The Risk Assessment Information System

Toxicity Summary for 1,4-DICHLOROBENZENE

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.

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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

Prepared by: James C. Norris, Ph.D, Chemical Hazard Evaluation Group in the Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, Oak Ridge National Laboratory*.

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

1,4-Dichlorobenzene (CAS 106-46-7), also referred to as para-DCB, p-DCB, paracide, Paramoth®, Parazene®, PDB, and Santochlor®, has a benzene ring with two chlorine atoms attached at the 1 and 4 carbon atoms; it does not occur naturally (ATSDR 1993). 1,4-Dichlorobenzene is used to make mothballs, deodorant blocks used in restrooms, and in animal holding facilities to control odors (ATSDR 1993). It also has applications in fumigants, insecticides, lacquers, paints, and seed disinfection products (Leber and Benya 1994). Of the 1300 sites on the United States Environmental Protection Agency's National Priorities List, 1,4-dichlorobenzene has been identified on at least 244 sites. Drinking water samples from U.S. surface water sources, environmental hazardous waste sites, and food have been reported to contain 1,4-dichlorobenzene (ATSDR 1993).

Detectable concentrations of 1,4-dichlorobenzene were found in adipose tissue and blood samples taken from Tokyo residents (Morita and Ohi 1975, Morita et al. 1975). A national survey of various volatile organic chemicals demonstrated 1,4-dichlorobenzene in the three adipose tissues sampled. In addition, studies have shown that babies can receive 1,4-dichlorobenzene from mother's milk (ATSDR 1993). 1,4-Dichlorobenzene is absorbed by experimental animals via inhalation, gavage, or subcutaneous injection (Hawkins et al. 1980). Data from oral administration of 1,4-dichlorobenzene to rabbits indicated oxidation to 2,5-dichlorophenol, which was found in the urine as a conjugate of glucuronic and sulfuric acids (Azouz et al. 1955). Other metabolites identified in the blood and urine of rats were 2,5-dichlorophenyl methyl sulfoxide and 2,5-dichlorophenyl methyl sulfone.

Severe hypochromic, microcytic anemia with excessive polychromasia, marginal nuclear hypersegmentation of the neutrophils, and a small number of red blood cells with Heinz bodies developed in a pregnant woman (21 years old) who consumed 1-2 blocks of 1,4-dichlorobenzene toilet air freshener per week throughout her pregnancy (Campbell and Davidson 1970). A 19-year-old female who consumed 4-5 moth pellets containing 1,4-dichlorobenzene on a daily basis for 2.5 years developed symmetrical, well-demarcated areas of increased pigmentation over various parts of her body, which disappeared over a 4-month period after discontinuing the ingestion (Frank and Cohen 1961).

In rats, 13-week gavage studies resulted in decreased hematocrit levels, red blood cell counts, and hemoglobin concentrations at 300 mg/kg/day (NTP 1987). Oral administration of 1200 and 1500 mg/kg/day resulted in degeneration and necrosis of rat hepatocytes. Increased incidences of hepatocellular degeneration and individual cell necrosis were observed in male and female mice gavaged with 600-1800 mg/kg/day.

Rats exposed via inhalation to 96-341 ppm of 1,4-dichlorobenzene intermittently for 5-7 months had cloudy swelling and degeneration of hepatic parenchymal cells in the central zone of the liver. Increased liver weights in the male and/or female rats occurred above 96 ppm (Hollingsworth et al. 1956). During a 2-generation study, adult rats exposed to 538 ppm exhibited tremors, ataxia, and hyperactivity; decreased grooming behavior; and an unkempt appearance (Tyl and Neeper-Bradley 1989). Both generations of offspring in the 538 ppm group had lower body weights at lactation day 4, and average litter size and survival were decreased. Selected animals from the first filial generation still had reduced body weights at 5 weeks postexposure.

No epidemiologic studies or case reports addressing the carcinogenicity of 1,4-dichlorobenzene in humans were available. In a 2-year study, female rats and male and female mice were gavaged with 300 and 600 mg/kg/day and male rats were gavaged with 150 and 300 mg/kg/day (NTP 1987). Nephropathy, epithelial hyperplasia of the renal pelvis, mineralization of the collecting tubules in the renal medulla, and focal hyperplasia of the renal tubular epithelium were noted in male rats receiving 150 and 300 mg/kg/day. Female rats gavaged with 300 and 600 mg/kg/day had an increased incidence of nephropathy and minimal hyperplasia of the renal pelvis or tubules. The following tumors were described as being present in the animals: renal tubular adenocarcinomas in male rats (controls, 2%; low dose, 6%; high dose, 14%), a marginal increase in mononuclear cell leukemia in male rats (control, 10%; low dose, 14%; high dose, 22%), hepatocellular carcinomas in male mice (controls, 28%; low dose, 22.5%; high dose, 64%) and in female mice (controls, 10%; low dose, 10.4%; high dose, 38%), and hepatocellular adenomas in male mice (controls, 10%; low dose, 26.2%; high dose, 32%) and in female mice (controls, 20%; low dose, 12.5%; high dose, 42%). In this NTP study, the tumor incidence in female controls was higher than the historical control. In both male and female mice, hepatocellular degeneration with resultant initiation of tissue repair was present. These findings resulted in a speculation by NTP (1987) that 1,4-dichlorobenzene was acting as a tumor promotor for liver tumors in male and female mice.

Reference concentrations (RfC) of 2.5 mg/m³ (0.42 ppm) for subchronic inhalation exposure (EPA 1995b) and 0.8 mg/m³ (0.13 ppm) for chronic inhalation exposure for 1,4-dichlorobenzene were derived (EPA 1995a) based on increased liver weights in the P1 males exposed via inhalation to 1,4-dichlorobenzene from the study of Tyl and Neeper-Bradley (1989). The No Observed Adverse Effects Level (NOAEL) was 301 mg/m³ (50 ppm). The Lowest Observed Adverse Effects Level (LOAEL) was 902 mg/m³ (150 ppm) (EPA 1995a). 1,4-Dichlorobenzene has been classified as C, possible carcinogen to humans (EPA 1995b). For oral exposure, the slope factor was 0.024 (mg/kg/day)^-1, and the unit risk was 6.8E-7 (µg/L)^-1 (EPA 1995 b).

1. INTRODUCTION

1,4-Dichlorobenzene (CAS 106-46-7), also referred to as para-DCB, p-DCB, paracide, Paramoth®, Parazene®, PDB, and Santochlor®, has a benzene ring with two chlorine atoms attached at the 1 and 4 carbon atoms. It is a white crystalline chemical with a penetrating, camphoraceous odor. It has a formula of C₆H₄C_l2, a molecular weight of 147.01, a melting point of 53.1C, and a vapor pressure of 64 torr at 20OC (Budavari et al. 1989). The odor threshold has been reported to be as low as 0.18 ppm (Amoore and Hautala 1983), and it does not occur naturally (ATSDR 1993).

1,4-Dichlorobenzene is used to make mothballs and deodorant blocks used in restrooms and in animal holding facilities to control odors (ATSDR 1993). It also has applications in fumigants, insecticides, lacquers, paints, and seed disinfection products (Leber and Benya 1994). Of the 1300 sites on the United States Environmental Protection Agency's National Priorities List, 1,4-dichlorobenzene has been identified on at least 244 sites. Drinking water samples from U.S. surface water sources, environmental hazardous waste sites, and food have been reported to contain 1,4-dichlorobenzene (ATSDR 1993). In the atmosphere, 1,4-dichlorobenzene reacts with photochemically generated hydroxyl radicals (Cuppitt 1980) with an estimated atmospheric residence time of 39 days (Singh et al. 1981). 1,4-Dichlorobenzene is expected to dissipate from the surface water into the atmosphere due to its low solubility in water and high volatility and to biodegrade in water under aerobic conditions (Bouwer and McCarty 1982). It is also expected that 1,4-dichlorobenzene is transported in the soil. Bioaccumulation is probable because of the high octanol-water partition coefficient, K_ow = 2455 (Leo et al. 1971). Biomagnification through the food chain has not been observed.

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

No controlled human study of absorption was evident in the literature. However, human experiences have indicated that absorption of 1,4-dichlorobenzene occurs via inhalation. One individual exposed for 6 months to vapors of 1,4-dichlorobenzene exhibited severe pallor, exhaustion, vomiting, intense gastric pain, headache, and rapidly developing hemolytic anemia (Gadrat et al. 1962). However, 13 coworkers exhibited no problems. In a Japanese report cited by EPA (1985), a young woman was exposed to unusually high concentrations of 1,4-dichlorobenzene lasting for 6 months; her symptoms were severe cerebellar ataxia, dysarthria, moderate weakness in all limbs, and hyporeflexia. Babies can receive 1,4-dichlorobenzene from mother's milk (ATSDR 1993). An estimated 35 micrograms are the average daily adult intake from breathing 1,4-dichlorobenzene released from home products (ATSDR 1993).

Rats administered ¹⁴C-labeled 1,4-dichlorobenzene via inhalation, gavage, or subcutaneous injection showed that tissue levels were similar regardless of the route of administration (Hawkins et al. 1980). The administration regimen was either exposure to 1000 ppm for 3 hours per day for 10 days, gavage with 250 mg/kg/day for 10 days, or injection with 250 mg/kg for 10 days (Hawkins et al. 1980). It was estimated that the rats with a body weight of 200 g and a breathing rate of 0.34 m³/day absorbed approximately 20% of the administered dose. (EPA 1985).

2.2. DISTRIBUTION

No distribution data are available for known inhalation exposures in humans. However, detectable concentrations of 1,4-dichlorobenzene, presumably from inhalation, were found in adipose tissue and blood samples taken from Tokyo residents (Morita and Ohi 1975, Morita et al. 1975). A national survey of various volatile organic chemicals demonstrated 1,4-dichlorobenzene in the three adipose tissues sampled (subcutaneous, perirenal, and mesenteric adipose tissue). Nine geographic regions and three age groups (0-14, 15-40, and greater than 45 years) were sampled. Concentrations ranging from 0.012 to 0.5 µg/g of wet tissue were reported (EPA 1986).

Hawkins et al. (1980) reported that tissue distribution was similar in female rats regardless of the exposure route (inhalation, oral, and subcutaneous). The highest concentration was found in fat (up to 598 µg/g via inhalation), and the next highest concentrations (5-10% of the fat concentrations via inhalation) were in the liver and kidney. Similar tissue distributions for all routes were also reported by Kimura et al. (1979). Oral administration of 1,4-dichlorobenzene in rats demonstrated that adipose tissue is the major depository. Male rats receiving a single gavage dose of 200 mg/kg retained 1,4-dichlorobenzene in adipose tissue up to 120 hours postexposure (Kimura et al. 1979). The next highest concentrations were in the kidney and liver ( 4 and 3%, respectively, of the adipose tissue concentrations). Low concentrations were present in the blood, lung, heart, and brain. Within 48 hours, most of the 1,4-dichlorobenzene had disappeared from all tissues except the adipose tissue. After 120 hours, 1,4-dichlorobenzene was still present in the adipose tissue. In the Hawkins et al. (1980) study, female rats received doses ranging from 50 to 500 mg/kg/day for 10 days. Distribution patterns were the same as previously described in Kimura et al. (1979).

2.3. METABOLISM

Analysis of urine from a 3-year-old boy exposed to 1,4-dichlorobenzene indicated the presence of 2,5-dichlorophenol and four unidentified phenols which were conjugated with glucuronic and sulfuric acid (Hallowell 1959). Data from oral administration of 1,4-dichlorobenzene to rabbits indicated oxidation to 2,5-dichlorophenol which was found in the urine as a conjugate of glucuronic and sulfuric acids (Azouz et al. 1955). Other metabolites in the blood and urine of rats include 2,5-dichlorophenyl methyl sulfoxide and 2,5-dichlorophenyl methyl sulfone.

2.4. EXCRETION

Hawkins et al. (1980) reported that female rats exposed to ¹⁴C-1,4-dichlorobenzene (1000 ppm for 3 hours/day for 10 days) excreted 97.4% of the ¹⁴C in the urine. Following gavage administration of ¹⁴C-1,4-dichlorobenzene (250 mg/kg/day for 10 days), 97% of the recovered ¹⁴C was found in the urine within 5 days post-treatment. Expiration of ¹⁴C represented a small proportion (0.2% and 1%) of the total ¹⁴C excreted for inhalation exposure and oral administration, respectively.

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

A 3-year-old boy who had been playing with 1,4-dichlorobenzene crystals (no indication of ingestion) developed acute hemolytic anemia and methemoglobulinuria (Hallowell 1959).

3.1.1.2. Animal

A single gavage dose of 1000 mg/kg in rats and 1600 mg/kg in guinea pigs did not induce death; however, 4000 mg/kg in rats and 2800 mg/kg in guinea pigs resulted in 100% mortality (Hollingsworth et al. 1956). Oral LD₅₀ values in adult rats were reported by Gaines and Linder (1986) to be 3900 and 3800 mg/kg for males and females, respectively. Administration of gradually increasing doses up to 770 mg/kg/day for 5 days produced high urinary excretion of porphyrin, coproporphyrin, uroporphyrin, porphobilinogen, and delta-aminolevulinic acid (ALA) (Rimington and Ziegler 1963). Liver concentrations of uroporphyrin and protoporphyrin were elevated, while concentrations of coproporphyrin were not. Rats gavaged with 250 mg/kg/day for 3 days had increased microsomal protein content and no change in the cytochrome P450 content. Several hepatic microsomal xenobiotic metabolic systems increased at low doses of 20 and 40 mg/kg/day. Protein droplet formation was noted in males but not females administered 1,4-dichlorobenzene by gavage with 7 daily doses of 120 or 300 mg/kg/day (Charbonneau et al. 1989). A single dose (500 mg/kg, gavage) of ¹⁴C-1,4-dichlorobenzene produced a similar protein droplet formation, and the ¹⁴C was reversibly associated with -2µ-globulin.

3.1.2. Subchronic Toxicity

3.1.2.1. Human

A pregnant woman (21 years old) consumed 1-2 blocks of 1,4-dichlorobenzene toilet air freshener per week throughout her pregnancy and developed severe hypochromic, microcytic anemia with excessive polychromasia, marginal nuclear hypersegmentation of the neutrophils, and a small number of red blood cells with Heinz bodies (Campbell and Davidson 1970). Her consumption of 1,4-dichlorobenzene ceased at about 38 weeks of gestation, and her hemoglobin concentrations increased.

3.1.2.2. Animal

Four 14-day gavage studies have reported deaths from 1,4-dichlorobenzene at the following doses: no deaths in male rats administered up to 1000 mg/kg/day, 80% (4/5) in female rats at 1000 mg/kg/day, 100% in male and female rats at 2000 mg/kg/day and higher, 70% in mice at 1000 mg/kg/day, and 100% in mice at 4000 mg/kg/day (NTP 1987). In 13-week gavage studies, mortality percentages were 0% for mice administered 900 mg/kg/day, 40% (8/20) for mice receiving 1500 mg/kg/day, and 85% (17/20) for rats dosed with 1500 mg/kg/day (NTP 1987).

In the NTP study (1987), F344/N rats were dosed with 0, 300, 600, 900, 1200, and 1500 mg/kg for 13 weeks, and B6C3F₁ mice were dosed with 0, 600, 900, 1200, and 1800 mg/kg for 13 weeks. The findings encompassed four systems: digestion, liver, blood, and kidney. Gastrointestinal irritation, described as epithelial necrosis and villar bridging of the mucosa of the small intestine, was observed in rats dosed with 1200 mg/kg/day. Decreased hematocrit levels, red blood cell counts, and hemoglobin concentrations were present in male rats dosed with 300 mg/kg/day. Mice dosed with 600 to 1800 mg/kg/day demonstrated 34 to 50% lower white cell counts. Rats displayed degeneration and necrosis of hepatocytes at 1200 and 1500 mg/kg/day. Serum cholesterol concentrations were elevated in the male rats receiving 600 mg/kg/day and in the female rats receiving 900 mg/kg/day. The serum triglycerides and protein concentrations were reduced in male rats dosed with 300 mg/kg/day. Both sexes of rats demonstrated increased urinary porphyrins at 1200 mg/kg/day. Male mice had increased serum cholesterol concentrations at doses of  900 mg/kg/day and serum protein and triglyercide concentrations at doses of 1500 mg/kg/day. Hepatocellular cytomegaly was present in mice administered 600 mg/kg/day. Hepatocellular degeneration was noted in male and female mice administered 600-1800 mg/kg/day. Male rats exhibited renal tubular degeneration, ranging from slight to severe at 300 mg/kg/day and moderate at the 600 mg/kg/day. Mice, however, did not exhibit renal effects at dose ranges of 600-1000 mg/kg/day or 80-900 mg/kg/day.

In another 13-week study, male rats dosed with 75-600 mg/kg/day were observed to have renal hyaline droplets in all males from the 150 mg/kg/day group and above (Bomhard et al. 1988).  During a 13-week study (Carlson and Tardiff 1976), rats dosed with 20 and 40 mg/kg/day were observed to have increased O-ethyl-O-p-nitrophenyl phenylphosphorothionate detoxification and benzpyrene hydroxylase and azoreductase activities, suggesting hepatic enzyme induction. At the end of a 30-day recovery period, the benzpyrene hydrolase and azoreductase activities were still elevated. No effect on the hemoglobin or hematocrit concentrations of rats receiving 40 mg/kg/day was observed. Carlson (1977) reported increased liver porphyrins in rats dosed by gavage with 50 to 200 mg/kg/day for up to 120 days. Males may have been more sensitive than the females.

3.1.3. Chronic Toxicity

3.1.3.1. Human

A 19-year-old female had consumed 4-5 moth pellets containing 1,4-dichlorobenzene on a daily basis for 2.5 years. She developed symmetrical, well-demarcated areas of increased pigmentation over various parts of her body which disappeared over a 4-month period after discontinuing the ingestion (Frank and Cohen 1961). However, after the consumption ceased, she developed tremors and unsteadiness that were considered psychological and not physical effects of withdrawal.

3.1.3.2. Animal

In a 2-year study, 52% (26/50) of the male rats receiving 300 mg/kg/day died, while female rats dosed with 600 mg/kg/day had the same mortality rate as male and female controls. Mice administered up to 600 mg/kg/day for 2 years also had mortality rates similar to controls (NTP 1987).

No respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, dermal, or ocular effects were noted after 2 years of gavaging at 300 and 600 mg/kg/day in female rats and male and female mice and at 150 and 300 mg/kg/day in male rats (NTP 1987). Increased incidences of alterations in cell size (cytomegaly and karyomegaly), hepatocellular degeneration, and individual cell necrosis were observed in mice gavaged with 300 and 600 mg/kg/day. Nephropathy, epithelial hyperplasia of renal pelvis, mineralization of the collection tubules in the renal medulla, and focal hyperplasia of renal tubular epithelium were noted in male rats receiving 150 and 300 mg/kg/day. Female rats gavaged with 300 and 600 mg/kg/day demonstrated an increased incidence of nephropathy and minimal hyperplasia of the renal pelvis or tubules.

3.1.4. Developmental and Reproductive Toxicity

3.1.4.1. Human

The infant from the pregnant woman mentioned in Sect. 3.1.2.1 exhibited no hematological problems 6 weeks after delivery.

3.1.4.2. Animal

Pregnant female rats gavaged with 500 or 1000 mg/kg/day on gestation days 6-15 presented fetuses with a dose-related incidence of an extra rib, fetal weight loss at 1000 mg/kg/day, and reduced maternal weight gain at 500 and 1000 mg/kg/day (Giavini et al. 1986). Another study dosing rats with 250, 500, 750, or 1000 mg/kg/day on gestation days 6-15 resulted in similar findings at  500 mg/kg/day. Additionally, the number of skeletal variations increased at 750 and 1000 mg/kg/day (Ruddick et al. 1983).

3.1.5. Reference Dose

Reference doses have not been derived for 1,4-dichlorobenzene.

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

Information on the acute toxicity of 1,4-dichlorobenzene in humans or animals following inhalation exposure was not available.

3.2.2. Subchronic Toxicity

3.2.2.1. Human

A husband (60 years old) and wife were exposed to supposedly high concentrations of 1,4-dichlorobenzene in their house for a period of 3 to 4 months. Clinical signs included severe headaches, diarrhea, numbness, clumsiness, burning sensation in the man's legs, slurred speech, weight loss (50 pounds in 3 months for the man), and jaundice; both individuals died. The woman died within a year of the initial exposure, and the man died within a few months of his wife. Both had acute yellow atrophy of the liver (also known as massive hepatic necrosis or fulminant hepatitis). No additional information was provided regarding confounding factors (Cotter 1953).

A 69-year-old man exposed in his chair at home for approximately 3 weeks to 1,4-dichlorobenzene developed petechiae, purpura, and swelling of his hands and feet (Nalbandian and Pearce 1965). An indirect basophil degranulation test demonstrated a strong positive reaction suggesting a sensitivity to 1,4-dichlorobenzene. A 36-year-old woman using 1,4-dichlorobenzene as a moth killer in her home reported intense headaches. A 34-year-old woman who demonstrated the use of 1,4-dichlorobenzene in an enclosed booth in a department store complained of headaches, nausea, and vomiting (Cotter 1953).

3.2.2.2. Animal

Male rats, female guinea pigs, and one female rabbit exposed for 16 days to 173 ppm developed pulmonary interstitial edema and congestion and alveolar hemorrhage (Hollingsworth et al. 1956). After 12 weeks of exposure to 798 ppm, two rabbits displayed lung congestion and emphysema. Two rabbits, exposed for 12 weeks to 798 ppm, developed ocular effects described as reversible [nonspecific eye ground changes (changes in the fundus or back of the eye)]. Guinea pigs exposed to 341 ppm for a comparable duration exhibited focal necrosis, slight cirrhosis, and hepatocyte swelling and degeneration. Rats exposed to 96-341 ppm intermittently for 5-7 months had cloudy swelling and degeneration of hepatic parenchymal cells in the central zone of the liver and increased liver weights in the male and/or females above 96 ppm. No changes were observed at 96 ppm. Kidney weights in the male rats (not the females) increased slightly after 5-7 months of intermittent exposure to 158 or 341 ppm. These findings (Hollingsworth et al. 1956) must be viewed with the understanding that several inconsistent variables were employed in the study design, such as species, numbers, sex of the animals per species, observations on controls, and duration of exposure at each exposure level. During a two-generation study, adult rats exposed to 538 ppm (6 hours/day and 7 days/week for 10 weeks) exhibited tremors, ataxia, hyperactivity, decreased grooming behavior, and an unkempt appearance (Tyl and Neeper-Bradley 1989).

3.2.3. Chronic Toxicity

3.2.3.1. Human

For 12-15 years on a weekly basis, a 53-year-old woman had been inhaling 1,4-dichlorobenzene crystals that were scattered on the carpet and furniture (Weller and Crellin 1953). Pulmonary findings included lung parenchyma distorted by fibrosis, a thickening of the alveolar walls, and a marked infiltration of lymphocytes, mononuclear phagocytes, some thickening of the muscular walls of the small arteries, and focal fibrous thickening of the pleura. The authors attributed these findings to the physical interaction of the crystals with the lung tissue rather than chemical toxicity.

In a plant using 1,4-dichlorobenzene, 58 men employed from 8 months to 25 years (average 4.75 years) reported painful irritation of the nose and eyes (Hollingsworth et al. 1956). Exposure concentrations were from 80 to 160 ppm with concentrations greater than 160 ppm being unbreathable by unacclimated persons. No cataracts or any other lens changes were observed. After 6 years of using 1,4-dichlorobenzene as an insect repellant and being exposed to high concentrations, a 25-year-old woman presented severe ataxia, speech difficulties, moderate weakness of her limbs, and marked delays of certain brain waves as demonstrated by brainstem auditory evoked potentials (BAEP) (Miyai et al. 1988). Exposure was terminated, and her symptoms gradually improved over the next 6 months. After 8 months, the BAEPs were normal.

3.2.3.2. Animal

Rat liver and kidney weights were increased after 76 weeks of exposure to 500 ppm (Riley et al. 1980).

3.2.4. Developmental and Reproductive Toxicity

3.2.4.1. Human

Information on the developmental and reproductive toxicity of 1,4-dichlorobenzene via inhalation in humans was not available.

3.2.4.2. Animal

Pregnant rats were exposed to concentrations up to 500 ppm for 6 hours per day on gestation days 6-15 with no effect on the offspring (Hodge et al. 1977). Exposure of rabbits to 800 ppm for 6 hours per day on days 6-18 of gestation resulted in decreased maternal body weight gain on the first 3 days of exposure, suggesting maternal toxicity (Hayes et al. 1985). At 300 ppm, the rabbits showed an increase in the litter resorptions and percentages of resorbed implantations per litter. Since this latter effect was not present in the 800 ppm group, the authors did not consider it exposure-related. In a two-generation study, rats exposed to 66.3, 211, or 538 ppm 1,4-dichlorobenzene developed liver and kidney weight changes and hepatocellular hypertrophy in the 211 and 538 ppm groups and hyaline droplet nephropathy in all male kidneys. Both generations of offspring in the 538 ppm group had lower body weights at lactation day 4, and average litter size and offspring survival were decreased (Tyl and Neeper-Bradley 1989). Selected animals from the first filial generation still had reduced body weights 5 weeks postexposure. The authors concluded that these effects were the result of parental toxicity. Anderson and Hodge (1976) reported that the reproductive performance was not affected in male mice exposed to 75 to 450 ppm for 6 hours per day for 5 days.

3.2.5. Reference Concentration

3.2.5.1. Subchronic

INHALATION REFERENCE CONCENTRATION: 2.5 mg/m³ (EPA 1995b)

NOAEL: 301 mg/m³ (50 ppm)

UNCERTAINTY FACTOR: 30

PRINCIPAL STUDY: Tyl and Neeper-Bradley (1989)

COMMENTS: The subchronic reference concentration is based on the same study as the chronic reference concentration. An uncertainty factor of 10 was used to account for sensitive subpopulations and an uncertainty factor of 3 rather than 10 was used to account for interspecies differences since dosimetry adjustments were applied.

3.2.5.2 Chronic

INHALATION REFERENCE CONCENTRATION: 0.8 mg/m³ (EPA 1995a)

NOAEL: 301 mg/m³ (50 ppm)

LOAEL: 902 mg/m³ (150 ppm)

UNCERTAINTY FACTOR: 100

CONFIDENCE:

Study: Medium

Data Base: Medium

Reference Concentration: Medium

VERIFICATION DATE: 6/25/92

PRINCIPAL STUDY: Tyl and Neeper-Bradley (1989)

COMMENTS: The chronic reference concentration is based on increased liver weights observed in P generation male rats in a two-generation reproductive toxicity study. An uncertainty factor of 10 was used to account for sensitive subpopulations among humans. An uncertainty factor of 3.33⁽¹⁾ rather than 10 was used to account for interspecies differences since dosimetry adjustments were applied. An additional factor of 3.33¹ was used since the NOAEL was based on a subchronic rather than a chronic study. A full factor of 10 was not used because the LOAEL was estimated by a route-to-route extrapolation from the chronic oral study (NTP 1987) that suggested limited progression of the hepatic lesions when terminal results were compared with interim kills. In addition, comparison of histopathologic results from the interim and final kills of the Riley et al. (1980) study also indicated that there was no progression in severity of liver lesions.

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

Information on the acute toxicity of 1,4-dichlorobenzene by other routes of exposure in humans was not available.

3.3.1.2. Animal

The dermal LD₅₀ value for 1,4-dichlorobenzene in rats was suggested to be greater than 6000 mg/kg (Gaines and Linder 1986).

3.3.2. Subchronic Toxicity

Information on the subchronic toxicity of 1,4-dichlorobenzene by other routes of exposure in humans or animals was not available.

3.3.3. Chronic Toxicity

Information on the chronic toxicity of 1,4-dichlorobenzene by other routes of exposure in humans or animals was not available.

3.3.4. Developmental and Reproductive Toxicity

Intraperitoneal injections of 800 mg/kg in rats increased the concentrations of abnormal sperm consisting of misshapen heads and tails (Murty et al. 1987).

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organ(s)

1. Liver: Acute, subchronic, and chronic gavage studies in rats resulted in changes in hepatic enzyme concentrations, degeneration and necrosis of hepatocytes, reduced serum triglycerides and protein concentrations, increased hepatic uroporphyrin and protoporphyrin, and hepatic cytomegaly and karyomegaly.

2. Kidney: Subchronic exposure by gavage produced renal tubular degeneration in rats. Chronic exposure of rats resulted in epithelial hyperplasia of the renal pelvis, mineralization of the collecting tubules in the renal medulla, and focal hyperplasia of renal tubular epithelium.

3.4.1.2. Other Target Organ(s)

1. Developmental and reproductive: Oral (gavage) administration during gestation in rats produced an extra rib, fetal weight loss, and decreased maternal weight gain in rats.

2. Blood: Acute hemolytic anemia and methemoglobulinuria occurred after possible oral consumption in a child. A pregnant woman, who consumed 1-2 blocks of 1,4-dichlorobenzene toilet air freshener per week through about gestation week 38, developed severe hypochromic, microcytic anemia with excessive polychromasia; marginal nuclear hypersegmentation of the neutrophils; and a small number of red blood cells with Heinz bodies.

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organ(s)

1. Liver: A subchronic study in rats reported cloudy swelling and degeneration of hepatic parenchymal cells, increased liver weights, focal necrosis, and slight cirrhosis. These findings must be viewed with an understanding that several inconsistent variables were employed in the study design, such as species, numbers, sex, observations on controls, and duration of exposure at each exposure level. Another chronic study in rats also found increased liver weights.

2. Central nervous system: Humans exposed by inhalation for 3 to 6 months developed clinical signs, such as severe headaches, slurred speech, nausea, vomiting, severe cerebellar ataxia, and dysarthria. A woman exposed for 6 years presented severe ataxia, speech difficulties, and marked delay of certain brain waves as demonstrated by brainstem auditory evoked potentials. In a two-generation study, adult rats exhibited tremors, ataxia, hyperactivity, decreased grooming behavior, and an unkempt appearance.

3.4.2.2. Other Target Organ(s)

1. Development and reproductive: A two-generation study found both generations of offspring with lower body weights at lactation day 4 and decreased litter size, offspring survival, and body weights 5 weeks postexposure for some animals. However, the author of the study concluded that these effects were the result of parental toxicity.

3.4.3 Other Routes of Exposure

Target organs for other routes of exposure were not identified.

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

4.1.1. Human

Information on the carcinogenicity of 1,4-dichlorobenzene in humans following oral exposure was not available.

4.1.2. Animal

In a 2-year study, female rats and male and female mice were gavaged with 300 or 600 mg/kg/day and male rats were gavaged with 150 or 300 mg/kg/day (NTP 1987). Renal tubular adenocarcinomas in the male rats were increased in a dose related manner (controls, 2%; low dose, 6%; high dose, 14%). A marginal increase in mononuclear cell leukemia was also observed in all dose groups (controls, 10%; low dose, 14%; high dose, 22%). The male and female mice in the 600 mg/kg/day group had increased incidences of hepatocellular carcinomas [(male - controls, 28%; low dose, 22.5%; high dose, 64%) (female - controls, 10%; low dose, 10.4%; high dose, 38%)]. Hepatocellular adenomas were also noted in male mice from the 300 and 600 mg/kg/day groups (controls, 10%; low dose, 26.2%; high dose, 32%) and in female mice from the 600 mg/kg/day group (controls, 20%; low dose, 12.5%; high dose, 42%).

Hepatoblastomas (a rare form of hepatocellular carcinoma) were observed in 4/50 males of the 600 mg/kg/day group. Male mice exhibited an increase in thyroid gland follicular cell hyperplasia, and the female mice had a marginal positive trend in the incidence of follicular cell adenomas of the thyroid gland. The male mice in the 600 mg/kg/day group had an increased incidence of adrenal pheochromocytomas. Adrenal gland medullary hyperplasia and focal hyperplasia of the adrenal gland capsule incidences were higher in the male mice. Renal tumors occurring in only male rats may have been the result of an _2µ-globulin increase. In this NTP study, the liver tumor incidence in female controls was higher than the historical control numbers. Additionally, no mutagenicity in microbial or mammalian systems was demonstrated. In both the male and female gavaged mice, hepatocellular degeneration with resultant initiation of tissue repair was present. These findings resulted in a speculation by NTP (1987) that 1,4-dichlorobenzene was acting as a tumor promotor for liver tumors in male and female mice.

4.2. INHALATION EXPOSURES

4.2.1. Human

Information on the carcinogenicity of 1,4-dichlorobenzene in humans following inhalation exposure was not available.

4.2.2. Animal

No evidence of carcinogenicity was observed in rats exposed to 500 ppm for 76 weeks (Riley et al. 1980). However, organ toxicity may not have been achieved suggesting that a maximum tolerated dose was not obtained. In addition, the exposure length was less-than-lifetime.

4.3. OTHER ROUTES OF EXPOSURE

Information on the carcinogenicity of 1,4-dichlorobenzene by other routes of exposure in humans or animals was not available.

4.4. EPA WEIGHT-OF-EVIDENCE

Classification--C Group, possible human carcinogen (EPA 1995b)

Basis: Based on an increase in liver tumors in mice administered 1,4-dichlorobenzene for 103 weeks.

4.5. CARCINOGENICITY SLOPE FACTORS

4.5.1. Oral

Slope Factor: 0.024 (mg/kg/day)^-1

Unit Risk: 6.8E-07 (µg/L)^-1

Principal Study: NTP (1987)

Comment: The oral slope factor for 1,4-dichlorobenzene is under review and is subject to change.

4.5.2. Inhalation

Inhalation slope factors have not been developed for 1,4-dichlorobenzene.

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1. Values in EPA (1995a) were reported to be 3. However, in a personal communication with John L. Cicmanec/OHEA, it was explained that these values were supposed to be 3.33. Retrieve Toxicity Profiles Condensed Version

Last Updated 2/13/98