1,2-Benzenedicarboxylic acid, di-C9-11-branched alkyl esters, C10-rich

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

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 treatment related 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).  Therefore, DIDP is not carcinogenic and does not meet the criterion for T based on carcinogenicity.

 

This conclusion is consistent with that in the ECHA 2013 report "there is no concern for carcinogenicity of DIDP in humans" (ECHA, 2013. Evaluation of new scientific evidence concerning DINP and DIDP. ECHA-13-R-07-EN: ISBN: 978-92-9244-001-5; https://echa.europa.eu/documents/10162/31b4067e-de40-4044-93e8-9c9ff1960715).   

   

 

Additional information

The absence of  relevant tumor formation in a 2-year carcinogenicity study with DIDP establishes that there is no concern with regards to carcinogenicity (Cho, 2008). A marginal increase of mononuclear cell leukemia (MNCL was observed in the high dose group. MNCL is a lesion that occurs almost exclusively in the F-344 rat and is the most common cause of spontaneous death in that strain and species (Maronpot R et al. 2016 Crit. Rev. Toxicol. 46(8):641-75).   Given this understanding and the fact that the incidences in this study were within historical control ranges, the observation is not considered an indicator of carcinogenicity risk in humans.   C-cell hyperplasia was decreased in the 2000ppm exposed males and increased in the 400 and 2000ppm exposed female treatment groups.  Given the lack of a clear dose response and that C-cell adenomas of the thyroid gland were within historical control range, the evidence does not support that c-cell hyperplastic effects are treatment related.  No treatment related neoplastic lesions [of the thyroid] were observed. Spongiosis hepatis and microgranuloma of the liver were observed at a very low, but statistically significant incidence in all male treatment groups.  However there was not a clear dose response for either effect and the incidences observed were well within the historical control range. The relevance of spongiosis hepatis to human health has been questioned by ECHA (ECHA, 2013 Evaluation of new scientific evidence concerning DINP and DIDP p 88) and other regulators (Australian National Industrial Chemicals Notification and Assessment Scheme. Diisononyl Phthalate. Priority Existing Chemical Assessment Report. No. 35. September 2012. Page 64).   In any case, spongiosis hepatis is not considered a neoplasm (Karbe and Kerlin, 2002).  Focal aggregates of inflammatory cells such as microgranulomas are common spontaneous lesions in the liver of laboratory animals, irrespective of age (Greaves P.Liver and pancreas. In: Histopathology of Preclinical Toxicity Studies, Elsevier Inc., CA, 457–503.2007. ISBN: 9780444527714).  Given the lack of a dose response and the spontaneous nature of the lesion, the microgranulomas were not considered an adverse effect nor indicator of carcinogenicity.

 

While no liver tumors were observed in the 2-year carcinogenicity study with rats (Cho 2008), DIDP was shown to induce liver adenomas in a 26-week study in rasH2 mice (Cho, 2011). As discussed in the ECHA 2013 Evaluation of new scientific evidence concerning DINP and DIDP (ECHA-13-R-07-EN: ISBN: 978-92-9244-001-5; https://echa.europa.eu/documents/10162/31b4067e-de40-4044-93e8-9c9ff1960715).   “Transgenic rasH2 mice are reported to have a relatively low susceptibility for liver carcinogenicity (Mitsumori et al. 1998 as cited in Cho et al. 2011). Importantly, Cohen et al. (2001) indicated that the rasH2 model did not respond to most classes of non-genotoxic rodent carcinogens. As DIDP is assumed to be non-genotoxic, and the study covered only 1/4th of the life-time assay in mice, the results from the Cho et al. 2011 need to be interpreted with care (with respect to lack of tumors in the lower dose levels and lack of tumors in all dose levels in female transgenic mice).”  Cho et al (2011) suggested peroxisome proliferation is the underlying mode of action for the observed tumors.  The current scientific consensus in the literature concludes that the  mode of action in rodents for liver tumors mediated by PPARα is “not relevant” or “unlikely to be relevant” humans (Corton et al. 2014. Crit Reviews in Toxicol. 44:1-49) .  It has been established that peroxisome proliferators exhibit their pleiotropic effects due to activation of PPARα expressed only at low levels in humans.  Therefore there is a major quantitative difference in the ability to invoke PPARα-mediated proliferative effects in rodents versus humans.  While many conclude this quantitative difference is significantly extensive enough to lack practical human relevance, some consider the lack of understanding of the specific mechanistic basis for cell growth effects between species, precludes an absolute conclusion of lack of human relevance because of the possiblity-albiet low- of identifying factors that may increase concern for human relevance (Corton et al. 2014).  In this latter instance it would be the case that relevance would be limited to very potent PPARα agonists and/or exposure to exceptionally high doses would be necessary to elicit a possible response.   Given that phthalate monoesters-in general-are much less avid agonists for human than for rodent PPARα receptors (Klaunig et al., 2003), and DIDP did not induce liver tumors in the 2-year carcinogenicity assay up to 8000 ppm (Cho., et al 2008) (Doull, 1999;), observed liver effects do not warrant concern for carcinogenicity of DIDP in humans.