1,2-benzenedicarboxylic acid, di-C10-12-branched alkyl esters

Carcinogenicity

Description of key information

A two year bioassay was conducted in which DIDP was administered in the diet at concentrations of 400, 2000, and 8000 ppm to F344 rats (Cho et al., 2008). The average daily doses of DIDP were reported to be calculated from the body weights and feed consumption data using the concentrations of DIDP in the diet. For doses of 400, 2000, and 8000 ppm, the calculated average daily doses of DIDP over 2 years for male rats reported in the paper are incorrect. Actual exposures for male rats were 21.9, 110.3 and 479.2 mg/kg-bw/day and for female rats 22.9, 128.2 and 619.6 mg/kg-bw/day (personal communication with Wan-Seob Cho). Rats of both sexes exhibited significant decreases in overall survival and body weights, and increases in the relative weights of kidneys and liver with 8000 ppm DIDP.  No treatment related neoplastic lesions were observed in the internal organs, including the liver. In addition, measurement of catalase enzyme activity, a marker for cell peroxisome proliferating activity, suggests that DIDP can induce peroxisome proliferation at an early stage (12 weeks of treatment) but fails to maintain the catalase-inducing potential by 32 weeks of treatment.  An increased incidence of mononuclear cell leukemia (MNCL) was observed in this study, but MNCL is a common neoplasm in F344 rats, and the observed increased incidence is likely to be a species-specific effect with little or no relevance to humans.  Therefore, DIDP was not considered to be carcinogenic at doses up to 8000 ppm in rats.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

479 mg/kg bw/day

Justification for classification or non-classification

No classification for carcinogenicity is indicated according to the general classification and labeling requirements for dangerous substances and preparations (Directive 67-548-EEC) or the classification, labeling and packaging (CLP) regulation (EC) No 1272/2008.

Additional information

The High Molecular Weight Phthalate Ester (HMWPE) Category consists of phthalate esters with an alkyl carbon backbone with 7 carbon (C7) atoms or greater. The category is formed on the principle that substances of similar structure have similar toxicological properties. The data available on high molecular weight phthalates demonstrate that members of this category have similar biological activities and toxicological properties; verifying the use of read-across data as an appropriate approach to characterize endpoints. DIUP (C11) is a high molecular weight phthalate ester. Where data maybe lacking for DIUP, DINP (C9) and DIDP (C10), which are also high molecular weight phthalate esters, are used as read-across substances to provide toxicological information.  

The absence of tumor formation in the carcinogenicity test for DIDP, and the lack of genotoxicity, establishes minimal concern with regards to carcinogenicity for DIUP. In regards to peroxisome proliferation, as noted previously, a marked species difference is anticipated. The current literature reported that only rats and mice are responsive to the carcinogenic effects of peroxisome proliferators, while dogs, non-human primates and humans are essentially non-responsive or refractory (IARC, 1995; Doull, 1999).

Carcinogenicity: via oral route (target organ): digestive: liver