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Carcinogenicity

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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

Additional information

The absence of tumor formation in the carcinogenicity test establishes that there is no concern with regards to carcinogenicity. 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

Justification for classification or non-classification

In order to meet the criterion for T, sufficient evidence must be available to show the substance is carcinogenic to man (Category 1) or to presume that human exposure to the substance may result in the development of cancer based on long-term animal studies or other relevant information (Category 2). The absence of tumor formation in the two-year carcinogenicity bioassay in which rats were administered 400, 2000, or 8000 ppm in the diet establishes that there is no concern in regards to carcinogenicity (Cho et al., 2008). As regards to the liver and kidney effects observed in rodents, it is now well-accepted that peroxisome proliferation is species-specific and not relevant to humans. It has been established that peroxisome proliferators exhibit their pleiotropic effects due to activation of PPARα expressed only at low levels in humans, and that phthalate monoesters are much less avid agonists for human than for rodent PPARα receptors, explaining the absence of significant response in humans to the action of peroxisome proliferators (IARC, 1995; Doull, 1999; Klaunig et al., 2003). Therefore, DIDP is not carcinogenic and does not meet the criterion for T based on carcinogenicity.