Reaction products of phosphoryl trichloride and 2-methyloxirane

Carcinogenicity

Description of key information

Overall we conclude, that TCPP is not genotoxic in vivo. The study of longest duration available for TCPP is a 90 day oral study in rats. In this study no pre-neoplastic lesions were observed and the the LOEL (probably close to the NOAEL) in this study is based on liver weight changes only without any histopathological alterations. Furthermore the effect levels in the 28-day and 3-month study are comparable and do not suggest any aggravation of effects with study duration. In the rat, TCPP is metabolised to 0,0-[bis(1-chloro-2-propyl)]-0-(2-propionic acid)phosphate, bis(1-chloro-2-propyl)monophosphoric acid and 1-chloro-2-propanol. (1, 2).
It is important to note that 1-chloro-2-propanol has been studied in 2-year studies for its carcinogenicity in rats and mice and was not carcinogenic in both species . Thus the results of repeated dose and carcinogenicity studies of one of the main metabolites of TCPP corroborate the findings with TCPP and provide some supporting evidence for the mode of action and behaviour in studies with longer duration. Therefore it is in our opinion reasonable to assume that at exposure levels below the levels that cause changes in liver weight, no tumour formation is to be expected with TCPP. Consequently we suggest basing the risk assessment and DNEL derivation for carcinogenicity on the LOAEL for repeated dose toxicity and using the same assessment factor as for repeated dose toxicity (3).
References:
1 Stauffer chemical company (1984). 
2 Herbst HJ (1997). Untersuchungen zum Mechanismus der Tumorigenität und Toxizität der Flammschutzmittel Tris-(2-chlorethyl)-phosphat und Tris-(chlorpropyl)-phosphat. Thesis for Doctorate Degree in Natural Sciences at the Bayerischen Julius Maximilian University, Würzburg 1997.
3 NTP TR 477 (1998). NTP Technical Report on the Toxicology and Carcinogenesis studies of 1-chloro-2-propanol (technical grade) (CAS No. 127-00-4) in F344/N rats and B6C3F1 mice (drink water studies). NTP, Sept 1998.

Justification for classification or non-classification

No classification for this endpoint is proposed.

Additional information

Hazards identified by EU Risk Assessment in May 2008:

During the EU Draft Risk Assessment it is concluded that TCPP it not genotoxic and there are no carcinogenicity data available. Carcinogenicity data are available for one TCPP metabolite, 1-chloro-2-propanol, which has been evaluated in 2-Year carcinogenicity studies in both rats and mice. There was no evidence of a carcinogenic effect in either species (NTP 1998).

During the Risk Assessment a comprehensive read-across was performed and documented for TCPP and two similar compounds with limited evidence of a carcinogenic effect TDCP and TCEP (EU Risk Assessment dated May 2008; Appendix D).

During the read-across the following aspects were discussed in detail: chemical structure, physical and chemical properties, QSAR models, reactivity and toxicokinetic.

The EU Risk Assessment discussed that a qualitative read-across from TDCP and TCEP might indicate a potential concern for carcinogenicity for TCPP by a non-genotoxic mechanism but concluded "However, based on the available data, there are some differences in the metabolism and target organs of the three substances, which indicate that a quantitative read-across for carcinogenicity from either TDCP or TCEP to TCPP may not be appropriate" and “Therefore, differences in the target organs, the severity of the effects observed and the potency of the three substances also indicates that a direct read-across to carcinogenicity data on TCEP or TDCP is not appropriate”.

Based on the available data and the read-across the EU Risk Assessment "proposed that the effects observed in the 90-day study for TCPP are taken as a starting point for risk characterization."

 

Updated relevant information (March 2018):

Tris(chloropropyl)phosphate (M20263) [= TCPP] is on the Testing List of the National Toxicology Program (NTP) with, amongst others, 2 year carcinogenicity studies in rats and mice. According to NTP the animal experimental phase of the carcinogenicity studies is completed and histopathology is in progress. See:

http://ntp.niehs.nih.gov/testing/status/agents/ts-m20263.html

As soon as the results of these NTP studies are publically available they will be taken into account for a reliable carcinogenicity assessment of TCPP.