Reassessing the carcinogenic potential of dibutyl hydrogen phosphate: new insight from repeated-dose toxicity studies

Dibutyl hydrogen phosphate (DBP) has a self-classification as suspected rat urinary bladder carcinogen. Substance-specific repeated-dose toxicity or carcinogenicity data are unavailable for DBP, which is generally only present in multi-constituent substances (MCS) and mixtures. The suspected carcinogenicity of DBP is based on read-across to tributyl phosphate (TBP), which has a harmonised classification (Carcinogenicity Category 2) as non-genotoxic carcinogen since it may cause bladder tumours in Sprague-Dawley rats. DBP and TBP have irritant properties, and bladder lesions following (sub-)chronic exposure to TBP are considered a result of sustained irritation possibly caused by DBP, as DBP is the major metabolite of TBP and eliminated via urine. To further explore the toxicological properties of DBP, two test guideline-conforming oral repeated-dose toxicity studies are presented here. Wistar rats were administered MCS-41D-0.8T (41.3% DBP, 0.8% TBP). After 28- and 90-day exposure to 50−1000 and 50–400 mg/kg body weight/day, respectively, of MCS-41D-0.8T, there were no observable (pre-)carcinogenic bladder lesions, such as reported after similar exposures to TBP or the technical mixture Mix-62D-19T (62% DBP, 19% TBP). Supported by kinetic considerations and in silico predictions, the weight-of-evidence indicates that orally administered DBP does not elicit the characteristic chemical irritation associated with TBP exposure and that the (pre-)carcinogenic effects observed upon exposure to TBP or Mix-62D-19T are caused by TBP and/or its metabolites in the bladder. Hence, distinct kinetic and physiological fates were observed for orally administered DBP versus TBP, indicating that orally administered DBP is not a rat carcinogen. This challenges the current self-classification of DBP.