An Evaluation of the Human Carcinogenic Potential of Ethylene Glycol Butyl Ether (EGBE)

Background

The position paper, "An Evaluation of the Human Carcinogenic Potential of Ethylene Glycol Butyl Ether," was developed in support of the Agency's evaluation of a petition from the American Chemistry Council requesting EPA to delist EGBE per the Clean Air Act Amendments (CAAA), Title III, section 112(b)(1). The position paper was a key component of the Agency's recent determination to grant this petition. It will also be used in the Agency's IRIS assessment of ethylene glycol butyl ether (EGBE).

An NTP (1998; 2000) study has reported some evidence of carcinogenic activity in male B6C3F1 mice based on increased incidence of hemangiosarcomas of the liver, and some evidence of carcinogenic activity in female B6C3F1 mice based on increased incidence of forestomach squamous cell papillomas or carcinomas. EPA completed an IRIS assessment for EGBE in 1999 and concluded that, in accordance with 1996 proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996), the human carcinogenicity of EGBE cannot be determined, but that suggestive evidence exists from rodent studies. This position paper reviews recent scientific findings and provides an up-to-date evaluation of the mode-of-action (MOA) involved in the origin of these tumors in mice and their human relevance that is consistent with recent EPA draft cancer guidelines (U.S. EPA, 2003). The position paper proposes:

that nonlinear MOAs are associated with tumor development in laboratory animals,

that aspects of these MOAs were not relevant to humans and,

that noncancer benchmarks (RfC/RfD values) would be protective of cancer effects.

The major conclusions of the paper with respect to the two tumor types assessed can be summarized as follows:

• Female Mouse Forestomach Tumors - Due to the lack of a comparable organ for storage and long term retention, the exposure concentrations necessary to cause hyperplastic effects and tumors in humans, if attainable, are likely to be much higher than the concentrations necessary to cause forestomach effects in mice, and much higher than the existing EGBE noncancer reference dose (RfD) and concentration (RfC).
• Liver Tumors - Existing evidence supports a hemolysis-dependent, nonlinear MOA for the development of tumors in male mice exposed to EGBE. Given the relatively low sensitivity of humans, including subpopulations such as children, to the hemolytic effects of EGBE, it is reasonable to assume that the EGBE RfC and RfD are sufficient for the prevention of hemolysis and associated tumors in humans.

History/Chronology

• 1999 EPA/NCEA finalizes and distributes EGBE assessment online
• 2002 Chemical Manufacturers Association (CMA) presents new information and new studies of EGBE to EPA/NCEA
• 2003 EPA/NCEA reviews the draft position paper internally and externally
• 2003 EPA/NCEA delivers interim final position paper to EPA/OAQPS and EPA/OAQPS promulgates Proposed Rule to delist EGBE
• 2004 CMA and others submit new information and new studies of EGBE to EPA/OAQPS
• 2004 External panel of experts completes review of the interim final position paper in light of new studies
• 2004 EPA/OAQPS promulgates Final Rule to delist EGBE
• 2005 EPA/NCEA finalizes the EGBE Position Paper

Citation