Tris[2-chloro-1-(chloromethyl)ethyl] phosphate

Carcinogenicity

Description of key information

The results obtained in a two year carcinogenicity study (Stauffer Chemical Company, 1981a; Freudenthal, R.I. and Henrich, R.T., 2000) indicate possible concern for man due to the development of adenomas (renal, hepatocellular and adrenal) in addition to Leydig cell tumours in rats. 

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

LOAEL

5 mg/kg bw/day

Justification for classification or non-classification

TDCP is classified as Carc. Cat. 2 H351 " suspected causing cancer” based on the results of the above carcinogenicity study further supported by a non-genotoxic mode of action for carcinogenic effects for TDCP.

Additional information

In a 2-year carcinogenicity study, in which groups of 60 male and 60 females rats were fed diets containing TDCP to achieve dose levels of 0, 5, 20 and 80 mg/kg/day, there was a significant increase in the incidence of renal cortical adenomas in mid and high dose animals at 24 months. There was no increase at 12 months.  The incidence of benign testicular interstitial cell tumours was also increased in the mid- and high-dose animals at both 12 and 24 months. Hepatocellular adenomas and adrenal cortical adenomas were statistically increased in the high dose animals at 24 months.

In the testes, there was an increased incidence of Leydig cell tumours in the mid and high dose males at both 12 and 24 months. The mechanism by which TDCP induces such tumours is not known. It is reported that one non-genotoxic mode of action by which chemicals can induce such tumours is attributed to alterations in the Hypothalmus-Pituitary-Testis (HPT) Axis which results in elevated levels of luteinising hormone (LH). Increases in LH levels have been shown to be necessary for the induction of Leydig cell tumours through chronic stimulation of the Leydig cells. There are seven known non-genotoxic hormonal mechanisms which have the potential to disrupt the HPT axis leading to Leydig cell tumour induction. Two of these modes of action are not considered of relevance to humans (GnRH antagonism and dopamine agonism) (Clegg et al.,1997). However, the other five mechanisms, (5 α-reductase inhibition, androgen receptor antagonism, inhibition of testosterone biosynthesis, aromatase inhibition and exogenous oestrogen agonism) have been considered to be potentially relevant to humans.

Overall, while the mode of action by which these tumours are induced cannot be identified, there may be some concern for man regarding their formation.

A LOAEL of 5 mg/kg/day is based on the hyperplasia of the convoluted tubule epithelium with increased incidences observed in all treated male animals and in high dose females at 24 months. Hyperplasia was observed from the lowest dose tested. Hyperplasia is often considered as a pre-neoplastic lesion, which can lead to tumour formation. The study report does not provide enough detailed information to conclude whether the hyperplasia observed following treatment with TDCP would progress to cancer or whether the tumours observed with TDCP arise through a different mechanism. However, it is not unreasonable to assume that the tumours have developed through hyperplastic changes.

There is some evidence to suggest that TDCP is mutagenic in vitro. However, in vivo mutagenicity studies were negative, indicating that, in vivo, TDCP is non-genotoxic. This indicates that TDCP may be assumed to be a threshold carcinogen.

In a study carried out to look at the mortality experience of worker in a TDCP manufacturing plant, there was a higher than expected number of lung cancers among male workers. However, the report concluded that there was no evidence linking these lung cancers with exposure to TDCP. There were no other cancers observed.

Carcinogenicity: via oral route (target organ): urogenital: kidneys; urogenital: testes