The Risk Assessment Information System

Toxicity Profiles

Condensed Toxicity Summary for BIS(2-ETHYLHEXYL)PHTHALATE

NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.

MARCH 1993

Prepared by Andrew Francis, M.S., DABT, Chemical Hazard Evaluation Group, Biomedical Environmental Information Analysis Section, Health and Safety Research Division, *, Oak Ridge, Tennessee.


*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400

Bis(2-ethylhexyl)phthalate is a colorless oily liquid that is extensively used as a plasticizer in a wide variety of industrial, domestic and medical products. It is an environmental contaminant and has been detected in ground water, surface water, drinking water, air, soil, plants, fish and animals (Sittig, 1985; Sandmeyer and Kirwin, 1978). It is rapidly absorbed from the gastrointestinal tract primarily as mono(2-ethylhexyl)phthalate (Pollack et al., 1985; Teirlynck and Belpaire, 1985). The diester can be absorbed through the skin and from the lungs (Elsisi et al., 1989; Pegg, 1982). It is rapidly metabolized in the blood and tissues to the monoester, which can be excreted as a glucuronide conjugate or further hydrolyzed to phthalic acid and excreted (Kluwe, 1982; Albro et al., 1982).

Animal studies have indicated that the primary target organs are the liver and kidneys (Carpenter et al., 1953; U.S. EPA, 1987a,b); however, higher doses are reported to result in testicular effects and decreased hemoglobin and packed cell volume (Kluwe et al., 1982; Gray et al., 1977). The primary intracellular effects of bis(2-ethylhexyl)phthalate in the liver and kidneys are an increase in the smooth endoplasmic reticulum and a proliferation in the number and size of peroxisomes (Kluwe et al., 1982; Reddy and Lalwani, 1983; Tomaszewski et al., 1986). An epidemiological study reported no toxic effects from occupational exposure to air concentrations of bis(2-ethylhexyl)phthalate up to 0.16 mg/m3 (Thiess et al., 1978). Other studies on occupational exposures to mixtures of phthalate esters containing bis(2-ethylhexyl)phthalate have reported polyneuritis and sensory-motor polyneuropathy with decreased thrombocytes, leukocytes and hemoglobin in some exposed workers (Milkov et al., 1973; Gilioli et al., 1978). Developmental toxicity studies with rats and mice have shown that bis(2-ethylhexyl)phthalate is fetotoxic and teratogenic when given orally during gestation (Wolkowski-Tyl et al., 1984a and b; Shiota and Mima, 1985). Oral exposure has also been shown to result in decreased sperm count in rats (Siddipui and Srivastava, 1992)

A Reference Dose (RfD) of 0.02 mg/kg/day for both subchronic and chronic oral exposure was calculated from a lowest-observed-adverse-effect level (LOAEL) of 19 mg/kg/day based on increased relative liver weight in guinea pigs given 0, 19, or 64 mg bis(2-ethylhexyl) phthalate/kg/day for 12 months in their diet (Carpenter et al., 1953; U.S. EPA, 1992 a,b). A Reference Concentration (RfC) for inhalation exposure is not available (U.S. EPA, 1992b).

bis(2-ethylhexyl)phthalate is known to induce the proliferation of peroxisomes, which has been associated with carcinogenesis (Rao and Reddy, 1991). Dose-dependent, statistically-significant increases in the incidences of hepatocellular carcinomas and combined carcinomas and adenomas were seen in mice and rats exposed to bis(2-ethylhexyl)phthalate in their diet for 103 weeks (Kluwe, et al., 1982). An increased incidence of neoplastic nodules and hepatocellular carcinomas was also reported in rats (Rao et al., 1990).

Based on U.S. EPA guidelines, bis(2-ethylhexyl)phthalate was assigned to weight-of-evidence Group B2, probable human carcinogen, on the basis of an increased incidence of liver tumors in rats and mice. A carcinogenicity slope factor (q1*) of 0.014 (mg/kg/day)-1 for oral exposure was based on the combined incidence of hepatocellular carcinomas and adenomas in male mice (Kluwe, et al., 1982; U.S. EPA, 1992b). A drinking water unit risk of 4.0E-7 (µg/L)-1 was calculated based on the q1*. A quantitative estimation of carcinogenic risk from inhalation exposure is not available (U.S. EPA, 1992b). Retrieve Toxicity Profiles Formal Version

Last Updated 10/07/97

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