Registration Dossier

Administrative data

Description of key information

Oral: 
Read across to HDDA: rat, oral, combined 28d reproductive, daily application, OECD 422: NOAEL (systemic, rats) = 250 mg/kg bw/d (ReachCentrum, 2010, Stump D.G.)
Dermal:
Read across to TMPTA:, rats, dermal, subacute 14/28 days (16 days, 5days/week), NTP protocol: NOAEL, (f/m, systemic, rats): ≥200 mg/kg bw, NOAEL (f/m, local, rats): 25mg/kg bw (Publication: 14/28 day NTP, Battelle Columbus Laboratories, 2005)
Carcinogenicity, mice, dermal, 94 weeks (2 times/week/25µL 10% v/v aceton): not carcinogenic, no systemic effects NOAEL ≥ 19.5 mg/kg bw/d (Cytec, Kettering Laboratory, 1987, Barkley W.) but less reliable
Inhalation:
No data available

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
rat

Additional information

There are no valid sub acute / chronic study data available to assess the repeated dose toxicity of ethoxylated trimethylolpropane triacrylate (TMPeoTA). Nevertheless information about the repeated dermal toxicity is available from the structural similar substance Trimethylolpropane triacrylate (TMPTA CAS:15625-89-5) and information about the oral toxicity of acrylates can be adapt from 1,6-hexamethylene diacrylate (HDDA CAS: 13048-33-4) containing similar structure elements. Primarily a read across is performed but results were underlined by a repeated dose dermal carcinogenicity study performed with an outdated protocol an therefore rated as less reliable. 

 

Studies according to other protocols:

A lifetime study was conducted to assess the carcinogenic potential and chronic dermal toxicity of TMPeoTA in male C3H/HeJ mice (Cytec, Kettering Laboratory, 1987, Barkley W.). Therefore groups of male C3H/HeJ mice (50/dose) were topically treated with 25 µL of 10 % v/v in acetone, twice weekly for 94 weeks. The dose and concentration of each material were selected after completion of a pilot study. Control animals received no treatment or 50 µL of acetone twice weekly. Positive control group received 50 µL twice weekly of 0.025 % benzo(a)pyrene (BaP) in acetone. The skin from all animals was examined histologically for non-neoplastic and neoplastic lesions. Histological examination of internal organs was performed on one half of the mice of each group. Survival (%) in mice treated with TMPeoTA was calculated to be 100, 98, 92, 62, 58, 32 and 24 at 13, 26, 39, 52, 65, 78 and 91 weeks, respectively. No significant difference in body weight gains was observed between the test and control groups. Slight to moderate hyperkeratosis (in 12 mice); no treatment-related skin neoplasms (one lesion, diagnosed grossly as a skin tumor, was actually an abscess in the dermis; skin tumor in another mouse was a metastasis from lymphocytic lymphoma) were observed at the application sites. Examination of internal organs revealed no treatment related lesions. Pathological examination revealed infectious diseases; age-related atrophy of testes and keratosis of the epithelium in the forestomach; epithelial papilloma in the urinary bladder (in 1 mouse), angioma in the spleen (in 1 mouse) and liver (in 2 mice) and hepatocellular carcinomas (in 2 mice). In conclusion, TMPeoTA was not carcinogenic in male C3H/HeJ mice. (Applicant calculation of application per day: 1000/30 (correction bw) * 25µL * 0.1 (concentration) 0.82 g/cm3 (density correction 20µl TI + 180µL aceton (ideal calculated))) * 2/7 (two time per week application without depot)=19.5 mg/kg bw/d, no systemic effects observed at this concentration).

 

Read across to structural similar substances:

As there are no information on oral/dermal subacute / subchronic toxicity for TMPeoTA are available a read across to the structural similar substance trimethylolpropane triacrylate (TMPTA) and 1,6-Hexamethylene Diacrylate (HDDA) was conducted.

 

Dermal:

In a NTP 14/28 day study TMPTA (CAS 15625-89-5) (a structural similar substance to TMPeoTA) was dermal applied to rats. In this study groups of five male and five female F344/N rats were administered 0, 12.5, 25, 50, 100, or 200 mg trimethylol propane triacrylate (CAS: 15625-89-5) /kg body weight in acetone 5 days per week for 16 days (Publication: 14/28 day NTP, Battelle Columbus Laboratories, 2005). All rats survived to the end of the study, and mean body weights of dosed groups were similar to those of the vehicle controls. Dosed rats had irritation at the site of application; this clinical finding was most commonly seen in rats administered 50 mg/kg or greater. Male and female rats had epidermal hyperplasia, hyperkeratosis, sebaceous gland hyperplasia, inflammation of the epidermis and dermis, ulceration, epidermal degeneration, and parakeratosis at the site of application. In consequence a NOAEL (rat/mice, systemic, dermal):≥ 200mg/kg bw was deduced.

 

Oral:

1,6-Hexamethylene Diacrylate (HDDA) 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 regulations by WIL Research Laboratories for ReachCentrum (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 moribundity. 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.

The 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). To the opinion of the applicant 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.

According to the applicant 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.

 

 

Assessment repeated dose toxicity:

All available information is taken into account to assess the repeated dose toxicity of TMPeoTA. As there are no information on oral/dermal subacute / subchronic toxicity for TMPeoTA are available a read across to the structural similar substance trimethylolpropane triacrylate (TMPTA) and 1,6-Hexamethylene Diacrylate (HDDA) was conducted. Results from these study were used as key information underline by the result from an outdated repeated dose study (carcinogenicity study) with TMPTA. This carcinogenicity study is rated as less reliable as the protocol is outdated and only one (low) dosage was tested.

 

Both reliable sub acute (read across) studies show a low oral and dermal toxicity (NOAEL (oral, systemic, rats) = 250 mg/kg bw/d(ReachCentrum, 2010, Stump D.G.)and NOAEL (dermal, systemic, rats): ≥200 mg/kg (Publication: NTP, Research Triangle Institute, 2005)) These result are confirmed by the results of a less reliable lifetime carcinogenicity study. In this study if 25µL 10% TMPeoTA were applied twice a week dermal to mice without systemic effects (NOAEL ca 19.5mg/kg bw/d). This dosage might be much lower but the chronic application has to be taken into account. Nevertheless the real NOAEL maybe also higher.

Summarising a low dermal and oral toxicity can be assumed from read across to structural similar substance whereas the low dermal toxicity is also confirmed by a less reliable lifetime carcinogenicity study.

Subacute study values were used for risk assessment.

 

Key study assignment:

As there is only one reliable and relevant study per route investigating the long term effects of TMPeoTA via read across both studies(ReachCentrum, 2010, Stump D.G.) and(Publication: 14/28 day NTP, Battelle Columbus Laboratories, 2005) are entered as key studies. Nevertheless the outdated carcinogenicity study (Cytec, Kettering Laboratory, 1987, Barkley W.) is attached as supportive information.

Justification for classification or non-classification

As the lowest NOAEL obtained was ≥200 mg/kg (Publication: NTP, Research Triangle Institute, 2005) and no specific target organ toxicity could be observed at this concentration a classification according to GHS (Regulation (EU) 1272/2008) as specific target organ toxicity or an additional classification according to DPD (67/548/EEC) as harmful R48 is not indicated or justified.

 

Labelling for specific target organ toxicity or danger at prolonged exposure:

GHS: no additional labelling

DSD: no additional labelling