Evidence on Developmental and Reproductive Toxicity of Methyl Tertiary-Butyl Ether: Abstract

Sep 18, 1998

The Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65, California Health and Safety Code 25249.5 et seq.) requires that the Governor cause to be published a list of those chemicals "known to the state" to cause cancer or reproductive toxicity. The Act specifies that "a chemical is known to the state to cause cancer or reproductive toxicity...if in the opinion of the state’s qualified experts the chemical has been clearly shown through scientifically valid testing according to generally accepted principles to cause cancer or reproductive toxicity."

The lead agency for implementing Proposition 65 is the Office of Environmental Health Hazard Assessment (OEHHA) of the California Environmental Protection Agency. The "state’s qualified experts" regarding findings of reproductive toxicity are identified as the members of the Developmental and Reproductive Toxicant (DART) Identification Committee of OEHHA’s Science Advisory Board (22 CCR 12301).

The Local Drinking Water Protection Act of 1997 (SB1189 and AB592) requires that the OEHHA Science Advisory Board make recommendations on or before January 1, 1999 as to whether methyl tertiary butyl ether (MTBE) should be listed under Proposition 65. A public request for information relevant to the reproductive toxicity assessment was announced in the California Regulatory Notice Register on December 5, 1997.

This draft document Evidence on Developmental and Reproductive Toxicity of Methyl Tertiary-Butyl Ether was developed to provide the DART Identification Committee with relevant information for use in its deliberations. The document reviews the available scientific evidence on the reproductive toxicity potential of methyl tertiary-butyl ether. A public meeting of the Committee to discuss this evidence is scheduled for December 1998. The exact meeting date will be published in the California Regulatory Notice Register. Written public comment on the document should be submitted to OEHHA by November 24, 1998, in order to be considered by the Committee in advance of the meeting. During the December meeting, the public will have an opportunity to present verbal comments to the Committee.

Abstract

Methyl tertiary-butyl ether (MTBE) is a volatile compound used as a gasoline additive. Risk assessment activities for MTBE are currently being conducted in California due principally to concerns about MTBE contamination of drinking water sources. The acute toxic effects of MTBE include CNS depression and chronic effects include increased incidence of tumors in animal studies.

This document addresses potential developmental and reproductive hazards of MTBE. There are no human studies directly relevant to MTBE developmental and reproductive toxicity. There are 2 sets of animal reproductive and developmental toxicity studies conducted by the inhalation route of exposure using standard regulatory testing guidelines. The maximum inhalation concentration was 2500 ppm for the first set of studies and 8000 ppm for the second set of studies.

The first set of studies, using the lower concentration range, did not report MTBE effects on development. A possible exception to this lack of findings was the report of increased early postnatal death in a rat one-generation study. The second set of studies, using the higher concentration range, found dose-dependent effects on fetal weight and incidence of delayed ossification in mice after exposure at 4000 and 8000 ppm from gestation day 6 to 15. Other effects (intra-uterine death, cleft palate) occurred only at 8000 ppm. Developmental toxicity was not reported in a similar rabbit study; maternal clinical observations indicated that rabbits were less sensitive to MTBE than mice. A rat two-generation reproductive toxicity study described MTBE effects on postnatal growth and survival of offspring at 3000 and 8000 ppm exposures.

No effects on male or female fertility were reported in 2 available rat reproductive toxicity studies, a one-generation study with a maximum exposure of 2500 ppm and a two-generation study with a maximum exposure of 8000 ppm. In addition to these reproductive toxicity studies, there are a few published and ongoing studies of potential endocrine effects of MTBE. These studies reported decreased uterine and ovarian weights, altered uterine histology and longer estrous cycles in mice exposed by inhalation to 8000 ppm MTBE. Lower doses were not evaluated. Several possible mechanisms of action of MTBE in producing these effects have been considered, but none has been confirmed experimentally. Reduction in circulating testosterone after MTBE exposure was reported in an abstract. Subchronic and chronic toxicity studies in rats using other routes, doses and durations of exposure have not reported effects on ovary or testis weights or histopathology.