 29 died; at 1500 mg/kg bw 1 of 27 died; and at 1000 mg/kg bw 1 of 30 died. At the 1500 mg/kg bw dose and higher, average maternal body weight gain was significantly reduced. Fetal body weights were significantly reduced at doses of 1500 mg/kg bw and above. At 2500 and 3000 mg/kg bw, the percentage of resorptions was significantly increased. At 100, 1000, 1500 and 2000 mg/kg bw, and in the control group, variations and malformations occurred sporadically on different sides (i.e. single cases of cleft palate, fused ribs, fused sternebrae, fused arches, extra arches, branched ribs) in a non-dose-dependent manner, with a slight dose-dependent increase when taking the sum of all events per dose group together. In the 2500 mg/kg bw and 3000 mg/kg bw groups, the number of fetuses with external and skeletal malformations and variations (cleft palate, exencephaly, open eyes, fused arches, fused ribs) was significantly increased (Rohm and Haas Co. 1979).

Taking maternal mortality and reduced weight gain into account; the NOAEL for maternal toxicity was 100 mg/kg bw. The NOAEL for developmental toxicity was 1000 mg/kg bw and the NOAEL for teratogenicity was 2000 mg/kg bw.

 

 

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).

 

 

Conclusion

 

After inhalation, n-butyl acrylate caused fetotoxic effects only at high maternal toxic doses. No teratogenicity occurred after inhalation of n-butyl acrylate in animal studies. After oral gavage at very high doses (2500 mg/kg bw and above) to mice, n-butyl acrylate caused malformations, only in the presence of maternal toxicity. At concentrations where no maternal toxicity was observed, n-butyl acrylate did not cause developmental toxicity or teratogenicity.

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.

 

 

Based on the data from the structural analogues n-butyl acrylate and methyl acrylate, isobutyl acrylate is not expected to cause fetotoxic, developmental or teratogenic effects at doses below the maternally toxic dose levels.

 

Justification for classification or non-classification

EU classification according to Annex VI of Directive 67/548/EEC: no classification required

GHS classification (GHS UN rev.3, 2009): no classification required