Reaction mass of (2,4,6-trioxo-1,3,5-triazine-1,3,5(2H,4H,6H)-triyl)tri-2,1-ethanediyl triacrylate and 2-Propenoic acid, 1,1'-[[dihydro-5-(2-hydroxyethyl)-2,4,6-trioxo-1,3,5-triazine-1,3(2H,4H)-diyl]di-2,1-ethanediyl] ester

Carcinogenicity

Description of key information

Carcinogenicity, mice and rats, dermal (NTP 2012, similar to OECD 451, acc. to GLP)

Carcinogenicity, mice, dermal, 80 weeks (2 times/week/50mg): not carcinogenic (Cytec, Kettering, 1982 Barkley W.) but less reliable.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

chronic

Species:

other: rats and mice

Quality of whole database:

Key study according to GLP, following NTP standard protocol. Thus, a klimisch score of 1 for key study.

Justification for classification or non-classification

In summary, no human relevant carcinogenic hazard can be deduced from these studies. Margnial differences observed in the NTP study are considered incidental and not test-substance related based on the arguments presented above and in the robust study summary. Thus TMPTA does not fulfil the requirement according to GHS (Regulation (EU) 1272/2008) or DPD (67/548/EEC) to be labelled as carcinogen.

Classification carcinogenicity:

GHS: no classification

DSD: no classification

Additional information

In a carcinogenicity study performed by NTP in 2012, 65 male and female mice or rats per group were dermally exposed to 0, 0.3, 1.0, and 3.0mg/kg trimethylolpropane triacrylate for 2 years. Interim kills of 5 animals per sex and group were performed after 2, 13, and 52 weeks to evaluate effects on the skin. Survival and body weight gain was unaffected by the test substance. Rats and mice of the mid and high dose groups and low dose female rats showed increased incidences of epidermal hyperplasia, hyperkeratosis, and signs of chronic inflammation (mice). Despite these local effects, no increase in skin tumors compared to control animals could be detected. No test-substance related increase in neoplastic lesions was found for male mice and female rats.

In male rats, there was a positive trend in the incidences of malignant mesothelioma (0%, 4%, 4%, 10% for 0, 0.3, 1, 3mg/kg). In all cases, they arose from the tunics around the testes. The increase was significant in animals receiving 3mg/kg, but only exceeded the recent historical control range by one tumor. In addition, this is a common spontaneous lesion of the peritoneal cavity in male F344/N rats (Hall, 1990). Because of the variability of these tumors in the historical controls and the fact that the incidence in the high dose group was only one tumor outside of the historical control range, the marginally increased incidences were considered to be equivocal evidence of carcinogenic activity of trimethylolpropane triacrylate in male rats. A recently published review by Maronpot and colleagues examined the nature of tunica vaginalis mesothelioma (TVM) responses in 21 published rat cancer bioassays. Maronpot reported that TVM induction is a male F344 rat-specific (and possibly strain-specific) event, and in the absence of other chemical-induced tumorigenesis, is likely to be irrelevant in human risk assessment. Also in contrast to rats, the tunica vaginalis in the adult human does not directly connect to the peritoneal cavity. 

In female mice the increase in hepatoblastoma was not significant and not dose related (0%, 4%, 0%, 6% for control, low, mid, and high dose). Thus they are not considered to be treatment related by the registrant despite low incidences in historical control animals. 1 and 2 of 50 mid and high dose female mice developed hepatocholangiocarcinoma. This rare tumor has not been observed in concurrent and recent historical controls, but occured with a frequency of 0-4% (0-2 tumors per 50 mice) in older historical controls.

The incidences of uterine stromal polyps showed a positive trend and were significantly increased in the 3mg/kg group. The incidences of 0%, 2%, 4%, and 10% in control, low, mid, and high dose female mice exceeded recent historical control data by on tumor (0-8%), but were within older historical control data (0-16%). The incidences of uterine sarcoma was not affected by the test substance. In a publication by Davis (2012), a range of 0 -14.3% is reported in B6C3F1/N female mice for the incidence of benign stromal polyps. Endometrial stromal polyps in rodents appear as age-related lesions. Endometrial polyps that occur in women have distinctly different characteristics. Human endometrial polyps develop from both endometrial and stromal components, whereas rodent stromal polyps develop from stromal components only. Endometrial polyps in women are clearly hormone sensitive, while in rodents, these lesions do not appear to be hormonally sensitive. Based on these key differences, stromal polyps observed in rodents have at most limited, but probably no relevance to humans.

It should be noted that TMPTA was not carcinogenic on the skin of rats and mice, even though it was dermally applied at doses, which produced significant irritation and dermal injury. Although NTP absorption studies showed uptake of approximately 30% through the skin, the highest amount of TMPTA must have been present on or in the skin. Additionally, TMPTA is rapidly metabolized (most likely conjugated to glutathione in blood) and excreted via urine, so that quantification of the parent compound in blood was impossible. Considering that TMPTA is not genotoxic as discussed in the section on mutagenicity and does not accumulate in vivo, the applied doses of up to 3mg/kg b.w. are too low for tumor induction especially in non-target tissues. The observed increases in tumor incidence are marginal (1 tumor above recent historical control data), and are within historical control data obtained with a different kind of diet (NIH07). Interpretation of historical control data is also limited by the fact that no studies exist in the database, which used aceton as vehicle for dermal application. In conclusion, the increases in tumor incidences are considered incidental by the registrant and not substance related.

Studies according to other protocols:

A study was conducted to assess the carcinogenic potential of trimethylolpropane triacrylate (TMPTA) in C3H/HeJ male mice (Cytec, Kettering, 1982 Barkley W.). Therefore Groups of C3H/HeJ male mice (50/dose) received topical application of 50 mg of the test substance (5 % in white mineral oil) to shaved area of the back, twice weekly for 80 weeks. A group of solvent control and positive control (0.05% benzo(a)pyrene in mineral oil) were also maintained along with no-treatment control group in the study. Parameters evaluated included clinical signs, mortality, body weight, gross pathology and histopathological (neoplastic and non-neoplastic) examinations. The gross observations made at necropsy were dark red lesions in lungs, liver tumors, kidney haemorrhages, enlarged spleen, skin ulcers, flaky skin, enlarged and grey lymph nodes, haemorrhages in stomach, grey or yellow spots in adrenals. Non-neoplastic histopathologic lesions included ulcer, abscess, acanthosis, dysplasia, fibrosis, pigmentation, hyperkeratosis and retention cyst. In accordance with the NTP study, no skin tumors were found in treated animals. In conclusion, test substance trimethylolpropane triacrylate (TMPTA) was considered to not carcinogenic in mice.

Justification for selection of carcinogenicity via dermal route endpoint:

Two relevant studies available:

Carcinogenicity, mice and rats, dermal (NTP 2012, similar to OECD 451, acc. to GLP) identified as key study.

Carcinogenicity, mice, dermal, 80 weeks (2 times/week/50mg): not carcinogenic (Cytec, Kettering, 1982 Barkley W.) but less reliable, thus supporting study.

Carcinogenicity: via dermal route (target organ): other: skin