1,3-Propanediol, 2,2-bis(hydroxymethyl)-, polymer with 2-(chloromethyl)oxirane, 2-propenoate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No data exist for Pentaerythritol, olig. react. prod. with 1-chloro-2,3-epoxypropane, react. prod. with acrylic acid. Thus read across was performed to the structurally similar multifunctional acrylate 2-Propenoic acid, reaction products with pentaerythritol (PETIA, CAS 1245638-61-2). Justification for this approach can be found in the discussion for developmental toxicity.

PETIA was tested in an OECD 422 combined repeated dose/reproduction and developmental toxicity screening study via oral route with CRL:CD(SD) rats at concentrations of 0, 25, 75 and 200 mg/kg.

Parental animals

Male and female mating and fertility, male copulation and female conception indices, mean number of days between pairing and coitus, gestation length, and the process of parturition were unaffected by test substance administration at all dosage levels. Mean numbers of pups born, live litter size, percentage of males at birth, mean pup body weights, and pup body weight gains were unaffected by parental test substance administration.

Offspring

Mean numbers of pups born, live litter size, percentage of males at birth, mean pup body weights, and pup body weight gains were unaffected by parental test substance administration. No test substance-related clinical findings or macroscopic findings for pups that were found dead were noted at any dosage level. The NOAEL for fertility and developmental toxicity was set to 200 mg/kg b.w. (the highest dose tested). At this dose, maternal toxicity was observed (reduced body weight gain, premature deaths probably due to local irritation in the stomach), and the NOAEL for systemic toxicity was set to 75mg/kg b.w.

Short description of key information:
Read across studies
PETIA: rat, oral, NOAEL reproduction = 200mg/kg b.w. (OECD 422, GLP, PARAD Consortia (2010))

Effects on developmental toxicity

Description of key information

Read across studies
PETIA: rat, oral, NOAEL reproduction = 200mg/kg b.w. (OECD 422, GLP, PARAD Consortia (2010))
PETIA: rat, oral, NOAEL teratogenicity = 10mg/kg b.w. (equ. to OECD 414, Cytec (1984),less reliable due to low dose tested and absence of maternal toxicity)
TMPeoTA: rat, oral, NOAEL teratogenicity = 1000mg/kg b.w. (equ. to OECD 414, Cytec (1984))
GPOTA: rat, oral, NOAEL teratogenicity = 1000mg/kg b.w. (equ. to OECD 414, Cytec (1984))

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Additional information

No data exist for Pentaerythritol, olig. react. prod. with 1-chloro-2,3-epoxypropane, react. prod. with acrylic acid. Thus read across was performed to the structurally similar multifunctional acrylates: 2-Propenoic acid, reaction products with pentaerythritol (PETIA, CAS 1245638-61-2), Trimethylolpropane ethoxylated triacrylate (TMPeoTA, CAS 28961-43-5), and glycerol propoxylated triacrylate (GPOTA, CAS 52408-84-1) as a weight of evidence approach.

In comparison to Pentaerythritol, olig. react. prod. with 1-chloro-2,3-epoxypropane, react. prod. with acrylic acid the read across substance 2-Propenoic acid, reaction products with pentaerythritol lacks the chain elements derived from 1-chloro-2,3 epoxipropane in between the pentaerythritol and acrylic acid groups. Consequently this leads to a lower molecular weight of app. 300g/mol compared to app 850g/mol for the oligomere. The molecular weight for TMPeoTA and GPOTA is in the same range of app. 300-600g/mol, depending on the amount of ethoxylation, and thus in between the two former substances. All substances are liquids with a low vapour pressure << 0.01hPa and low water solubility of 500-1200mg/l. The log Pow value increases with increasing chain length from 1.5-2.7 for PETIA to 2.5 - 3 for TMPeoTA and GPOTA to > 3 for Pentaerythritol, olig. react. prod. with 1-chloro-2,3-epoxypropane, react. prod. with acrylic acid. All substances are moderate skin sensitizers, but due to the higher amount of acrylic acid on a weight per weight basis, which is presumably quickly hydrolysed, PETIA and to a lesser extent TMPeoTA and GPOTA show an increased irritation potential. While PETIA causes skin irritation, eye corrosion and low acute oral toxicity as a consequence of severe mucosal irritation / erosion, TMPeoTA and GPOTA only lead to eye irritation. In all available repeated dose studies for these substances the primary effect is local irritation in the stomach mucosa. No specific organ toxicity or effects on fertility or developmental toxicity have been observed.

PETIA was tested in an OECD 422 combined repeated dose/reproduction and developmental toxicity screening study via oral route with CRL:CD(SD) rats at concentrations of 0, 25, 75 and 200 mg/kg. Though data on developmental toxicity that can be derived from this study is limited, the fact that no adverse effects on the offspring were observed up to the highest dose of 200mg/kg, which produced maternal toxicity, supports the negative results obtained in other studies using multifunctional acrylates.

The same substance was also tested in an OECD 414 guideline study according to GLP. 25 pregnant females were treated by gavage from gestation day 6 to 15 with 10mg/kg bw of the test substance in corn oil or with the vehicle only. Females were sacrificed on gestation day 20, and the number of corpora lutea, implantation sites, early and late resorptions and live and dead fetuses were recorded. All fetuses were examined externally, weighed and sexed. About one third was subjected to visceral examination, while the remaining fetuses were stained for skeletal examinations. The only clinical signs noted were alopecia, which was considered incidental, and wheezing in a few animals. One female died on day 15, but no cause of death could be determined during necropsy. No substance related lesions were observed in the surviving females. Pregnancy rate, mean number of corpora lutea and implantation sites were unaffected by treatment. No differenes in fetal viability, sex, skeletal or visceral malformations were noted. Thus the NOAEL for teratogenicity was 10mg/kg in this study. But because no maternal toxicity was observed, reliability of the study is limited.

The dosage was selected based on a range finding study, in which 10, 50, and 100mg/kg b.w. in corn oil were administered to 6 pregnant rats per group. No clinical signs except bloody crust and alopecia in one animal each in the high dose group were observed. No effects on body weight or food consumptions were noted in all dose groups throughout the study. Gross pathology revealed dark red areas in the lung of one low dose and one high dose female and mucosal irritation in the stomach in one high dose female. Despite the lack of clear toxicity at all dosage groups, only the lowest dose was tested in the OECD 414 study. In the above mentioned OECD 422 screening study, the NOAEL for systemic toxicity was 75mg/kg after at least 4 weeks of treatment. Thus the required MTD was not reached in the teratology study and it is considered mere supporting information.

Embryotoxic and teratogenic effects of TMPeoTA were examined in a study equivalent or similar to OECD Guideline 414 according to GLP (Cytec, 1984).The test substance was administered orally, admixed in corn oil, to one group of 30 rats at a dosage level of 1,000 mg/kg bw/day, from gestation Day 6 through 15. Control group consisting of 30 bred rats received the corn oil vehicle on a comparable regimen, at 10 mL/kg. All surviving animals were sacrificed on gestation day 20 for the scheduled cesarean section. Fetuses were sexed, weighed and examined for external, skeletal and soft tissue anomalies and developmental variations. Clinical signs of toxicity such as salivation prior to and following dosing, urogenital matting and hair loss from various body surfaces were observed. Mean body weight gains were significantly reduced over the entire treatment period. No embryotoxic effects were apparent. Developmental variations were not remarkably different between the control and test material group. No statistically significant or biologically meaningful differences occurred between the control and treatment regarding the occurrence of malformations. In conclusion, TMPeoTA produced substantial maternal toxicity at a dose level of 1,000 mg/kg bw/day but did not induce a teratogenic or embryotoxic effect in rats.

GPOTA was administered by gavage to 30 rats per group in a GLP guideline study similar to current OECD guideline 414 (Cytec, 1984). The substance was administered in corn oil at a dosage level of 1,000 mg/kg bw/day, from gestation day 6 to 15. The control group received the vehicle only. All surviving animals were sacrificed on gestation day 20 for the scheduled cesarean section. Fetuses were sexed, weighed and examined for external, skeletal and soft tissue anomalies and developmental variations. Clinical signs of toxicity such as salivation prior to and following dosing, urogenital mating and hair loss from various body surfaces were observed. Mean body weight gains were significantly reduced over the entire treatment period. No embryotoxic effects were apparent and developmental variations were not remarkably different between the control and test material group. No statistically significant or biologically meaningful differences occurred between the control and treatment regarding the occurrence of malformations. In conclusion, GPOTA produced observable maternal toxicity at a dose level of 1,000 mg/kg bw/day but did not induce a teratogenic or embryotoxic effect in rats.

Justification for classification or non-classification

No effects on fertility were observed in an OECD 422 study using PETIA. Additionally, pubs were not affected by treatment up to 75mg/kg. In a partly reliable OECD 414 study, in which the maternal MTD was not reached, no effects on parameters for developmental toxicity or teratogenicity were noted. Two GLP guideline studies equivalent to OECD 414 with two further structurally related multifunctional acrylates revealed no hints for developmental toxicity or teratogenicity up to the limit dose of 1000mg/kg b.w., which caused substantial maternal toxicity. In summary, based on these data no concern is raised that the multifunctional acrylates cause toxicity to reproduction. As a result, no effects are expected for Pentaerythritol, olig. react. prod. with 1-chloro-2,3-epoxypropane, react. prod. with acrylic acid. Therefore, the test substance does not require classification according to 67/548/EEC or CLP/EU-GHS concerning reproductive toxicity.