The Risk Assessment Information System

Toxicity Profiles

Formal 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.

EXECUTIVE SUMMARY

1. INTRODUCTION

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION 2.2 DISTRIBUTION 2.3 METABOLISM 2.4 EXCRETION

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES 3.2 INHALATION EXPOSURES 3.3 OTHER ROUTES OF EXPOSURE 3.4 TARGET ORGANS/CRITICAL EFFECTS

4. CARCINOGENICITY

4.1 ORAL EXPOSURES 4.2 INHALATION EXPOSURES 4.3 OTHER ROUTES OF EXPOSURE 4.4 EPA WEIGHT-OF-EVIDENCE 4.5 CARCINOGENICITY SLOPE FACTORS

5. REFERENCES

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.

Prepared for OAK RIDGE RESERVATION ENVIRONMENTAL RESTORATION PROGRAM

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

EXECUTIVE SUMMARY

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).

1. INTRODUCTION

Bis(2-ethylhexyl)phthalate or di(2-ethylhexyl)phthalate (C₂₄H₃₈O₄, CAS registry number 117-81-3) is a clear oily liquid with a molecular weight of 390.54. It has a melting point of -50^oC; a boiling point of 387^oC at 760 mm Hg and 230^oC at 5 mm Hg; and a vapor pressure of 1.2 mm Hg at 200^oC. It has a density of 0.9861 and is practically insoluble in water (0.40 mg/L at 25^oC). bis(2-ethylhexyl)phthalate has a flash point of 218.3^oC. The relatively high flash point, boiling point and low vapor pressure contribute to the high stability of this phthalic acid ester (Sittig, 1985; Sandmeyer and Kirwin, 1978; U.S. EPA, 1987a).

Bis(2-ethylhexyl)phthalate is primarily used in the plastics industry as a plasticizer with such varied applications as wire insulation, food packaging and biomedical applications such as tubing and blood containers. Other uses include vacuum pump oil and as a dielectric fluid in capacitors (U.S. EPA, 1987b; Budavari, 1989). The combined annual production of dioctyl phthalates in the United States exceeds 300 million pounds (U.S. EPA, 1987b). The wide-spread uses of bis(2-ethylhexyl)phthalate have made the compound, along with other phthalic acid esters, ubiquitous in the environment. It has been detected in ground water, surface water, drinking water, air, soil, plants, fish and animals. Air concentrations in certain PVC manufacturing plants have been reported to range from below 0.02 to 0.5 mg/m³ (Vainiotalo and Pfaffli, 1990). Some exposure occurs from leaching of the compound from containers used in the food and medical industries (U.S. EPA, 1987b; Callahan et al., 1979). This is of particular concern to patients exposed to large amounts of blood or blood products. The chemical is extracted from the containers by the blood and is converted to mono(2-ethylhexyl)phthalate by a plasma enzyme (Labow et al., 1988). Experiments have shown that 3.3 mg bis(2-ethylhexyl)phthalate/gm of bag material were extracted in five days with bovine calf serum, whereas bags tested with saline resulted in no soluble plasticizers (Chawla and Hinberg, 1991).

In the environment, bis(2-ethylhexyl)phthalate undergoes biodegradation in water and soil, and is predicted to react with hydroxyl radicals in the atmosphere. It is estimated to have a half life of about 12 hours in the air, 10 to 20 days in the soil, and days to weeks in water (U.S. EPA, 1987a,b). Volatilization of bis(2-ethylhexyl)phthalate from contaminated water does not contribute significantly to its removal. The half-life of the molecule due to evaporation alone from bodies of water has been estimated to be as long as 15 years (U.S. EPA, 1987a,b; Callahan et al., 1979). In the marine environment bis(2-ethylhexyl)phthalate has been shown to be rapidly degraded by experimental microcosms (Davey et al., 1990). It has been found to bind to organic acids in the soil and water resulting in an increase in its solubility and its mobility in the environment (Matsuda and Schnitzer, 1971). It also adsorbs to both freshwater and marine sediments where it may serve as a long-term sink (U.S. EPAb, 1987; Sullivan et al., 1982).

Experiments have shown that fish do not extensively bioaccumulate bis(2-ethylhexyl)phthalate. Rainbow trout studies indicate that the diester is converted to the monoester by the gills before absorption from the water occurs, thus limiting the absorption of the diester (Barron et al., 1989).

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION

Bis(2-ethylhexyl)phthalate can be absorbed from the gastrointestinal tract, the lungs, and through the skin. Over 90% of an oral dose of bis(2-ethylhexyl)phthalate was absorbed by the gastrointestinal tract of rats as evidenced by the excretion of metabolites (Williams and Blanchfield, 1974). However, gastrointestinal absorption is complicated by the hydrolysis of the diester to the monoester derivative by pancreatic enzymes and enzymes in intestinal mucosal cells. The monoester is then absorbed. Gavage studies on rats by Teirlynck and Belpaire (1985) showed an average plasma concentration of 8.8 µg/ml of the diester compared to 63.2 µg/ml of the monoester 3 hours following a single oral dose of 2.8 g/kg of bis(2-ethylhexyl)phthalate. Similar studies by Pollack et al. (1985) demonstrated that 80% of a single oral dose was absorbed as the monoester, whereas only 13% of the dose was absorbed as bis(2-ethylhexyl)phthalate. These observations must be taken into account when route-to-route extrapolations are considered (U.S. EPA, 1987b).

Although it is known that phthalic acid esters can be absorbed by inhalation, there are little quantitative data available for this route of exposure (U.S. EPA 1987a). Pegg (1982) studied the pulmonary absorption of an aerosol of ¹⁴C-bis(2-ethylhexyl)phthalate by adult male Sprague-Dawley rats. The animals were exposed for 6 hours to a concentration of 100 mg/m³ in a heads-only chamber. The radioactivity appearing in the blood at various times following exposure and the radioactivity recovered from urine, feces, skin and the carcass were measured 72 hours after exposure. The disappearance of radioactivity from lung tissue was also measured leading to the conclusion that absorption was rapid and complete.

Bis(2-ethylhexyl)phthalate can also be absorbed through the skin. This is primarily a hazard for workers in the plastics industry, but other exposures can occur such as contact with the chemical leached from vinyl swimming pool liners (U. S. EPA 1980). Quantitative absorption data are not available, however, guinea pig studies have indicated a LD₅₀ of 10 g/kg for dermal exposure (Autian, 1973; U.S. EPA, 1980). Excretion and distribution of radioactive labeled [¹⁴C]-bis(2-ethylhexyl)phthalate applied to the shaved backs of male F-344 rats at concentrations of 30 to 40 mg/kg was followed over a period of seven days demonstrating dermal absorption by rats (see sections 2.2 and 2.4) (Elsisi et al., 1989).

2.2 DISTRIBUTION

Bis(2-ethylhexyl)phthalate and its metabolites are distributed primarily to plasma, liver, kidney, the gastrointestinal tract, and fat following oral exposure. Some metabolites have been found in almost all tissues especially the monoester metabolite, which has been found in relatively high concentration in the testes of rats. Maximum concentrations of bis(2-ethylhexyl)phthalate and the monoester metabolite were reached in blood and the tissues in 6-24 hours after a single oral dose of 9.8 g/kg in corn oil (Oishi and Hiraga, 1982; U.S. EPA, 1987b). Elsisi et al. (1989) applied 30 to 40 mg bis(2-ethylhexyl)phthalate/kg to the shaved backs of F-344 rats and followed the distribution of radioactive label. Most of the label was found in fat, skin and muscle after seven days.

2.3 METABOLISM

The first step in metabolism of bis(2-ethylhexyl)phthalate is hydrolysis to the monoester derivative, which primarily occurs in the gastrointestinal tract following oral exposure, but also occurs in the tissues. A glucuronide conjugate can be formed with the monoester or the terminal or next to last carbon in the monoester molecule can be oxidized. After the carboxylic acid derivative is formed, the length of the side chain can be decreased by ß oxidation. The monoester can also be hydrolyzed to phthalic acid (Klue, 1982; Albro et al., 1982; Williams and Blanchfield 1974; U.S. EPA, 1987b).

Rat studies indicate that the diester is removed faster from most tissues than the monoester with half-lives from 1.5 hours for lung tissue to 28.4 hours for liver and 156 hours for epididymal fat. bis(2-ethylhexyl)phthalate is fat soluble and remains unmetabolized in fat tissue much longer than in other tissues. The monoester has a half-life of about 32 hours in liver tissue and 68 hours in epididymal fat. It also has a half-life of about 50 hours in the testes, compared to 8.3 hours for the diester (Oishi and Hiraga, 1982; U.S. EPA 1987b).

The mono(2-ethylhexyl)phthalate metabolite has been shown to accumulate in the testes of rats following treatment with bis(2-ethylhexyl)phthalate (Oishi, 1990). In vitro studies have shown that testicular tissue does not further metabolize the monoester (Albro et al., 1989).

2.4 EXCRETION

Since bis(2-ethylhexyl)phthalate is rapidly converted to the monoester derivative, solubilization and excretion of the monoester becomes the primary metabolic task. Most species tested, including humans, excrete the monoester as a glucuronide conjugate in the urine, feces and bile. Rats, apparently, are an exception and primarily oxidize the terminal or next to last carbon in the monoester molecule before excretion. The monoester can also be further hydrolyzed to phthalic acid and excreted (Kluwe, 1982; Albro et al., 1982). An average half-life of about 12 hours has been reported in humans following a single dose of bis(2-ethylhexyl)phthalate (Schmid and Schlaffer, 1985; U.S. EPA, 1987b). Excretion of [¹⁴C]-bis(2-ethylhexyl)phthalate after dermal absorption in F-344 rats was followed over a period of seven days. Radioactive label was found in the urine and feces; urine was the major route of elimination (Elsisi et al., 1989).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES

3.1.1 Acute Toxicity

3.1.1.1 Human

Ingestion of 5 and 10 g of bis(2-ethylhexyl)phthalate by human volunteers resulted in mild gastrointestinal disturbances with the 10 g dose and no effects from the 5 g dose (Shaffer et al., 1945).

3.1.1.2 Animal

Oral LD₅₀ values of 30 g/kg, 30.6 g/kg, and 34 g/kg have been listed for mice, rats and rabbits respectively (Sittig, 1985; Sax and Lewis, 1989).

3.1.2. Subchronic Toxicity

3.1.2.1. Human

Information on the subchronic oral toxicity of bis(2-ethylhexyl)phthalate in humans was not available.

3.1.2.2. Animal

Gray et al. (1977) observed a variety of symptoms after feeding groups of 15 male and 15 female Sprague Dawley rats 0, 0.2, 1.0, or 2% bis(2-ethylhexyl)phthalate (0, 150, 750, or 1500 mg/kg/day, respectively) in their diet for 17 weeks. Increased absolute and relative liver weights were observed in all treated groups. Food consumption and growth rates were reduced in the 1 and 2% treated groups. A dose-related reduction in testicular weight and an increase in testicular damage were observed. Decreased hemoglobin concentration was observed in male rats, and decreased packed red cell volume was also observed in both sexes in the two highest dose groups. An interstitial nephritis, increased SGPT and decreased blood glucose were reported by Nagasaki et al. (1974) in a 48 week rat study (U.S.EPA, 1987a). Animals in this study were fed 500 or 1000 ppm bis(2-ethylhexyl)phthalate in the diet (25 or 50 mg/kg/day, respectively). Ota et al. (1974) reported degenerative changes in the kidneys and liver of mice given 0.5 to 5 g/kg/day in the diet for 1 to 3 months. Male albino ferrets fed 1% bis(2-ethylhexyl)phthalate in the diet for 14 months exhibited decreased body weight, increased liver weight with morphological and biochemical changes, and testicular damage (Lake et al., 1976; U.S. EPA 1987b).

3.1.3. Chronic Toxicity

3.1.3.1. Human

Information on the chronic oral toxicity of bis(2-ethylhexyl)phthalate in humans was not available.

3.1.3.2. Animal

Carpenter et al. (1953) fed groups of 32 male and 32 female Sherman rats 0, 0.04, 0.13, or 0.4% bis(2-ethylhexyl)phthalate (0, 20, 60, or 200 mg/kg/day, respectively) in the diet for one year during which time they were allowed to breed. After one year, groups of eight males and eight females were continued on the same regimen and groups of 32 male and 32 female offspring were fed 0, and 0.4% (200 mg/kg/day) bis(2-ethylhexyl)phthalate in the diet. Significantly increased liver and kidney weights were observed with the high dose in the male parental group and in both sexes of the F₁ groups. No other treatment related effects were reported in the rats. The same study also included guinea pigs and dogs. Groups of 22-24 male and 22-24 female guinea pigs were fed the equivalent of 0, 19 or 64 mg/kg/day bis(2-ethylhexyl)phthalate for one year. Groups of 4 dogs randomly selected were given the equivalent of 54.7 mg/kg/day for about four weeks and then 0.06 mg/kg/day for about 48 weeks. One dog was given a TWA dose of 79.3 mg/kg/day for a total of 246 days. Increased relative liver weight was seen in all treated groups of female guinea pigs, however, no histological changes were reported. The dog that received the TWA dose of 79.3 mg/kg/day developed fatty vacuolation and congestion in the liver and cloudy swelling and congestion in the kidneys. No effects were reported for the other groups of dogs (U.S. EPA, 1987a).

Two year dietary studies have been performed on groups of 50 male and 50 female F344 rats and B6C3F₁ mice (NTP, 1982; Kluwe et al., 1982). Rats were given 0, 6000, or 12,000 ppm in the diet (0, 322, 674 mg/kg/day for males; 0, 394, 774 mg/kg/day for females). Mice were given 0, 3000, or 6000 ppm in the diet (0, 672, 1325 mg/kg/day for males; 0, 799, 1821 mg/kg/day for females). Decreased body weight was observed in all treated male rats, and female rats in the high dose group, and in all treated female mice. An increased incidence of seminiferous tubule degeneration was observed at the highest dose in both rats and mice (U.S. EPA, 1987b). Renal cysts have been reported to appear in rats fed 150 mg/kg three times/week for a year, but not when the chemical is given for six months (Woodward, 1990).

One of the most commonly observed effects of bis(2-ethylhexyl)phthalate treatment is an increase in liver and kidney weights. The intracellular effects that accompany or account for the increase weights are an increase in the smooth endoplasmic reticulum and a proliferation in number and size of peroxisomes. Ganning et al. (1990) fed male Sprague-Dawley rats a diet containing 0.02, 0.2 or 2% bis(2-ethylhexyl)phthalate for 102 weeks. Decreased body weight was seen only in the 2% group, however enzyme changes that reflect the proliferation of peroxisomes occurred in a dose related manner. Peroxisomal palmitoyl-CoA dehydrogenase and mitochondrial carnitine acetyltransferase activities increased to a maximum in 20 weeks. Comparable levels were also reached in the 0.2% dose group by the end of the experiment. Peroxisomal catalase increased during the first year, but decreased to control levels during the second year of treatment. All enzyme activities returned to control values within 2-3 weeks following cessation of treatment. Peroxisomes contain a number of oxidative enzymes that affect the metabolism of the bis(2-ethylhexyl)phthalate and other intracellular molecules, especially fats. This proliferation of peroxisomes has been linked with carcinogenic activity (Reddy and Lalwani, 1983; Tomaszewski et al., 1986).

3.1.4. Developmental and Reproductive Toxicity

3.1.4.1. Human

Information on developmental and reproductive toxicity of bis(2-ethylhexyl)phthalate in humans following oral exposure was not available.

3.1.4.2. Animal

A number of studies have reported fetotoxic and teratogenic effects in rats and mice following exposure to bis(2-ethylhexyl)phthalate. Nikonorow et al. (1973) observed increased resorption of fetal implants and decreased fetal weight when 1.7 g bis(2)-ethylhexyl)phthalate/kg body weight was given orally on days 0-21 of gestation. Bell et al. (1979) reported decreased fetal body weights, increased relative fetal liver weights, and reduced sterologenesis in fetal brain and liver in Sprague Dawley rats fed 0.5% bis(2-ethylhexyl)phthalate on days 5-18 of gestation. Wolkowski-Tyl et al. (1984a) fed groups of rats 0, 0.5, 1.0, 1.5, or 2.0% bis(2-ethylhexyl)phthalate (equivalent to 0, 356.7, 666.4, 856.5, or 1054,8 mg/kg/day, respectively) in their diet on days 0-20 of gestation. Some maternal effects were seen, including decreased body weight, increased absolute and relative liver weight, and increased gravid uterine weight. Dose-related increases in the number of fetal resorptions and in the number of dead and malformed fetuses per litter were also reported. There was a dose-related decrease in fetal weight that was significant in all treated groups.

Wolkowski-Tyl et al. (1984b) also studied the effect of 0, 0.025, 0.05, 0.1, or 0.15% bis(2-ethylhexyl)phthalate (equivalent to 0, 44, 91, 191, or 292 mg/kg/day, respectively) in the diet given to mice on days 0-18 of gestation. Maternal effects observed were decreased body weight and increased relative liver weight, both effects significant at 0.1 and 0.15% in the diet. Dose-related increases in resorptions and in dead fetuses per litter were significant at doses of 0.1 and 0.15%. Significant increases in malformed fetuses per litter, with external, visceral and skeletal defects, were observed at doses of 0.15%. Studies utilizing higher oral doses (250, 500, 1000 or 2000 mg/kg) by Shiota and Mima (1985) and (0.05, 0.1, 0.2, 0.4 or 1.0% diet) by Shiota and Nishimura (1982) and Shiota et al. (1980) demonstrated increased numbers of fetuses with gross external malformations, including neural tube defects. The incidence of resorptions increased up to 100% in animals fed 0.4 and 1% bis(2-ethylhexyl)phthalate in their diets. Mice were shown to be most sensitive to the teratogenic effects of bis(2-ethylhexyl)phthalate on days 7 and 8 of gestation. Treatment on day 7 with 1 ml/kg resulted in increased fetal mortality, resorptions, and gross external and skeletal anomalies. Treatment on day 9 or 10 with up to 30 ml/kg produced no resorptions, fetal mortality or malformed fetuses (Yagi et al., 1980).

Mono(2-ethylhexyl)phthalate, a principle metabolite of bis(2-ethylhexyl)phthalate, was fed to pregnant CD-1 mice on days 0 through 17 of gestation (0, 0.13, 0.26, 0.48 or 0.97 mmol/kg/day). Increased maternal liver weight was observed at doses >0.48 mmol/kg and decreased weight gain was observed at the 0.97 mmol dose. Dose related increased fetal mortality, the % of litters with malformed fetuses, and the % of malformed fetuses per litter were seen in all treated groups. Other metabolites including 2-ethylhexanol had no effect. Qualitatively, the effect of the monoester was similar to the diester in oral studies (Price et al., 1991).

A dose related decrease in sperm count has been reported in rats given 500 or 1000 mg/kg/day orally bis(2-ethylhexyl)phthalate for 15 days. Decreased epididymis weight was seen in the 1000 mg/kg/day dose group (Siddiqui and Srivastava, 1992). Decreased absolute and relative testicular weights were seen in rats given 2000 mg/kg/day orally for 15 days. A decrease in testicular 17-betahydroxysteroid dehydrogenase activity was observed at 1000 and 2000 mg/kg/day indicative of possible decreased steroidogenesis in treated animals (Srivastava and Srivastava, 1991). The monoester metabolite accumulates in the testes and has been shown in vitro to inhibit testicular mitochondrial respiration (Oishi, 1990).

3.1.5. Reference Dose

3.1.5.1. Subchronic

ORAL RfD_s: 0.02 mg/kg/day (U.S. EPA, 1992a)

UNCERTAINTY FACTOR: 1000

LOAEL: 19 mg/kg/day

PRINCIPAL STUDIES: The same studies and comments apply to both the subchronic and chronic RfD derivations. See section 3.1.5.2.

3.1.5.2. Chronic

ORAL RfD_c: 0.02 mg/kg/day (U.S. EPA, 1992b)

UNCERTAINTY FACTOR: 1000

MODIFYING FACTOR: 1

LOAEL: 19 mg/kg/day

CONFIDENCE:

Study: Medium

Data Base: Medium

RfD: Medium

VERIFICATION DATE: 05/20/85

PRINCIPAL STUDY: Carpenter et al. (1953).

COMMENTS: The LOAEL was calculated from a 12 month experiment in which guinea pigs were given 0, 19, or 64 mg di(2-ethylhexyl)phthalate/kg body weight in the diet. The LOAEL of 19 mg/kg was based on increased relative liver weight. See section 3.1.3.2.

3.2 INHALATION EXPOSURES

3.2.1 Acute Toxicity

3.2.1.1. Human

Information on the acute inhalation toxicity of bis(2-ethylhexyl)phthalate in humans was not available.

3.2.1.2. Animal

Rats could survive a two hour exposure to a vapor mist created by bubbling air through heated (170^oC) bis(2-ethylhexyl)phthalate, but died after a four hour exposure (Sandmeyer and Kirwin, 1978).

3.2.2. Subchronic Toxicity

3.2.2.1. Human

A total of 101 workers in a bis(2-ethylhexyl)phthalate production plant were examined for adverse effects due to phthalate ester exposure. The air concentration of bis(2-ethylhexyl)phthalate ranged from 0.01 to 0.16 mg/m³, and the exposure was from four months to 35 years. Some of the chemical was found in the blood and urine of both the control and exposed groups, however, no compound-related effects were reported (Thiess et al., 1978).

3.2.2.2. Animal

Information on subchronic inhalation toxicity of bis(2-ethylhexyl)phthalate in animals was not available.

3.2.3. Chronic Toxicity

3.2.3.1. Human

No compound related effects were observed in a study of 101 workers in a bis(2-ethylhexyl)phthalate production plant exposed to 0.01 to 0.16 mg/m³ for up to 35 years (average 12 years, see section 3.2.2.1) (Thiess et al., 1978).

Other studies have been conducted on populations chronically exposed to mixtures of phthalic acid esters containing bis(2-ethylhexyl)phthalate; therefore, the observed effects may or may not be caused by the bis(2-ethylhexyl)phthalate. Ambient air concentrations of total phthalate esters ranged from 1 to 40 mg/m³ in one study (Milkov et al., 1973), and from <1 to 5 mg/m³ and 5 to 60 mg/m³ in a second study (Gilioli et al., 1978). These studies reported polyneuritis and mild to moderate sensory-motor and motor polyneuropathy, which increased in frequency and duration with the length of employment. The Milkov et al. (1973) study also reported decreased vestibular and olfactory excitability and decreased thrombocytes, leukocytes, and hemoglobin in some exposed individuals. No effects were reported by Gilioli et al. (1978) in populations employed less than two years.

3.2.3.2. Animal

Information on the chronic inhalation toxicity of bis(2-ethylhexyl)phthalate in animals was not available.

3.2.4. Developmental and Reproductive Toxicity

3.2.4.1. Human

No increase in the incidence of miscarriages or offspring deformities was seen in female workers or in the wives of male workers in a study of 101 employees at a bis(2-ethylhexyl)phthalate production facility with exposures of 0.01 to 0.16 mg/m³ for up to 35 years (average 12 years, see section 3.2.2.1) (Thiess et al., 1978).

3.2.4.2. Animal

Information on developmental and reproductive toxicity in animals resulting from inhalation exposure to bis(2-ethylhexyl)phthalate was not available.

3.2.5. Reference Concentration

3.2.5.1. Subchronic

A subchronic Reference Concentration is not available at this time.

3.2.5.2 Chronic

A chronic Reference Concentration is not available at this time.

3.3 OTHER ROUTES OF EXPOSURE

3.3.1 Acute Toxicity

3.3.1.1 Humans

Bis(2-ethylhexyl)phthalate is mildly irritating to the skin and irritating to the eyes and mucous membranes on contact (Sittig, 1985; Sax and Lewis, 1989). Humans are also susceptible to introduction of bis(2-ethylhexyl)phthalate by intravenous route since this substance is known to leach from blood containers and other PVC plastic medical equipment. However, no reports describing acute adverse effects as a result of this route of exposure are available.

3.3.1.2. Animal

Bis(2-ethylhexyl)phthalate can be absorbed through the skin and LD₅₀ values of 25 and 10 g/kg have been listed for rabbits and guinea pigs, respectively. A dose of 500 mg/24 hours is mildly irritating to the skin and eyes of rabbits (Sax and Lewis, 1989).

3.3.2. Subchronic Toxicity

3.3.2.1. Human

Information on the subchronic toxicity of bis(2-ethylhexyl)phthalate by other routes of exposure in humans was unavailable.

3.3.2.2. Animal

Information on the subchronic toxicity of bis(2-ethylhexyl)phthalate by other routes of exposure in animals was unavailable.

3.3.3. Chronic Toxicity

3.3.3.1. Human

Humans needing chronic transfusions of blood are susceptible to the introduction of bis(2-ethylhexyl)phthalate by intravenous route since this substance is known to leach from blood containers and other PVC plastic medical equipment (Sittig, 1985). The diester leached from the plastic can be metabolized to the monoester by blood enzymes. The monoester has been shown to inhibit platelet phospholipase A2 possibly resulting in reduced platelet function (Labow et al., 1988). Long term hemodialysis patients often develop renal cysts similar to that reported for rats chronically exposed to bis(2-ethylhexyl)phthalate, however, a causal relationship has not been shown with leached plasticizer (Woodward, 1990). No reports specifically describing adverse effects as a result of this route of exposure were located.

3.3.3.2. Animal

Information on the chronic toxicity of bis(2-ethylhexyl)phthalate by other routes of exposure in animals was unavailable.

3.3.4. Developmental and Reproductive Toxicity

3.3.4.1. Human

Information on the developmental and reproductive toxicity of bis(2-ethylhexyl)phthalate by other routes of exposure in humans was unavailable.

3.3.4.2. Animal

Male and female mice were given subcutaneous injections of 1 to 100 ml bis(2-ethylhexyl)phthalate/kg on days 1, 5, and 10 and evaluated on day 21 of the experiment for reproductive performance, biochemical parameters of the gonads and histological alterations. Decreased numbers of pregnancies were reported when either sex of treated mice were mated with untreated mice. Decreased testicular weight but not ovarian weight was reported. Histological damage and increased lysosomal activity was seen in both sexes. Decreased fertility was the most sensitive indicator for gonadotoxicity (Agarwal et al., 1989).

In addition to the monoester derivative of bis(2-ethylhexyl)phthalate, another principal metabolite, 2-ethylhexanoic acid, exists in two enantiomeric forms. The S enantiomer was found to not be embryotoxic or teratogenic. However, intraperitoneal injection of pregnant rats with 500 mg/kg twice daily on day 7 and 8 of gestation with the R enantiomer caused decreased fetal survival, decreased weight of surviving fetuses, and neural tube defects in 59% of living fetuses (Hauck et al., 1990).

3.4 TARGET ORGANS/CRITICAL EFFECTS

3.4.1 Oral Exposures

3.4.1.1 Primary Target Organs

1. Liver: Increased liver weight was observed in animals following oral treatment with bis(2-ethylhexyl)phthalate.

2. Kidney: Increased kidney weight was observed in animals following oral treatment with bis(2-ethylhexyl)phthalate.

3.4.1.2. Other Target Organ(s)

1. Fetus: Exposure to bis(2-ethylhexyl)phthalate during gestation has resulted in increased fetal mortality and malformations in rats and mice.

2. Testis: Treatment with bis(2-ethylhexyl)phthalate has resulted in decreased testicular weight and degeneration of the seminiferous tubules in rats and mice.

3. Blood: Decreased hemoglobin and packed cell volume was observed in rats exposed to bis(2-ethylhexyl)phthalate.

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organ(s)

1. Blood: Decreased hemoglobin and blood cell counts were observed in humans exposed to a mixture of phthalate esters containing bis(2-ethylhexyl)phthalate.

2. Nervous system: A polyneuritis and mild to moderate sensory-motor and motor polyneuropathy were observed in humans exposed to a mixture of phthalate esters containing bis(2-ethylhexyl)phthalate.

3.4.2.2. Other Target Organ(s)

1. Liver: The effects on liver are likely to be independent of route of exposure.

2. Kidney: The effects on kidney are likely to be independent of route of exposure.

4. CARCINOGENICITY

4.1 ORAL EXPOSURES

4.1.1. Human

Information on the oral carcinogenicity of bis(2-ethylhexyl)phthalate in humans was unavailable.

4.1.2. Animal

Groups of 50 male and 50 female Fisher 344 rats were given 0, 6000, or 12000 ppm bis(2-ethylhexyl)phthalate in their diet for 103 weeks. Groups of 50 male and 50 female B6C3F₁ mice were given 0, 3000, or 6000 ppm of the chemical in their diets for 103 weeks. All animals were examined when moribund or after 105 weeks from the beginning of treatment. No clinical signs of toxicity were observed in any of the animals. Female rats, and male and female mice demonstrated a statistically significant dose-dependent increased incidence of hepatocellular carcinomas and combined carcinomas and adenomas. A significant increase in the combined incidence of neoplastic nodules and hepatocellular carcinomas was seen in the high-dose male rats (NTP, 1982; Kluwe, et al., 1982).

Combined neoplastic nodules and hepatocellular carcinomas ranging from 0 to 4 per liver were reported in 11 of 14 F-344 rats on a diet containing 2% bis(2-ethylhexyl)phthalate for 108 weeks (Rao et al., 1990).

Bis(2-ethylhexyl)phthalate is known to induce the production of peroxisomes and the proliferation of peroxisomes has been linked with carcinogenesis (Rao and Reddy, 1991) (See also section 3.1.3.2.).

4.2 INHALATION EXPOSURES

4.2.1 Human

Information on the inhalation carcinogenicity of bis(2-ethylhexyl)phthalate in humans was unavailable.

4.2.2. Animal

Information on the inhalation carcinogenicity of bis(2-ethylhexyl)phthalate in animals was unavailable.

4.3 OTHER ROUTES OF EXPOSURE

Information on the carcinogenicity of bis(2-ethylhexyl)phthalate in animals or humans with other routes of exposure was unavailable.

4.4 EPA WEIGHT-OF-EVIDENCE

4.4.1. Oral

CLASSIFICATION: Group B2 -- Probable Human Carcinogen (U.S. EPA, 1987a, 1987b, 1991a, 1991b).

BASIS: Based on an increased incidence of hepatocellular carcinomas and adenomas in both rats and mice treated with bis(2-ethylhexyl)phthalate in the diet (NTP, 1982; Kluwe, et al., 1982).

4.4.2. Inhalation

CLASSIFICATION: Group B2 -- Probable Human Carcinogen (U.S. EPA, 1987a, 1992a, 1992b).

BASIS: Based on an increased incidence of hepatocellular carcinomas and adenomas in both rats and mice treated with bis(2-ethylhexyl)phthalate in the diet (NTP, 1982; Kluwe, et al., 1982).

4.5 CARCINOGENICITY SLOPE FACTORS

4.5.1. Oral

SLOPE FACTOR: 1.4E-2 (mg/kg/day)^-1 (U.S. EPA, 1992a, 1992b)

DRINKING WATER UNIT RISK: 4.0E-7 (µg/L)^-1 (U.S. EPA, 1992a, 1992b)

VERIFICATION DATE: 7/10/87

PRINCIPAL STUDY: NTP (1982); Kluwe, et al. (1982).

COMMENTS: Based on incidence of hepatocellular carcinomas and adenomas in male mice exposed orally to bis(2-ethylhexyl)phthalate. Both listed references discuss the same data set.

4.5.2. Inhalation

Quantitative estimation of carcinogenic risk from inhalation exposure is not available (U.S. EPA, 1992b)

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