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Key value for chemical safety assessment

Effects on fertility

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

No independent studies for toxicity to fertility of ethoxylated trimethylolpropane triacrylate (TMPeoTA) are available.However a read across to a structural similar substance can be performed to close the information gap.

 

Read across to OECD conform studies:

1,6-Hexamethylene Diacrylate (HDDA) containing similar structure elements like GPOTA was tested in a Combined 28-Day Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD TG 422 and in compliance with GLP (ReachCentrum, 2010, Stump D.G.). The test substance, in the vehicle corn oil, was administered orally by gavage once daily to 3 groups of Crl: CD(SD) rats, each group consisting of 12 males and 12 females. Dosage levels were 75, 250, and 750 mg/kg bw/day administered at a dosage volume of 5 mL/kg bw. A concurrent control group of 12 rats/sex received the vehicle on a comparable regimen. Males and females were approximately 11 weeks of age at the beginning of test substance administration. Males received 14 daily doses prior to mating. Males were dosed throughout the mating period through 1 day prior to euthanasia for a total of 28 doses. Females received 14 daily doses prior to pairing and were dosed through lactation day 4 for a total of 41-49 doses; females that failed to deliver were dosed through the day prior to euthanasia (post-mating or post‑cohabitation day 25) for a total of 39-52 doses.All animals were observed twice daily for mortality and morbidity. Clinical observations, body weights, and food consumption were recorded at appropriate intervals. and locomotor activity data were recorded for 6 males/group following approximately 28 days of dose administration and for 6 females/group on lactation day 4. All F0 females were allowed to deliver and rear their pups until lactation day 4. F1 clinical observations and body weights were recorded on PND 1 and 4. Pups were euthanized and discarded on PND 4. Clinical pathology evaluations (haematology, serum chemistry, and urinalysis [males only]) were performed on 6 F0 animals/sex/group at necropsy. F0 males were euthanized following completion of the mating period. F0 females were euthanized on lactation day 5 for females that delivered and post-mating or post-cohabitation day 25 for females that failed to deliver. Complete necropsies were conducted on all F0 animals, and selected organs were weighed. Selected tissues were examined microscopically from all F0 animals in the control and high-dose groups; the liver, stomach, and gross lesions from all animals in all dosage groups were also examined microscopically.No incidences of mortality or moribundity were attributed to systemic toxicity of the test substance. In the 750 mg/kg bw/day group, a single female was found dead following dose administration on gestation day 21. However, due to the lack of evidence of test substance-related toxicity in this female, as well as the time of mortality relative to dose administration (11 minutes following dosing), this single mortality was not attributed to systemic toxicity of the test substance. All other animals in all dosage groups survived to the scheduled necropsies. Test substance-related clinical findings were noted in the 250 and 750 mg/kg bw/day group males and females and included wiping mouth on cage floor and/or walls, excessive pawing of cage floor and/or walls, wiping mouth in bedding material following dosing (females only), salivation-related findings, and red material around the mouth. The salivation-related findings were also occasionally noted in the 75 mg/kg bw/day group animals. Because the aforementioned clinical findings were noted at the time of dosing and/or approximately 1 hour following dose administration, they were attributed to the irritative properties of the test substance and not considered adverse. In the 750 mg/kg bw/day group males, test substance-related lower mean body weight gain and food consumption were noted during the pre-mating period, resulting in mean male body weight that was 6.8% lower than the control group on study day 28. Mean body weights, body weight changes, and food consumption were unaffected by test substance administration in the 75 and 250 mg/kg bw/day group males throughout the study and in the 75, 250, and 750 mg/kg bw/day group females during the pre-mating, gestation, and lactation periods.No test substance-related effects were noted during the FOB or locomotor activity evaluations at any dosage level.Test substance administration was associated with micro- to macrovesicular vacuolar change within the liver at 75, 250, and 750 mg/kg bw/day. This vacuolar change was also present within the liver of 3 control group animals (2 males and 1 female). The change in the control group animals and all test substance-treated animals was minimal to mild and there was no evidence of cellular or tissue damage; therefore, the change was not considered to be an adverse effect. At 750 mg/kg bw/day, higher liver weights, higher serum bile acid values, and higher urea nitrogen values were noted in both males and females, a higher total bilirubin value was noted in males, and higher ALT, cholesterol, triglycerides, calcium, and phosphorous values were noted in females. At 250 mg/kg bw/day, a higher ALT value was noted for females; however, this difference was not statistically significant and was not considered to be an adverse effect. Test substance administration at dosage levels of 250 and 750 mg/kg bw/day to males and females was associated with squamous epithelial hyperplasia and hyperkeratosis in the non‑glandular stomach. This was a manifestation of local irritation rather than a systemic effect; therefore, it was not considered to be systemically adverse.

Based on reduced mean body weights and body weight gains in the 750 mg/kg bw/day group males and adverse changes in serum chemistry parameters associated with increased liver weights in the 750 mg/kg bw/day group males and females, the NOAEL for systemic toxicity was considered to be 250 mg/kg bw/day.

Under the conditions of this screening study, a test substance-related effect on the process of implantation was suspected in the 750 mg/kg/day group females by the author of the study. However, the described effects concerning the implantation process were also assessed and discussed independently by external experts. These effects were assessed to be equivocal, and accordingly the NOAEL for reproductive toxicity of HDDA when administered orally by gavage to Crl: CD(SD) rats was set at 750 mg/kg bw/day.


Short description of key information:
Combined 28d reproductive, rat, oral, daily application, OECD 422, read across to HDDA: NOAEL (reproductive) = 750 mg/kg bw/d (ReachCentrum, 2010, Stump D.G.)

Effects on developmental toxicity

Description of key information
Teratogenicity screening, rats, OECD 414: NOAEL (embryotoxicity, teratogenicity) ≥ 1000 mg/kg bw, NOAEL (maternal toxicity)  < 1000 mg/kg bw (Cytec, WIL research laboratories, 1984, Rodwell D.E.).
Effect on developmental toxicity: via dermal route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information

Valid experimental data are available to assess the developmental toxicity of ethoxylated trimethylolpropane triacrylate (TMPeoTA). However a read across to a structural similar substance can be performed to close the information gap.

 

OECD conform studies:

A study was designed to screen potential maternal, embryotoxic and teratogenic effect of TMPeoTA in rats. The study was conducted equivalent or similar to OECD Guideline No. 414 in compliance with Good Laboratory Practices (Cytec, WIL research laboratories, 1984, Rodwell D.E.).The test substance was administered orally, admixed in corn oil, to one group of 30 bred 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. Throughout gestation, all rats were observed twice daily for signs of toxicity. Body weights were recorded at appropriate intervals. 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.

Assessment of toxicity on reproduction:

No information for TMPeoTA on fertility are available. But nevertheless a read across to a acrylate containing similar structure elements shows an NOAEL of 750mg/kg bw (i.e. the highest tested dose). Additional no embryotoxicity or teratogenicity could be observed in a screening study up to highest tested dosage (Cytec, WIL research laboratories, 1984, Rodwell D.E.). 

 

In summary results from a fertility and developmental toxicity study did not reveal any reason of concern for offspring and for parent animals with respect to developmental toxicity or fertility. Since significant scientific evidence for a lack of reprotoxic effects of the substance is drawn from these results and an additional two generation study is not expected to add any further relevant knowledge on this endpoint. Due to animal welfare aspects and/or laws, an additional study is therefore not warranted.

 

Key study assignment:

As there is only one reliable and relevant study investigating the reproductive toxicity this study is integrated as key study.

Justification for classification or non-classification

As there is, in result, no evidence for reproduction toxicity potential from a human or animal study the test material does not fulfil the requirement according to GHS (Regulation (EU) 1272/2008) or DPD (67/548/EEC) to be labelled as reproductive toxicant.

Labelling reproductive toxicant:

GHS: no labelling

DSD: no labelling