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Carcinogenicity

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Description of key information

While a GLP, oral gavage, rat carcinogenicity study similar in design to OECD test guideline 451 is available (Belpoggi 2002), due to flaws in the study methodology and data interpretation for this study, the utility of this study for providing information on the carcinogenicity of diisopropyl ether is unclear.  As negative results were reported in all genotoxicity studies and the repeated dose study does not indicate that the test substance induces hyperplasia or pre-neoplastic lesions, and in accordance with column 2 of REACH (Regulation (EC) No 1907/2006) Annex X, the carcinogenicity study (required in section 8.9.1.) does not need to be conducted.

Key value for chemical safety assessment

Justification for classification or non-classification

While REACH does not require a carcinogenicity study as negative results were reported in all genotoxicity studies and the repeated dose study does not indicate that the test substance induces hyperplasia or pre-neoplastic lesions, Belpoggi et al. (2002) published a study indicating DIPE is a potential carcinogen. Based on expert opinion, the Belpoggi et al. study is considered to be of limited usefulness for the purpose of identifying a potential carcinogenic effect of diisopropyl ether as it provides no convincing evidence for such an effect. As a result, the data is inconclusive for classification according to Regulation (EC) No 1272/2008, Annex I section 3.6.

Additional information

The carcinogenicity of diisopropyl ether (DIPE) was evaluated in a lifetime carcinogenicity study in rats (Belpoggi 2002). This GLP study was similar in design to OECD test guideline 451.  DIPE was administered by oral gavage at 0 (olive oil vehicle), 250, or 1000 mg/kg bw/day to Sprague-Dawley rats for 78 weeks, 4 days a week (100 rats/sex/group).  Animals remained untreated until spontaneous death and were then assessed for complete gross necropsy and microscopic examinations.   There were no differences in mortality, body weight, food consumption, behaviour, or treatment-related non-oncological pathological changes between treatment and control groups. The study authors concluded that there was an increase in various neoplastic lesions in DIPE-treated animals. This included an increase in total malignant tumors in males and females, increased incidence of ear duct carcinomas in males and females, the onset of interstitial cell adenomas of the testis, and slight increase in malignant sarcomas of the uterus and vagina. Based on these findings, the study authors did not identify a NOAEL.

A review of the data in the publication indicates that many of the conclusions made by the authors are not consistent with the data presented in the report. A comparison of incidence values for many of these findings to those reported for controls in other studies at the same facility indicates that the incidence of tumors reported in the DIPE-treated animals were in many cases consistent with those observed in control animals in other studies. Additionally, the reliability of the ear duct findings is in question as Cruzan (2009) conducted an independent review of slides from the same facility for another study and did not agree with the classification of lesions as ear duct carcinomas. Therefore, this study is considered to be of limited usefulness for the purpose of identifying a potential carcinogenic effect of DIPE due to flaws in study methodology, data analysis, and interpretation.

Reference

 

Cruzan G (2009). Assessment of the cancer potential of methanol. Crit Rev Toxicol 39(4):347-363.