The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for AROCLOR-1260

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

Prepared by C. B. Bast, Ph.D., D.A.B.T., Chemical Hazard Evaluation Group, Biomedical and Environmental Information Analysis Section, Health Sciences 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

Aroclor® 1260 is a polychlorinated biphenyl (PCB) mixture containing approximately 38% C₁₂H₄Cl₆, 41% C₁₂H₃Cl_7, 8% C₁₂H₂Cl_8, and 12% C₁₂H₅Cl₅ with an average chlorine content of 60% (USAF 1989). PCBs are inert, thermally and physically stable, and have dielectric properties. In the environment, the behavior of PCB mixtures is directly correlated to the degree of chlorination. Aroclor® is strongly sorbed to soil and remains immobile when leached with water; however, the mixture is highly mobile in the presence of organic solvents (USAF 1989). PCBs are resistant to chemical degradation by oxidation or hydrolysis. However, biodegradation, especially of lower chlorinated PCBs, can occur (USAF 1989). PCBs have high bioconcentration factors, and due to lipophilicity, especially of highly chlorinated congeners, tend to accumulate in the fat of fish, birds, mammals, and humans (ATSDR 1995). The use of PCBs in the United States was limited to closed systems in 1974, and in February, 1977, the U.S. Environmental Protection Agency (EPA) issued final regulations prohibiting PCB discharge into waterways (EPA 1977).

PCBs are absorbed after oral, inhalation, or dermal exposure and are stored in adipose tissue. The location of the chlorine atoms on the phenyl rings is an important factor in PCB metabolism and excretion. The major route of PCB excretion is in the urine and feces; however, of more importance is elimination in human milk. Metabolites are predominately found in urine and bile, while small amounts of parent compound are found in the feces. Biliary excretion appears to be the source of fecal excretion (ATSDR 1995).

Accidental human poisonings and data from occupational exposure to PCBs suggest initial dermal and mucosal disturbances followed by systemic effects that may manifest themselves several years post-exposure. Initial effects are enlargement and hypersecretion of the Meibomian gland of the eye, swelling of the eyelids, pigmentation of the fingernails and mucous membranes, fatigue, and nausea. These effects were followed by hyperkeratosis, darkening of the skin, acneform eruptions, edema of the arms and legs, neurological symptoms, such as headache and limb numbness, and liver disturbance (USAF 1989).

Hepatotoxicity is a prominent effect of PCBs, including Aroclor® 1260, that has been well characterized (EPA 1996a). Effects include hepatic microsomal enzyme induction, increased serum levels of liver-related enzymes (indicative of hepatocellular damage), liver enlargement, lipid deposition, fibrosis, and necrosis. Chloracne and Immune function disorders have been observed in humans and several animal species after PCB exposure. Reproductive and developmental effects, including low-birth weight, and decreased gestational time, and decreased reproductive capacity, have been observed in human and animal species. No reference dose (RfD) or reference concentrations (RfC) have been verified for Aroclor® 1260.

Data are suggestive but not conclusive concerning the carcinogenicity of PCBs in humans. The EPA has not determined a weight-of-evidence classification or slope factor for Aroclor® 1260 specifically. However, hepatocellular carcinomas in three strains of rats and two strains of mice have led the EPA (1996b) to classify PCBs as group B2, probable human carcinogen. The carcinogenicity slope factor (q₁*) for oral exposure to PCBs is

7.7 (mg/kg/day)^-1 based on an increase of hepatocellular tumors in female Sprague-Dawley rats treated with Aroclor® 1260. A drinking water unit risk of 2.2E-4 (µg/L)^-1 for PCBs was calculated based on the q₁* (EPA 1996b).

1. INTRODUCTION

Aroclor® 1260 (CAS registry number 11096-82-5) is a colorless liquid with an average molecular weight of 376 (USAF 1989). It is a polychlorinated biphenyl (PCB) mixture containing approximately 38% C₁₂H₄Cl₆, 41% C₁₂H₃Cl_7, 8% C₁₂H₂Cl_8, and 12% C₁₂H₅Cl₅ with an average chlorine content of 60% (USAF 1989). PCBs, including Aroclor® 1260, are inert, thermally and physically stable, and have dielectric properties. They have been used in closed systems such as heat transfer liquids, hydraulic fluids and lubricants, and in open systems such as plasticizers, surface coatings, inks, adhesives, pesticide extenders, and for microencapsulation of dyes for carbonless duplicating papers. The Monsanto Corporation was the major U.S. producer of PCBs from 1930 to 1977, and marketed the mixtures under the trade name Aroclor® (ATSDR 1995).

In the environment, the behavior of PCB mixtures is directly correlated to the degree of chlorination. In general, as the degree of chlorination increases, sorption increases and transport and transformation decrease (USAF 1989). Aroclor® is strongly sorbed to soil and remains immobile when leached with water; however, the mixture is highly mobile in the presence of organic solvents (USAF 1989). Water-borne PCBs not sorbed to sediment or suspended solids can readily volatilize due to low water solubility. PCBs are resistant to chemical degradation by oxidation or hydrolysis. However, biodegradation, especially of lower chlorinated PCBs, can occur (USAF 1989). PCBs have high bioconcentration factors, and due to lipophilicity, especially of highly chlorinated congeners, tend to accumulate in the fat of fish, birds, mammals, and humans (ATSDR 1995). In humans, relatively greater amounts of PCBs have also been identified in skin, liver, and breast milk (ATSDR 1995).

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION

PCBs are well absorbed after oral, inhalation, or dermal exposure (ATSDR 1995). Specific information concerning absorption of Aroclor® 1260 is limited. Rats, mice, and monkeys absorb between 75 to >90% of orally administered doses of PCBs. Oral exposure through consumption of contaminated food (including breast milk) is the major route of exposure to PCBs for the general population. Populations living near hazardous waste sites may be orally exposed via consumption of contaminated water or soil (ATSDR 1995). Both the inhalation and dermal routes of exposure are recognized as significant contributors of PCB accumulation in occupationally exposed individuals. Quantitative data concerning inhalation exposure to PCBs and dermal exposure to Aroclor® 1260 are not available.

2.2 DISTRIBUTION

Because of lipophilicity, PCBs accumulate mainly in fatty tissue, including breast milk. Long-term distribution of all PCBs in tissue follows the order
adipose tissue> skin> liver >muscle (Safe 1980). Specific information concerning the distribution of Aroclor® 1260 is limited.

2.3 METABOLISM

Metabolism of PCBs depends on the number and position of the chlorine atoms on the phenyl ring of the congeners and on the animal species. The metabolism of PCBs following oral and parenteral exposure has been well characterized, and although limited data are available concerning metabolism after inhalation and dermal exposure, there are no data to suggest that PCBs would be metabolized differently by these routes (EPA 1996a). PCBs are metabolized by the microsomal monooxygenase system catalyzed by cytochrome P-450 to polar metabolites that can undergo conjugation with glutathione and glucuronic acid (ATSDR, 1995). Experimental animal data suggest the following concerning PCB metabolism: (1) hydroxylation is favored at the para position in the least chlorinated phenyl ring unless this site is sterically hindered; (2) in the lower chlorinated biphenyls, the para position of both biphenyl rings and carbon atoms that are para to the chloro substituent are all readily hydroxylated; (3) the availability of two adjacent unsubstituted carbon atoms facilitates oxidative metabolism of the PCB substrate; (4) as the degree of chlorination on both phenyl rings increases, the rate of metabolism decreases; and (5) the metabolism of specific PCB congeners by different species can result in considerable variations in metabolite distribution (Safe 1980).

2.4 EXCRETION

The major route of PCB excretion is in the urine and feces; however, of more importance is elimination in human milk. Predominately metabolites are found in urine and bile, and small amounts of parent compound are found in the feces. Biliary excretion appears to be the source of fecal excretion (ATSDR 1995). The location of the chlorine atoms on the phenyl rings is an important factor in PCB excretion. Experimental studies in mice suggest that differential biotransformation results in compounds having at least one pair of unsubstituted adjacent ortho-meta carbon atoms being excreted faster than those with other configurations, regardless of the number of chlorine atoms (Gage and Holm 1976). Studies in rats have shown that at equilibrium, chlorobiphenyl congeners are eliminated from tissues according to individual kinetic parameters. In rats given six weekly doses of PCBs, di- and trichlorobiphenyls had elimination half lives of 1 to 2 days; tetrachlorobiphenyls had two elimination constants, one between 2 and 10 days and a second of <90 days; and penta- and hexachlorobiphenyls had single elimination half-lives of >90 days (Tanabe et al. 1981). Therefore, heavily chlorinated congeners are preferentially retained, probably due to a lower metabolic rate. Elimination half-lives from blood between 4.1 and 24.1 months were reported for 2,3',4,4',5-pentachlorobiphenyl in people who had consumed PCB contaminated rice. The elimination half life for 2,3,3',4,4'-pentachlorobiphenyl ranged from 3.3 to 12.4 months (ATSDR 1995). Larger amounts of PCBs are transferred to infants through mother's milk than through placental transfer (ATSDR 1995). A Canadian study estimated that after the first 14 days of breast-feeding, infants had ingested 144 g of PCBs, and their PCB body burden was 0.32 ppm (Mes et al. 1984).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES

3.1.1 Acute Toxicity

3.1.1.1 Human

PCBs are slowly metabolized compounds. Therefore, toxic symptoms usually occur after long-term exposure and bioaccumulation (USAF 1989). No specific data concerning effects of acute exposure to Aroclor® 1260 in humans were located in the available literature. Effects from acute exposure to PCBs (which may be manifested weeks to months after exposure) may include facial edema, ocular discharge, swollen eyelids, conjunctival hyperemia, visual and hearing disturbances, decreases in diastolic and systolic blood pressure, weakness and numbness of the extremities, neurobehavioral and psychomotor impairment, GI upset, diarrhea, hepatitis, chloracne, and asymptomatic hyperthyroxinemia (HSDB 1995).

3.1.1.2 Animal

In most species, the initial sign of acute PCB intoxication is weight loss or decreased weight gain. Severely intoxicated rats have shown ataxia, diarrhea, and lack of response to pain stimuli. Histopathological effects are observed mainly in the liver and kidney. The median time to death is 2-3 weeks for small laboratory animals, and toxicity generally decreases with increased chlorination (USAF 1989).

The oral LD₅₀ value for Aroclor® 1260 is 1315 mg/kg/day in male Sherman rats (ATSDR 1995). Autopsies of rats that were given a single, lethal gavage dose (not adequately quantified) of Aroclor® 1260 showed gastric hemorrhage and foci of ulceration in the stomach and duodenum (Kimbrough et al. 1972).

3.1.2 Subchronic Toxicity

3.1.2.1 Human

Information on the subchronic oral toxicity of Aroclor® 1260 in humans was not available.

3.1.2.2 Animal

Groups of 10 Sherman rats/sex were fed 0, 20, 500, or 1000 ppm Aroclor® 1260 in the diet for 8 months (Kimbrough et al., 1972). Several rats in the 500 and 1000 ppm groups died before 6 months. Adenofibrosis of the liver was observed in 2/10 males in the 1000 ppm group, and in 1/10, 1/10, and 4/10 females in the 100, 500, and 1000 ppm groups, respectively. Liver cell hypertrophy, with cytoplasmic inclusions and brown pigment in the Kupffer cells was also observed in these animals. In another study, groups of 12 female albino guinea pigs were fed 0, 10, or 50 ppm Aroclor® 1260 in the diet for 8 weeks (Vos and DeRoij 1972). Six animals per group received injections of tetanus toxin in the right footpad on days 35 and 49 to stimulate the lymphoid system. Decreased gamma-globulin containing cells in lymph nodes were observed in stimulated PCB-treated animals.

Rao & Banerji (1993) fed groups of 12 male Wistar rats diets containing 50 or 100 ppm Aroclor® 1260 for 120 days. Observed effects included necrosis and degeneration of the adrenal cortex and medulla; glomerulonephritis and degeneration of kidney proximal and distal tubules; degeneration and fibrosis of thyroid follicles, and increased liver enzyme activity, centrilobular hypertrophy and hyperplasia, and hepatocellular damage.

Monkeys were treated daily with 0, 0.8, 1.6, or 3.2 mg/kg Aroclor® 1260 in corn oil for 20 weeks (Seegal et al. 1991). In treated animals, dopamine concentrations were decreased in the caudate, putamen, and hypothalamus, but not in the substantia nigra, globus pallidus, or hippocampus.

3.1.3 Chronic Toxicity

3.1.3.1 Human

Specific information on the chronic oral toxicity of Aroclor® 1260 to humans was not available. However, information from accidental poisonings that occurred in Japan and Taiwan (Yusho and Yu-Cheng incidents) and from occupational exposure (Sect. 3.2.3.1) to PCBs is available.

Yusho

The most notable example of the possible effects of PCB exposure in humans is the Yusho incident which occurred in Japan in 1968. Kaneclor® 400 (48% Cl) inadvertently leached into a commercial rice oil preparation. After a latent period of 5 to 6 months, symptoms began to manifest. It was initially estimated that the oil was contaminated with 1000 to 3000 ppm PCBs but reanalysis revealed the presence of 968 ppm PCBs and 8 ppm polychlorodibenzofurans (PCDFs). The majority of people consumed about 200 µg/kg/day. Early symptoms of Yusho (literally "oil disease") included enlargement and hypersecretion of the Meibomian gland of the eye, swelling of the eyelids, pigmentation of the fingernails and mucous membranes, fatigue and nausea. These symptoms were followed by hyperkeratosis, darkening of the skin with follicular enlargement, acneform eruptions with secondary staphylococcal infection, edema of the arms and legs, and bronchitis-like respiratory symptoms which persisted for years (Masuda and Yoshimura 1984).

As dermal and mucosal conditions improved after a few years post-exposure, evidence of various systemic disturbances became apparent. Most victims displayed neurological symptoms (e.g., headache, numbness in the limbs, hypesthesia and neuralgic limbs). Central nervous system (CNS) damage was not apparent. A significant positive correlation was noted between PCB blood levels in Yusho victims and the severity of dermal lesions, ocular symptoms, elevated serum triglyceride concentrations, limb paresthesia and other symptoms (EPA, 1980).

The majority of Yusho victims complained of persistent cough, sputum production and chronic bronchitis-like symptoms. Secondary respiratory infections were often noted, although no fever and little change in leucocyte count or erythrocyte sedimentation rate was seen (Shigematsu et al., 1978). Examination of 400 Yusho patients revealed respiratory symptoms including expectoration in 40% and wheezing in 2% of 289 non-smokers; the former (along with persistent coughing) appeared with the development of skin eruptions, while the latter appeared several months later. Other respiratory symptoms included bronchiolitis in many, and pneumonia or atelectasis in about 10% of the patients. The incidence and severity of the respiratory symptoms correlated well with the concentration of PCB in the blood and sputa. Viral or bacterial infection increased the severity of the respiratory symptoms and persisted in patients with blood PCB levels over 10 ppb.

Examination of organs of deceased Yusho victims revealed high levels of PCDFs. Liver and adipose tissue samples of Yusho patients revealed 2-25 and 6-13 ppb PCDFs, respectively, while no PCDFs were detected in unexposed volunteers. PCDFs were also shown to be retained in the body, particularly in the liver, much longer than PCBs. In fact, 2, 3, 4, 7, 8-penta-CDF was still present in the tissue of a patient 9 years after the poisoning incident (Masuda and Yoshimura, 1984).

Yu-Cheng

An incident similar to Yusho was reported in Taiwan in 1979 following consumption of rice oil contaminated with PCBs. The resulting disease was called Yu-Cheng (oil disease). Symptoms included acneform eruptions and follicular accentuation, pigmentation of the skin and nails, swelling of the eyelids and eye discharge, headache, nausea, and numbness of the limbs. Blood disorders included a decrease in red blood cells, an increase in white blood cells and a decrease in hemoglobin and gamma-immunoglobin (EPA 1980).

Chang et al. (1981) measured B-cells to evaluate effects on humoral immunity and T-cells to test for effects on cell-mediated immunity in Yu-Cheng patients. Thirty patients with an average blood PCB level of 45 ppb were studied. PCB poisoning did not affect the total lymphocyte count or the number of B-cells. Suppressor T-cells were not affected, but helper T-cells were significantly decreased in Yu-Cheng patients (26.1% vs. 36.9% helper T-cells in control subjects) indicating a range in sensitivity of different lymphocytes to PCBs. Chang et al. concluded that cell-mediated immunity, as shown by decreased T-cell levels, was significantly correlated with PCB toxicity.

Chen et al. (1985) found that the severity of neuropathy was related to the concentration of PCB and PCB derivatives in the blood. The average blood level of PCB in 110 Yu-Cheng victims was 39 ppb. Sensory and motor nerve conduction velocities were shown to be significantly slower in PCB-intoxicated patients.

3.1.3.2 Animal

Information on chronic oral non-cancer toxicity of Aroclor® 1260 in animals was not available.

3.1.4 Developmental and Reproductive Toxicity

3.1.4.1 Human

The ability of PCBs to cross the placenta and affect the fetus was evident in babies born to Yusho (Sect. 3.1.3.1) mothers. Of the 12 infants born in 1968 to 11 Yusho mothers and 2 non-Yusho women with Yusho husbands, 10 infants lived and 2 were stillborn. All infants had eye discharge. Nine of the ten live infants had dark grayish skin and 5 had grayish pigmentation of the gums and nails. One of the stillborn fetuses had marked hyperkeratosis, atrophy of the epidermis and cystic dilation of the hair follicles. Also, an increase in melanin pigment was present in the blood cells and the epidermis. All newborns were small and the growth rate of the 10 infants was significantly slower than unaffected children. Teeth were erupted at birth and there was spotted calcification of the parieto-occipital skull, wide fontanelles and sagittal suture, along with facial edema and exophthalmic eyes (Yamashita 1977). Miller (1985) also reviewed the effects of PCBs on infants of exposed mothers. A deep brown pigmentation of the skin (usually referred to as cola-colored skin) was the most prevalent symptom. Biopsy of the skin showed an increase in melanin and hyperkeratosis. The pigmentation cleared up within 2 to 5 months. Low birth weights were also a primary effect of PCB toxicity. The majority of infants had a thick white discharge from the eye and cysts of the Meibomian gland. Some of the children exhibited severely swollen eyelids and facial edema. Gingival hyperplasia and teeth present at birth occurred in 16% of the infants investigated. The children with gum overgrowth and natal teeth eruption also had spotty calcification in the occipital region of the skull and a wide separation of the sagittal suture and large anterior and posterior fontanelles (membrane covering the unossified space in the skull). These symptoms suggest an irregular calcification which may explain the large unossified areas of the brain and the reduced resistance of the mandible to erupting teeth.

Taylor et al. (1984) examined personnel records from PCB manufacturing facilities engaged in producing capacitors using Aroclor® 1016, Aroclor® 1254, and Aroclor® 1242. There was a total of 388 pregnancies to 354 females and 51 births to 39 females who worked directly with PCB manufacturing. High exposure to PCBs was associated with reduced birth weight even after adjustment for year of birth, maternal parity, and sex of infant. Mean gestation age was reduced by 6.6 days after adjustment for these same variables. After adjusting for gestational age, the average birth weight in the high exposure group was reduced by 58 grams.

3.1.4.2 Animal

Numerous publications have demonstrated the ability of PCBs to cross the placenta and accumulate in fetal tissues. However, indications of structural malformations, genetic changes or other teratogenic effects have been few; most oral exposure studies have reported negative results. Reproductive capacity can be notably depressed with PCB exposure, particularly in females (USAF 1989).

Linder et al. (1974) fed male and female Sherman rats diets containing 500 mg Aroclor® 1260/kg for 67 or 186 days prior to mating. Decreased litter size, decreased preweaning survival, and lipid accumulation in the livers of offspring at weaning were observed. Reproduction and pup survival were not affected following oral doses of 100 mg/kg/day Aroclor® 1260 during days 7 to 15 of gestation (Linder et al. 1974).

Aroclor® 1260 was fed to rats at a concentration of 0, 1, 10 or 100 ppm. No effect was seen at the 1 or 10 ppm treatment level. Ingestion of 100 ppm Aroclor® 1260 resulted in an increased incidence of stillbirths (Burke and Fitzhugh 1970).

Calandra (1976) fed rats a diet containing 1, 10, or 100 ppm Aroclor® 1260 during a three generation reproduction study. No reproductive or teratogenic effects were observed in the first generation; however, a decrease in the mating index and in the incidence of pregnancy was observed in the 10 and 100 ppm groups in the second and third generations.

3.1.5 Reference Dose

3.1.5.1 Subchronic

None available.

3.1.5.2 Chronic

None verified.

3.2 INHALATION EXPOSURES

3.2.1 Acute Toxicity

3.2.1.1 Human

No specific data concerning acute inhalation exposure of Aroclor® 1260 to humans was available. Signs and symptoms of short-term human exposure may include anorexia, nausea, edema of the face and hands, abdominal pain, ocular discharge, and a burning sensation to the skin and eyes (USAF 1989).

3.2.1.2 Animal

No data concerning acute inhalation exposure of Aroclor® 1260 to animals was available.

3.2.2 Subchronic Toxicity

3.2.2.1 Human

Mild to moderate chloracne was observed in 7 of 14 workers exposed to 0.1 mg/m³ of an unspecified Aroclor® mixture for an average of 14.3 months (Meigs et al., 1954). The chloracne was primarily found on the face, especially the cheeks, forehead and ears. Pyrolytic formation of chlorinated dibenzofurans (CDFs) was a confounding factor in this study. In another study, Emmett et al. (1988a,b) studied 55 male transformer workers occupationally exposed to Aroclor®/ trichlorobenzene mixtures for an average of 3.75 years. The range of PCB concentrations (primarily Aroclor® 1260) measured in the breathing zone was 0.00001 to 0.012 mg/m³. Chest pain while walking (16% exposed), loss of appetite (20% exposed, 4% control), frequent headaches, sleeping problems and memory difficulties were also observed significantly increased in exposed workers when compared to controls. The concentration of CDF contamination was 13 to 116 ppb by weight.

3.2.2.2 Animal

No data concerning acute inhalation exposure of Aroclor® 1260 to animals was available.

3.2.3 Chronic Toxicity

3.2.3.1 Human

The relative contribution of the inhalation and dermal routes in occupational exposures is unknown; however, the data will be primarily presented in the inhalation section of this document. Occupational exposure to PCBs presents a different clinical picture than oral exposure from accidental poisoning. The symptoms most commonly observed appear to be dermal and mucosal effects but no consistent disturbances in liver function. An investigation of former capacitor workers was presented by Lawton et al. (1985). Exposure to PCBs occurred between 1954 to 1977 when Aroclor® 1242 and 1016 were used extensively. Air levels were estimated to be at least 690 µg/m³. Dermal contact also occurred. An 80% clearance of the lower chlorinated PCBs was noted in workers re-examined 29 months after exposure had ceased. Traces of highly chlorinated PCBs were found in the blood of long-time workers, particularly those exposed to Aroclor® 1254 before its use was discontinued in 1954. In 1976, blood levels of this compound were 8 ppm. By 1979, 25 years after exposure was discontinued, blood levels were 6 ppm. There was also a statistically significant association of log serum triglycerides and total cholesterol with every measure of log serum PCBs.

Smith et al. (1982) investigated cholesterol and triglyceride levels in PCB-exposed workers and the possible correlation to cardiovascular effects. Two-hundred twenty-eight employees of an electrical equipment manufacturing plant were evaluated. From 1959 to 1971, Aroclor® 1242 was used; Aroclor® 1016 was used thereafter. Forty-seven employees from a public utility plant were also evaluated, 14 of which worked in transformer maintenance. Another 46 employees of a private utility company, 15 working in transformer maintenance and 10 who worked in transformer overhaul, were included. Serum log PCBs correlated significantly with symptoms of mucous membrane and skin irritation, of systemic malaise, and of altered peripheral sensation. Serum log PCBs was also correlated with serum (SGOT), plasma log (triglycerides) and log high density lipoprotein, which indicate an effect on liver metabolism and possible development of cardiovascular disease.

3.2.3.2 Animal

Information on the chronic inhalation toxicity of Aroclor® 1260 or PCBs to animals was not available.

3.2.4 Developmental and Reproductive Toxicity

3.2.4.1 Human

No human reproductive or developmental data for inhalation exposure to Aroclor® 1260 were available. Fifty-one infants born to 39 mothers employed at two capacitor manufacturing plants who had a history of direct exposure to Aroclors 1254, 1242, and/or 1016 had lower mean birth weights and shorter mean gestational ages than those of 337 infants born to 280 women who worked in low-exposure areas (Taylor et al. 1984). The low-exposure infants were heavier than matched community controls; thus establishing no dose-response. The study results suggest that the decreased birth weights of the high-exposure infants may have been due to shortened gestational periods rather than decreased interuterine growth and that the decreased birth weights may have been partially mediated by high exposure to PCBs.

3.2.4.2 Animal

No data concerning developmental or reproductive effects from inhalation exposure of animals to Aroclor® 1260 or PCBs were available.

3.2.5 Reference Concentration

3.2.5.1 Subchronic

No data concerning the subchronic RfC were available.

3.2.5.2 Chronic

No data concerning the chronic RfC were available.

3.3 OTHER ROUTES OF EXPOSURE

3.3.1 Acute Toxicity

3.3.1.1 Human

Information on the acute toxicity of Aroclor® 1260 or other PCBs to humans by other routes of exposure was not available.

3.3.1.2 Animal

A range of 1300 to 2000 mg/kg has been reported for the dermal LD₅₀ of Aroclor® 1260 (50% solution in corn oil) in rabbits (IARC 1978).

3.3.2 Subchronic Toxicity

3.3.2.1 Human

Information on the subchronic toxicity of Aroclor® 1260 or other PCBs to humans by other routes of exposure was not available.

3.3.2.2 Animal

Vos and Beems (1971) studied the effects of Aroclor® 1260 applied to rabbit skin. One mL of 118 mg PCB-containing solution was dropped daily, 5 times a week for 38 days onto the shaved backs of female New Zealand rabbits. Microscopic examination of the Aroclor® 1260 treated animals revealed hyperplasia and hyperkeratosis of the follicular epithelium with the formation of comedo-like structures. These resulted from the plugging of the dilated hair follicles with keratin. Necroscopy of all animals that died or were killed on day 38 revealed a significant increase in liver and kidney weight. Liver lesions were present in all treated animals with periportal fibrosis being a common finding. Kidney damage was also found in all treated animals. Hydropic degeneration of the convoluted tubules was present in halfmals. There was a reduction in the number of germinal centers in the spleen and lymph nodes and atrophy of the thymus in the PCB-treated animals indicating an immunosuppressive effect. Vos and Beems concluded that PCBs are readily absorbed by the skin in quantities capable of causing similar systemic lesions of the liver, kidney and lymphoid tissue as seen during ingestion of PCBs.

3.3.3 Chronic Toxicity

3.3.3.1 Human

The relative contribution of the inhalation and dermal routes in occupational exposures is unknown; however, these data were primarily presented in the inhalation section of this document (Sect. 3.2.3.1). A study of capacitor workers showed PCB- exposure measurements ranging from 48 to 275 µg/m³ in workroom air and 2 to 28 µg/cm² for Pyralene® 3010 or Apirolio® on the skin of the palms (Maroni et al. 1981a, b). Of 80 exposed workers, 16 exhibited evidence of liver involvement including asymptomatic hepatomegaly and/or elevated serum SGTP, SGOT, or SGPT. No control group was included in this study.

3.3.3.2 Animal

Information on the chronic toxicity of Aroclor® 1260 or other PCBs to animals by other routes of exposure was not available.

3.3.4 Developmental and Reproductive Toxicity

Information on the developmental and reproductive toxicity of Aroclor® 1260 or other PCBs to humans or animals by other routes of exposure was not available.

3.4 TARGET ORGANS/CRITICAL EFFECTS

3.4.1 Oral Exposures

3.4.1.1 Primary target organs

1. Liver: Hepatotoxicity is a well-characterized effect of Aroclor® 1260 and other PCBs. The spectrum of effects include hepatic microsomal enzyme induction, increased serum levels of liver-associated enzymes suggestive of possible liver damage, liver enlargement, lipid deposition, fibrosis and necrosis.

2. Skin: Chloracne has been observed in humans and several animal species following PCB exposure.

3.4.1.2 Other target organs

Immune function disorders and decreased reproductive capacity, including low-birth weight and decreased gestational time, have been described in human and other animal species. Ocular discharge and swollen Meibomian glands have been described in humans. Thyroid and kidney damage has also been observed.

3.4.2 Inhalation Exposures

3.4.2.1 Primary target organs

1. Skin: Mild to moderate chloracne was observed in occupationally exposed individuals.

2. Liver: Liver toxicity similar to that observed from oral exposure to PCBs is also seen with inhalation exposure. However, comparatively high levels (compared to oral equivalents) were required to produce these effects by the inhalation route.

3.4.2.2 Other target organs

Lower mean birth weights and shorter mean gestational ages in infants born to occupationally-exposed mothers may have been mediated by PCB exposure.

3.4.3 Other Routes of Exposure

3.4.3.1 Primary target organs

1. Liver: Occupationally-exposed individuals exhibited asymptomatic hepatomegaly and elevated serum levels of liver-associated enzymes, perhaps due to a dermal contribution.

2. Skin: Chloracne has been observed in occupationally-exposed individuals. The relative contributions of the inhalation and dermal routes are not precisely known.

4. CARCINOGENICITY

4.1 ORAL EXPOSURES

4.1.1 Human

Information on the carcinogenicity of Aroclor® 1260 or any Aroclor®PCB formulation to humans following oral exposure was not available. There is inconclusive evidence of liver cancer in people who were exposed to heated non-Aroclor®PCBs during the Yusho and Yu-Ching incidents; however, chlorinated dibenzofurans were major contaminants (ATSDR 1995).

4.1.2 Animal

Aroclor® 1260

Norback and Weltman (1985; also Weltman and Norback 1982) fed 70 male and 70 female Sprague-Dawley rats Aroclor® 1260 in the diet at a level of 100 ppm for 16 months, followed by 50 ppm for 8 months and finally, a control diet for 5 months. Hepatocellular tumors developed in 95% of the female rats and 15% of the male rats. Seventy percent of the females also developed various forms of bile duct tumors; only 37% of the males developed such tumors. Norback and Weltman concluded that Aroclor® 1260 was a complete liver carcinogen acting as both an initiator and promotor.

Kimbrough et al. (1975) fed 0 or 100 ppm Aroclor® 1260 to female Sherman rats for 21 to 22 months. Hepatocellular carcinomas developed in 14.13% of the treated rats and in only 0.58% of control animals. Treated rats also developed a high incidence of neoplastic liver nodules (79.5% vs. zero in control animals) and hepatocellular alterations (98.9% vs. 16.2% in control rats).

Groups of male Wistar rats were fed a protein diet containing 50 ppm or 100 ppm Aroclor® 1260 for 120 days (Rao and Banerji 1988). Gross hepatic changes, neoplastic nodules and adenofibrosis in 75% and 50% of the treated animals, respectively, were observed. The authors were unable to explain the higher incidence of tumors found in the rats fed the lower concentration of Aroclor.

Male Wistar rats were fed a standard diet, a diet supplemented with 100 ppm Clophen A30 or a diet supplemented with 100 ppm Clophen A60 for 832 days (Schaeffer et al. 1984). Clophen A60 is almost identical in composition to Aroclor® 1260 (IARC 1978), while Clophen A30 appears to be similar in structure to Aroclor® 1016. Hepatocellular carcinoma was the most frequently found lesion in animals sacrificed at the end of the experiment, observed in 2, 3, and 61% of the animals in the control, Clophen A30 and Clophen A60 groups, respectively. Preneoplastic nodules and neoplastic lesions were found in 50-60% of the Clophen A30 animals after day 500, and 100% of the animals killed after day 800. However, 100% of the Clophen A60 animals had preneoplastic and neoplastic lesions after day 500. The incidence of preneoplastic nodules and neoplastic lesions in control animals was low until day 800 after which the incidence rose to 32%.

Other PCBs

Ito et al. (1973) fed male DD mice (12/group) with diets containing 100, 250, or 500 ppm Kanechlors 500, 400, and 300 for 32 weeks. The group fed 500 ppm Kanechlor 500 had a 41.7% incidence of hepatocellular carcinomas and a 58.3% incidence of nodular hyperplasia. No hepatocellular carcinomas or nodular hyperplasia was observed in mice fed 100 or 250 ppm Kanechlor 500 or among those fed any concentration of Kanechlors 400 or 300.

Kimbrough and Linder (1974) fed 300 ppm Aroclor® 1254 to male BALB/cJ mice for 11 months or for 6 months followed by the control diet for the remaining 5 months of the study. In the mice fed Aroclor® 1254 for 11 months, hepatomas were observed in 9/22 (41%) survivors and adenofibrosis and enlarged livers in all 22 survivors. Examination of livers of mice treated for 6 months and then allowed to recover for 5 months showed slight-to-moderate diffuse, interstitial fibrosis. One mouse developed a small hepatoma. No hepatic lesions were observed in 58 control mice.

In a study conducted by the National Cancer Institute (NCI 1978, Ward 1985) male and female F344 rats were administered 0, 25, 50, or 100 ppm Aroclor® 1254 daily for 104 to 105 weeks. Clinical signs of toxicity including alopecia, amber-colored urine, facial edema, exophthalmos and cyanosis were observed in the 50 or 100 ppm Aroclor® 1254 groups. An increased incidence of lymphoma and leukemia combined was seen in males (12.5% for control animals, 8.3% for the low dose animals, 20.8% for the 50 ppm group and 37.5% for the high dose group). However, comparisons of each treatment group with the matched controls were not statistically significant and the tumors could not clearly be related to Aroclor® 1254 treatment. Hepatocellular adenomas and carcinomas were found in Aroclor® 1254-treated animals but not in control animals. Furthermore, a dose-related incidence of nodular hyperplasia appeared in all animals treated with Aroclor® 1254, but this trend was not statistically significant. Adenocarcinomas of the stomach, jejunum, or cecum were observed in 2 treated male and 2 treated female rats as well as a carcinoma in a treated male. These lesions, although not statistically significant, appear to be treatment-related since no control animals developed these types of tumors. NCI concluded that Aroclor® 1254 was not carcinogenic in F344 rats but that the high incidence of hepatocellular proliferative lesions in both male and female rats was Aroclor® 1254-related. Additionally, the tumors found in the gastrointestinal tract may also have been due to Aroclor® 1254 administration.

Morgan et al. (1981) limited their investigation to the gastric effects of PCBs. Male and female F344 rats were fed a diet containing 0, 25, 50, or 100 ppm Aroclor® 1254 for 26 months. Rats fed 50 or 100 ppm Aroclor® 1254 had a lower body weight than the control animals and developed signs of PCB toxicity. The incidence of stomach lesions increased as the dietary intake of Aroclor® 1254 increased. In control animals, 6.4% developed lesions while in the 25, 50 and 100 ppm PCB-treated groups, 10.4%, 16.7% and 35.4% developed lesions, respectively. A total of 6 definite and 2 suspected, but not confirmed, adenocarcinomas developed in Aroclor® 1254-fed rats. Stomach adenocarcinomas rarely occur in F344 rats. Morgan et al. concluded that Aroclor® 1254 incorporated into the diet for 2 years induced intestinal metaplasia which resulted in the probable induction of adenocarcinomas in F344 rats.

4.2 INHALATION EXPOSURES

4.2.1 Human

Aroclor® 1260

No carcinogenicity data concerning inhalation exposure of humans to Aroclor® 1260 was available.

Other PCBs

A slight increase in the incidence of cancer, particularly melanoma of the skin, has been reported in a small group of men occupationally exposed to Aroclor® 1254. Eight cancers (in 7 workers) were reported between 1957 and 1975 in 92 workers exposed to Aroclor® 1254. Of these eight cancers, three were malignant melanoma and two were cancer of the pancreas. Data from the NCI estimate that 0.04 malignant melanomas should be expected to develop in this group. These data suggest a possible correlation between Aroclor® 1254 and the development of malignant melanomas. Exposure to other chemicals was not known (IARC 1978, NIOSH 1975).

An excess risk of cancer of the liver, biliary tract, or gall bladder was found in 2588 workers (1270 male and 1318 female) from two capacitor factories where PCBs were used. The workers had been employed at least 3 months between 1940 and 1976. Aroclor®1254 was used at first, but usage was later changed to Aroclor®1242 and then to Aroclor®1016. Aroclor®1254 exposure data were not available (ATSDR 1995).

4.2.1 Animal

Information on the carcinogenicity of Aroclor® 1260 or any PCB by inhalation exposure to animals was not available.

4.3 OTHER ROUTES OF EXPOSURE

Information on the carcinogenicity of Aroclor® 1260 or any PCB in humans or animals by other routes of exposure was not available.

4.4 EPA WEIGHT-OF-EVIDENCE

4.4.1 Oral--PCBs

CLASSIFICATION: Group B2--Probable Human Carcinogen (EPA 1996b)

BASIS: There is no EPA Cancer Classification specifically for Aroclor® 1260. Hepatocellular carcinomas in three strains of rats and two strains of mice are inadequate yet suggestive evidence of excess risk of cancer in humans by ingestion and inhalation or dermal contact. (EPA 1996b).

4.4.2 Inhalation

CLASSIFICATION: None

4.5 CARCINOGENICITY SLOPE FACTORS

4.5.1 Oral-PCBs

SLOPE FACTOR: 7.7 (mg/kg/day)^-1 (EPA 1996b)

DRINKING WATER UNIT RISK: 2.2E-4 (µg/L)^-1 (EPA 1996b)

VERIFICATION DATE: 4/22/87

PRINCIPAL STUDIES: Norback and Weltman 1985

COMMENTS: Values are for Polychlorinated biphenyls. There are no EPA values derived specifically for Aroclor® 1260. However, the values derived for PCBs as a class are based on an increase in hepatocellular tumors in female Sprague-Dawley rats treated with Aroclor® 1260 in the diet (EPA 1996b).

4.5.2 Inhalation

No inhalation slope factor or unit risk has been verified.

5. REFERENCES

ATSDR (Agency for Toxic Substances and Disease Registry). 1995. Toxicological Profile for Polychlorinated Biphenyls. Draft for Public Comment (Update). Prepared by Research Triangle Institute, under Contract No. 205-93-0606 for ATSDR, Public Health Service, U.S. Department of Health and Human Services.

Burke, J., and O. G. Fitzhugh. 1970. Suppl. No. 1, States Report of Chemistry and Toxicology of PCBs. Food and Drug Administration, Washington, D.C. (Cited in UASF 1989)

Calandra, J. C. 1976. Summary of toxicological studies on commercial PCB's. NTIS PB Report (PB-253 248):35-42. (Cited in USAF 1989)

Chang, K. J., K. H. Hsieh, T. P. Lee, S. Y. Tang, and T. C. Tung. 1981. Immunologic evaluation of patients with polychlorinated biphenyl poisoning: Determination of lymphocyte subpopulations. Toxicol. Appl. Pharmacol. 61:58-63. (Cited in USAF 1989)

Chen, R. C. S. Y. Tang, H. Miyata, T. Kashimoto, Y. C. Chang, K. J. Chang, and T. C. Tung. 1985. Polychlorinated biphenyl poisoning: Correlation of sensory and motor nerve conduction, neurologic symptoms, and blood levels of polychlorinated biphenyls, quaterphenyls and dibenzofurans. Environ. Res. 37:340-348. (Cited in USAF 1989)

Gage, J. C. and S. Holm. 1976. The influence of molecular structure on the retention and excretion of polychlorinated biphenyls by the mouse. Toxicol. Appl. Pharmacol. 36:555-560. (Cited in ATSDR 1995)

Emmett, E. A., M. Maroni, J. M. Schmith et al. 1988a. Studies of transformer repair workers exposed to PCBs: I. Study design, PCB concentrations, questionnaire, and clinical examination results. Am. J. Ind. Med. 13:415-427. (Cited in ATSDR 1995)

Emmett, E. A., M. Maroni et al. 1988b. Studies of transformer repair workers exposed to PCBs: II. Results of clinical laboratory investigations. Am. J. Ind. Med. 14:47-62. (Cited in ATSDR 1995)

EPA (U.S. Environmental Protection Agency). 1996a. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH. Aroclor®1254 file.

EPA. 1996b. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH. Polychlorinated biphenyls file.

EPA. 1980. Ambient water quality criteria for polychlorinated biphenyls. EPA Report No. 440/ 5-80-068. Washington, D.C.: U.S. Environmental Protection Agency, Office of Water Regulations and Standards. PB81-117798. (Cited in USAF 1989)

EPA. 1977. Code of Federal Regulations. 40 CFR 129.4.

HSDB (Hazardous Substances Data Base). 1995. Aroclor®1254 file. Retrieved online December 4, 1995.

IARC ( International Agency for Research on Cancer). 1978. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Some anti-thyroid and related substances, nitrofurans and industrial chemicals. Vol. 7. IARC, Lyon, France, pp. 261-289.

Ito, N., H. Nagasaki, M. Arai et al. 1973. Histopathologic studies on liver tumorigenesis induced in mice by technical polychlorinated biphenyls and its promoting effect on liver tumors induced by benzene hexachloride. JNCI. 51:1637-1646. (Cited in EPA 1996b)

Kimbrough, R. D., and R. E. Linder. 1974. Induction of adenofibrosis and hepatomas of the liver in BALB/cJ mice by polychlorinated biphenyls (Aroclor®1254). JNCI. 53:547-552.

Kimbrough, R. D., R. E. Linder, T. B. Gaines. 1972. Morphological changes in livers of rats fed polychlorinated biphenyls. Arch. Environ. Health. 25:354-364. (Cited in EPA 1996a)

Kimbrough, R. D., R. A. Squire, R. E. Linder, J. D. Strandberg, R. J. Montali, and V. W. Burse. 1975. Induction of liver tumors in Sherman strain female rats by polychlorinated biphenyl (Aroclor® 1260). J. Nat. Cancer Instit. 55(6):1453-1456. (Cited in USAF 1989)

Lawton, R. W., M. R. Ross, J. Feingold, and J. F. Brown, Jr. 1985. Effects of PCB exposure on biochemical and hematological findings in capacitor workers. Environ. Health Perspect. 60:165-184. (Cited in USAF 1989)

Linder, R. E., T. B. Gaines, R. D. Kimbrough. 1974. The effect of polychlorinated biphenyls on rat reproduction. Food. Cosmet. Toxicol. 12:63-77. (Cited in IARC 1978)

Maroni, M., A. Columbi, G. Arbosti et al. 1981a. Occupational exposure to polychlorinated biphenyls in electrical workers. II. Health effects. Br. J. Ind. Med. 38:55-60. (Cited in ATSDR 1995)

Maroni, M., A. Columbi, G. Arbosti et al. 1981b. Occupational exposure to polychlorinated biphenyls in electrical workers. I. Environmental and blood polychlorinated biphenyls concentrations. Br. J. Ind. Med. 38:49-54. (Cited in ATSDR 1995)

Masuda, Y., and H. Yoshimura. 1984. Polychlorinated biphenyls and dibenzofurans in patients with Yusho and their toxicological significance: A review. Am. J. Ind. Med. 5:31-44.

Mes, J., J. A. Doyle, B. R. Adam et al. 1984. Polychlorinated biphenyls and organochlorine pesticides in milk and blood of Canadian women during lactation. Arch. Environ. Contam. Toxicol. 13:217-223. (Cited in ATSDR 1995)

Morgan, R.W. J. M. Ward, and P. E. Hartman. 1981. Aroclor®1254-induced intestinal metaplasia and adenocarcinoma in the glandular stomach of F344 rats. Cancer Res. 41:5052-5059. (Cited in USAF 1989)

NCI (National Cancer Institute). 1978. Bioassay of Aroclor® 1254 for possible carcinogenicity. NCI Carcinogenesis Technical Report Series Number 38, NCI-CG-TR-38, DHEW Publication No. (NIH) 78-838. (Cited in USAF 1989)

NIOSH (National Institute for Occupational Safety and Health). 1975. Current Intelligence Bulletin 7, Polychlorinated Biphenyls (PCBs). (Cited in USAF 1989)

Norback, D.H., and R. H. Weltman. 1985. Polychlorinated biphenyl induction of hepatocellular carcinoma in the Sprague-Dawley rat. Environ. Health Perspect. 6:97-105. (Cited in USAF 1989)

Rao, C.V., and A. S. Banerji. 1993. Effect of polychlorinated biphenyls (Aroclor® 1260) on histology of adrenal of rats. J. Environ. Biol. 14:1-6. (Cited in ATSDR 1995)

Rao, C.V., and A. S. Banerji. 1988. Induction of liver tumors in male Wistar rats by feeding polychlorinated biphenyls (Aroclor® 1260). Cancer Lett. 39:59-67. (Cited in USAF 1989)

Safe, S. 1980. Metabolism, uptake, storage and bioaccumulation of halogenated aromatic pollutants. In: Kimbrough, R.D., ed. Halogenated biphenyls, terphenyls, naphthalenes, dibenzodioxins and related products. Amsterdam: Elsevier Science Publishers, 81-107.

Schaeffer, E., H. Greim, and W. Goessner. 1984. Pathology of chronic polychlorinated biphenyl (PCB) feeding in rats. Toxicol. Appl. Pharmacol. 75:278-288. (Cited in USAF 1989)

Seegal, R.F., K. O. Brosch, and B. Bush. 1991. Comparison of effects of Aroclors 1016 and 1260 on non-human primate catecholamine function. Toxicology. 66:145-163. (Cited in ATSDR 1995)

Shigematsu, N., S. Ishimaru, R. Saito, T. Ikeda, K. Matsuba, K. Sugiyama, and Y. Masuda. 1978. Respiratory involvement in polychlorinated biphenyls poisoning. Environ. Res. 16:92-100. (Cited in USAF 1989)

Smith, A.B., J. Schloemer, L. K. Lowry, A. W. Smallwood, R. N. Ligo, S. Tanaka, W. Stringer, M. Jones, R. Hervin, and C. J. Glueck. 1982. Metabolic and health consequences of occupational exposure to polychlorinated biphenyls. Br. J. Ind. Med. 39:361-369. (Cited in USAF 1989)

Tanabe, S., Y. Nakagawa, and R. Tatsukawa. 1981. Absorption efficiency and biological half-life of individual chlorobiphenyls in rats treated with Kanechlor products. Agric Biol Chem. 45:717-726. (Cited in ATSDR 1995)

Taylor, P. R., C. E. Lawrence, H.-L Hwang, and A. S. Paulson. 1984. Polychlorinated biphenyls: Influence on birthweight and gestation. Am. J. Public Health 74:1153-1154. (Cited in USAF 1989)

USAF (U.S. Air Force). 1989. The Installation Restoration Program Toxicology Guide. Volume 3. Aerospace Medical Division, Air Force Systems Command, Wright-Patterson Air Force Base, Ohio. pp. 52-1-52-68.

Vos, J. G., and R. B. Beems. 1971. Dermal toxicity studies of technical polychlorinated biphenyls and fractions thereof in rabbits. Toxicol. Appl. Pharmacol. 19:617-633. (Cited in USAF 1989)

Ward, J. R. 1985. Proliferative lesions of the glandular stomach and liver in F344 rats fed diets containing Aroclor®1254. Env. Health. Perspect. 60:89-95.

Weltman, R. H., and D. H. Norback. 1982. Development of hepatocellular and cholangiocellular neoplasms in the livers of male and female Sprague-Dawley rats after chronic administration of Aroclor® 1260. Fed. Proc. 41:446. Abstract No. 1029. (Cited in USAF 1989)

Yamashita, F. 1977. Clinical features of polychlorbiphenyls (PCB)-induced fetopathy. Paediatrician 6:20. (Cited in USAF 1989) Retrieve Toxicity Profiles Condensed Version

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