Tributyl phosphate

Carcinogenicity

Description of key information

The carcinogenic potential of tributyl phosphate was investigated in 2 studies in rats and mice.  Additionally a mechanistical study was conducted to clarify the findings.
Tributyl phosphate was administered orally, via dietary admixture, to Sprague-Dawlay CD rats at dose levels of 200, 700, and 3000 ppm in diet for a period of at least twenty-four month. Physical observations, body weight and food consumption measurements, hematology and urinalyses were performed on all animals pretest and at selected intervals during treatment period. After at least 24 months of treatment, all survivors were sacrifieded. Complete gross postmortem examinations and histopathological evaluation of selected tissues were conducted on all animals.
Tributyl phosphate was administerd orally, via dietary admixture, to 300 mice (50/sex/group) at dose levels of 150, 1000, and 3500 ppmfor a period of at least 18 month. Control animals (50/sex) received untreated standard laboratory diet. Complete gross postmortem examinations were performed on all animals. Histopathological evaluation of selected tissues was conducted on all animals in the control and high-dose groups as well as on any animal in the low-dose and mid-dose groups which died prior to the scheduled sacrifice interval. In addition, the kidney, liver, lungs, and urinary bladder and any lesions seen grossly at necropsy were examined from all animals in the low-and mid-dose groups.
A special subchronic dietary study to examine the mechanism of urinary bladder carcinogenesis in the rat was performed.
In this study, six groups of rats were administered either TBP (200, 700, or 3,000 ppm), NH4Cl (12,300 ppm), or TBP + NH4C1 (3.000 + 12.300 ppm) as an admix to their diet for 10 weeks. A 10 week reversibility (recovery) phase was also included in the study design, using animals from the control and 3.000 ppm TBP exposure groups. During Weeks 10 and 11 as well as 20 and 21 (reversibility animals), freshly voided urine was collected for ...

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

8.9 mg/kg bw/day

Additional information

Malignant tumors (transitional cell carcinoma or squamous cell carcinoma) in the rat were present in high-dose males and females. Microscopically, an increased incidence of tissue masses in the urinary bladder was seen in high-dose males. No other effect of the test material was evident from pathology examinations.

Macroscopic and microscopic pathology examinations in the mouse study revealed as the only difference related to tributyl phosphate administration a statistically significant increase in the incidence of begnin liver tumors (hepatocellular adenomas) in high-dose males.

In the mechanistic study TBP was again shown to produce urinary bladder proliferation. Proliferation occurred at the 700 and 3.000 pprn doses of TBP, with the changes being more severe at the higher dose. No changes were observed at a dose of 200 ppm. The proliferative response was completely reversible in a group fed 3,000 pprn TBP for 10 weeks followed by control diet for 10 weeks. Submucosal fibrosis was present at 21 weeks of the total study, representing repair of ulceration and inflammation produced by TBP administration.

One possible hypothesis behind the origin of TBP-induced urothelial necrosis and ulceration, might be that they are the consequence of secondary responses to the of one or more of the metabolites of TBP since little TBP is excreted unchanged in the urine. Repeated cellular damage followed by chronic compensatory repair eventually leads to the transformation of normal epithelial

cells to metaplastic and neoplastic forms. The indirect mechanism for this cell transformation is supported by the lack of genotoxicity, lack of increased mitotic activity (labeling index), and full reversal of the hyperplasia and proliferation after 10 weeks treatment followed by 10 weeks of recovery. These data support a low human health risk from exposure to TBP.

Justification for classification or non-classification

The results of the mechanistic study und confirm that TBP is not a genotoxic carcinogen. No evidence of a mutagen potential was evident in all genetic toxicity studies. In can be concluded that TBP via organspecific cytotoxicity causes urinary bladder hyperplasia and necrosis. The indirect mechanism for the cell transformation is supported by an increased mitotic activity and full reversal of the hyperplasia and proliferation after 10 weeks treatment followed by 10 weeks of recovery. These data support a low human risk from exposure to TBP.

Therefore a classification as Carc. Cat 3; R40 (GHS: Cat. 2, H 341) is justified.