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Toxicological information

Carcinogenicity

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The toxicology of TBEP has been investigated in oral studies of up to 18 weeks, leading to the conclusion that this substance is of low toxicity, causing mild effects on the liver at high doses. A subacute study by the dermal route did not report any systemic toxicity. The genotoxic potential of TBEP has been investigated both in vitro and in vivo. All tests gave negative results, leading to the conclusion that TBEP is not genotoxic.
Although no chronic carcinogenicity study has been performed, the available data indicate that TBEP does not present a carcinogenic hazard.

Key value for chemical safety assessment

Additional information

Genotoxicity

Substances are considered of greatest concern for carcinogenicity if they are able to interact with DNA to cause mutations or chromosomal damage. For such substances it is not possible to establish a threshold below which there would be not risk of genetic damage which could lead to cancer.

TBEP has been subjected to a series of tests to investigate its genotoxic potential:

Genotoxicity in vitro:

The mutagenic potential of TBEP has been examined in four separate studies in bacteria (Haworth 1979, 1983; Kouri, 1978; Monsanto 1984) using the reverse gene mutation assay (Ames test). There was no evidence of induction of mutations in any of these studies either with or without metabolic activation.

The potential of TBEP for mutagenicity in mammalian cells has been investigated in two different cell systems, the Chinese Hamster Ovary HGPRT mammalian cell forward gene mutation assay (Monsanto, 1985) and in mouse lymphoma cells (Kirby, 1981). There was no evidence of mutagenicity with or without metabolic activation in either of these tests.

Genotoxicity in vivo:

The potential of TBEP for genotoxicity in vivo has been investigated in the micronucleus test (Muller, 1991). TBEP was administered to male and female mice once by gavage at doses of 0 and 1800 mg/kg. The animals were killed 24, 48 or 72 hours after the administration of the test compound. The number of polychromatic and normochromatic erythrocytes containing micronuclei was not increased. The ratio of polychromatic/normochromatic erythrocytes was not affected by treatment in male or female mice. TBEP was considered not mutagenic in the micronucleus test.

Conclusion on TBEP Genotoxicity

The absence of mutations or chromosomal damage from TBEP exposure according to in vitro cells systems or in intact animals indicated that TBEP can be considered not to have genotoxic potential. TBEP therefore does not have any potential to cause cancer by such mechanisms.

 

Repeated dose Toxicity Studies

Data are available from toxicity studies on TBEP by the oral and dermal routes. No studies have been carried out by the inhalation route since its vapour pressure is very low (0.0000152 Pa at 25°C) and aerosol exposure is not to be expected from its use pattern.

In a subacute dermal study (Tierny, 1985), rabbits were exposed to 10, 100 and 1000 mg/kg TBEP on 21 consecutive days. There were no deaths and no adverse clinical signs of toxicity. No adverse systemic toxicity was observed following dosing at any dose level. Local irritation occurred in a dose-related manner and severity and increased with time.

The NOAEL for systemic toxicity was 1000 mg/kg bw/day, however no NOAEL for local effects could be established.

In one subchronic oral toxicity study (Reyna, 1987), TBEP was administered in the diet to Sprague-Dawley rats at 300, 3000 and 10,000 ppm (approximately 20.4, 204 and 612 mg/kg bw/day) for 18-weeks. The only haematological and clinical chemistry changes were increased platelet counts (at 10,000 ppm both sexes) and increased serum gamma glutamyl transpeptidase and a depressed plasma cholinesterase in the 3000 and 10,000 ppm groups. Increased liver weight (both absolute and relative in both sexes) was found in the 10,000 ppm dose group. Microscopic examination revealed mild periportal hepatocellular hypertrophy and periportal vacuolisation in males only at 3000 and 10,000 ppm. The liver was therefore the only target organ in this study, with treatment-related effects at the high dose level of 10,000 ppm and minimal effects at the mid-dose level of 3000 ppm. Based upon the results of this study the no-effect level (NOEL) is considered to be at least 300 ppm TBEP in the diet (equivalent to approximately 20.4 mg/kg bw/day), for both sexes. The LOAEL is 3000 ppm (204 mg/kg bw/day) based on mild liver effects.

In another subchronic study (Saito, 1994), Wistar rats were fed a diet containing 0.03, 0.3 or 3.0% TBEP for 5 or 14 weeks. Body weight gain was suppressed in all rats in the top dose groups (3.0%). Serum cholinesterase activity was significantly decreased in both sexes in the 0.3 and 3.0% groups and serum gamma glutamyl transferase was significantly increased in both sexes in the top dose group after both 5 and 14-weeks of exposure. Serum amylase levels were also increased in males (0.3 and 3.0 % groups) and in females (3%). The target organ in this study was the liver; absolute and relative liver weights in both sexes were significantly increased in the top dose group (3.0%) after both 5 and 14-weeks of treatment. Histopathological examination showed only male rats in the top dose group (3.0%) to exhibit moderate periportal hepatocyte swelling after 14-weeks. The authors concluded that the NOEL for the dietary study was 0.03 % diet (male rat: 20 mg/kg bw/day; female rat: 22mg/kg by/day), and LOAEL of 3.0% (200 mg/kg bw/day) based on mild liver effects.

The results of the two oral studies are consistent, establishing that the liver is the target organ for TBEP toxicity. Only mild effects on the liver were reported at 200 mg/kg bw/day, with no effects at 20 mg/kg bw/day.

Carcinogenicity

No chronic or carcinogenicity studies have been conducted on TBEP. In the oral sub-chronic studies the only organ affected was the liver. The liver toxicity was mild, with no evidence of an effect such as hepatocellular hyperplasia which could be considered as a precursor of changes potentially leading to cancer. There is therefore no evidence to consider TBEP likely to be a carcinogen by a non-genotoxic mechanism.

Justification for classification or non-classification

TBEP does not show genotoxicity in mutagenicity or clastogenicity studies in vitro or in vivo.There is no evidence from repeated dose toxicity studies that TBEP is able to induce hyperplasia and/or pre-neoplastic lesions. Therefore, although no full carcinogenicity study is available, there is no evidence to suggest that TBEP has any carcinogenic potential.

TBEP is therefore not classified for carcinogenicity according to the criteria of Annex VI Directive 67/748/EECor UN/EU GHS.