The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for ZINC AND ZINC COMPOUNDS

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 ORGAN/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. SLOPE FACTORS
5. REFERENCES

April 1992

Prepared by Dennis M. Opresko, Ph.D., Chemical Hazard Evaluation and Communication Group, Biomedical and Environmental Information Analysis Section, Health and Safety Research Division, Oak Ridge National Laboratory*, 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

Zinc is used primarily in galvanized metals and metal alloys, but zinc compounds also have wide commercial applications as chemical intermediates, catalysts, pigments, vulcanization activators and accelerators in the rubber industry, UV stabilizers, and supplements in animal feeds and fertilizers. They are also used in rayon manufacture, smoke bombs, soldering fluxes, mordants for printing and dyeing, wood preservatives, mildew inhibitors, deodorants, antiseptics, and astringents (Lloyd, 1984; ATSDR, 1989). In addition, zinc phosphide is used as a rodenticide.

Zinc is an essential element with recommended daily allowances ranging from 5 mg for infants to 15 mg for adult males (NRC, 1989).

Gastrointestinal absorption of zinc is variable (20-80%) and depends on the chemical compound as well as on zinc levels in the body and dietary concentrations of other nutrients (U.S. EPA, 1984). In individuals with normal zinc levels in the body, gastrointestinal absorption is 20-30% (ATSDR, 1989). Information on pulmonary absorption is limited and complicated by the potential for gastrointestinal absorption due to mucociliary clearance from the respiratory tract and subsequent swallowing. Zinc is present in all tissues with the highest concentrations in the prostate, kidney, liver, heart, and pancreas. Zinc is a vital component of many metalloenzymes such as carbonic anhydrase, which regulates CO2 exchange (Stokinger, 1981). Homeostatic mechanisms involving metallothionein in the mucosal cells of the gastrointestinal tract regulate zinc absorption and excretion (ATSDR, 1989).

In humans, acutely toxic oral doses of zinc cause nausea, vomiting, diarrhea, and abdominal cramps and in some cases gastric bleeding (Elinder, 1986; Moore, 1978; ATSDR, 1989). Ingestion of zinc chloride can cause burning in the mouth and throat, vomiting, pharyngitis, esophagitis, hypocalcemia, and elevated amylase activity indicative of pancreatitis (Chobanian, 1981). Zinc phosphide, which releases phosphine gas under acidic conditions in the stomach, can cause vomiting, anorexia, abdominal pain, lethargy, hypotension, cardiac arrhythmias, circulatory collapse, pulmonary edema, seizures, renal damage, leukopenia, and coma and death in days to weeks (Mack, 1989). The estimated fatal dose is 40 mg/kg. Animals dosed orally with zinc compounds develop pancreatitis, gastrointestinal and hepatic lesions, and diffuse nephrosis.

Gastrointestinal upset has also been reported in individuals taking daily dietary zinc supplements for up to 6 weeks (Samman and Roberts, 1987). There is also limited evidence that the human immune system may be impaired by subchronic exposures (Chandra, 1984). In animals, gastrointestinal and hepatic lesions, (Allen et al., 1983; Brink et al., 1959); pancreatic lesions (Maita et al., 1981; Drinker et al., 1927a); anemia (ATSDR, 1989; Fox and Jacobs, 1986; Maita et al., 1981); and diffuse nephrosis (Maita et al., 1981; Allen et al., 1983) have been observed following subchronic oral exposures.

Chronic oral exposures to zinc have resulted in hypochromic microcytic anemia associated with hypoceruloplasminemia, hypocupremia, and neutropenia in some individuals (Prasad et al., 1978; Porter et al., 1977). Anemia and pancreatitis were the major adverse effects observed in chronic animal studies (Aughey et al., 1977; Drinker et al., 1927a; Walters and Roe, 1965; Sutton and Nelson, 1937). Teratogenic effects have not been seen in animals exposed to zinc; however, high oral doses can affect reproduction and fetal growth (Ketcheson et al., 1969; Schlicker and Cox 1967, 1968; Sutton and Nelson, 1937).

The reference dose for chronic oral exposure to zinc is under review by EPA; the currently accepted RfD for both subchronic and chronic exposures is 0.2 mg/kg/day based on clinical data demonstrating zinc-induced copper deficiency and anemia in patients taking zinc sulfate for the treatment of sickle cell anemia (U.S. EPA, 1992). The chronic oral RfD for zinc phosphide is 0.0003 mg/kg/day (U.S. EPA, 1991a), and the subchronic RfD is 0.003 mg/kg/day (U.S. EPA, 1992).

Under occupational exposure conditions, inhalation of zinc compounds (mainly zinc oxide fumes) can result in a condition identified as "metal fume fever", which is characterized by nasal passage irritation, cough, rales, headache, altered taste, fever, weakness, hyperpnea, sweating, pains in the legs and chest, leukocytosis, reduced lung volume, and decreased diffusing capacity of carbon monoxide (ATSDR, 1989; Bertholf, 1988). Inhalation of zinc chloride can result in nose and throat irritation, dyspnea, cough, chest pain, headache, fever, nausea and vomiting, and respiratory disorders such as pneumonitis and pulmonary fibrosis (ITII, 1988; ATSDR, 1989; Nemery, 1990). Pulmonary inflammation and changes in lung function have also been observed in inhalation studies on animals (Amur et al., 1982; Lam et al., 1985; Drinker and Drinker, 1928).

Although "metal fume fever" occurs in occupationally exposed workers, it is primarily an acute and reversible effect that is unlikely to occur under chronic exposure conditions when zinc air concentrations are less than 8-12 mg/m3 (ATSDR, 1989). Gastrointestinal distress, as well as enzyme changes indicative of liver dysfunction, have also been reported in workers occupationally exposed to zinc (NRC, 1979; Stokinger, 1981; U.S. EPA, 1991a; Guja, 1973; Badawy et al., 1987a); however, it is unclear as to what extent these effects might have been caused by pulmonary clearance, and subsequent gastrointestinal absorption. Consequently, there are no clearly defined toxic effects that can be identified as resulting specifically from pulmonary absorption following chronic low level inhalation exposures. Animal data for chronic inhalation exposures are not available.

An inhalation reference concentration has not been derived for zinc or zinc compounds (U.S. EPA, 1992).

No case studies or epidemiologic evidence has been presented to suggest that zinc is carcinogenic in humans by the oral or inhalation route (U.S. EPA, 1991a). In animal studies, zinc sulfate in drinking water or zinc oleate in the diet of mice for a period of one year did not result in a statistically significant increase in hepatomas, malignant lymphomas, or lung adenomas (Walters and Roe, 1965); however, in a 3-year, 5-generation study on tumor-resistant and tumor-susceptible strains of mice, exposure to zinc in drinking water resulted in increased frequencies of tumors from the F0 to the F4 generation in the tumor-resistant strain (from 0.8 to 25.7%, vs. 0.0004% in the controls), and higher tumor frequencies in two tumor-susceptible strains (43.4% and 32.4% vs. 15% in the controls) (Halme, 1961).

Zinc is placed in weight-of-evidence Group D, not classifiable as to human carcinogenicity due to inadequate evidence in humans and animals (U.S. EPA, 1991a).

1. INTRODUCTION

Zinc is used primarily in galvanized metals and metal alloys. In addition, various inorganic zinc salts have numerous commercial uses. Zinc oxide is used in the rubber industry as a vulcanization activator and accelerator and to slow down oxidation, and also as a reinforcing agent, heat conductor, pigment, UV stabilizer, supplement in animal feeds and fertilizers, catalyst, chemical intermediate, and mildew inhibitor. Zinc sulfate is used in rayon manufacture, agriculture, zinc plating, and as a chemical intermediate and mordant. Zinc chloride is used in smoke bombs, in cements for metals, in wood preservatives, in flux for soldering; in the manufacture of parchment paper, artificial silk, and glues; as a mordant in printing and dye textiles, and as a deodorant, antiseptic, and astringent. Zinc chromate is used as a pigment in paints, varnishes, and oil colors (Lloyd, 1984; ATSDR, 1989). In addition, zinc phosphide is used as a rodenticide and zinc cyanide is used in electroplating (NRC, 1979). The toxicity of the latter two compounds is due primarily to their anion component. Zinc cyanide is discussed in the toxicity summary for cyanide.

Zinc is an essential element. The recommended daily allowance is 15 mg for adult males, 12 mg for adult females, 15 mg for pregnant women, 19 mg for nursing mothers during the first six months and 16 mg during the second six months, 10 mg for children older than 1 year, and 5 mg for infants 0-12 months old (NRC, 1989).

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

Gastrointestinal absorption of zinc is variable (20-80%) and depends on chemical characteristics of the compound, on the amount of zinc in the body, and on the dietary levels of other nutrients (U.S. EPA, 1984). High dietary levels of phytate, calcium, or phosphorus reduce absorption, but protein enhances uptake (ATSDR, 1989). In individuals with normal zinc levels in the body, gastrointestinal absorption is 20-30%. Information on pulmonary absorption is limited and complicated by the potential for gastrointestinal absorption following mucociliary clearance and swallowing.

2.2. DISTRIBUTION

Zinc is present in all tissues, but the highest concentrations occur in the prostate gland (Bertholf, 1988). Concentrations in the kidney, liver, heart, and pancreas are also high (Stokinger, 1981).

2.3. METABOLISM

After absorption into the body, zinc becomes bound to protein complexes, the most important of which is metallothionein, which acts as a carrier and transport mechanism (Stokinger, 1981). As an element zinc is not metabolized per se; however, it is a vital component of many metalloenzymes such as carbonic anhydrase, which regulates CO2 exchange (Stokinger, 1981). Other enzyme systems in which zinc plays a role are RNA polymerase, superoxide dismutase, carboxypeptidase, isocitric dehydrogenase, alcohol dehydrogenase, and ceruloplasmin.

2.4. EXCRETION

Homeostatic mechanisms control zinc absorption and excretion. Metallothionein in the mucosal cells lining the gastrointestinal tract binds with zinc and regulates uptake in the body (ATSDR, 1989). Under conditions where there is a physiological excess of zinc, the metallothionein-zinc complex is eliminated from the body when the mucosal cells are sloughed off. Mass balance studies indicate that most zinc is excreted in the feces, with small amounts in the urine, sweat and semen (Schroeder et al., 1967); however, a significant amount may be lost in sweat in hot climates (Prasad et al., 1963).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

Gastrointestinal distress is a common symptom of acute oral exposure to zinc compounds (ATSDR, 1989), particularly when zinc salts of strong mineral acids are ingested (Stokinger, 1981). Accidental poisonings have occurred as a result of the therapeutic use of zinc supplements and from food contamination caused by the use of zinc galvanized containers. Symptoms develop within 24 hr and include nausea, vomiting, diarrhea, and abdominal cramps (Stokinger, 1981; Elinder, 1986). The concentration in drinking water that can cause an emetic effect ranges from 675 to 2,280 ppm (Stokinger, 1981). High doses may result in gastrointestinal bleeding and subsequent hematological signs of anemia as was seen in the case of an individual taking zinc sulfate capsules (6.47 mg/kg/day) for one week (Moore, 1978).

Severe toxic effects have also been reported in cases of ingestion of zinc chloride. A single dose (amount not reported) caused burning in the mouth and throat, vomiting, pharyngitis, esophagitis, hypocalcemia, and elevated levels of amylase activity; the latter two changes being indicative of acute pancreatitis (Chobanian, 1981). An elevated serum amylase activity was also reported in an individual ingesting 12 g of elemental zinc (150 mg/kg) over a 2-day period (Murphy, 1970). Other reported symptoms were headache, lethargy, a staggering gait, and difficulty in writing.

Minimal clinical chemistry changes observed in individuals ingesting zinc sulfate include reductions in serum HDL-cholesterol levels following daily doses of 2.3 mg Zn/kg/day for 5-6 days (Hooper et al., 1980), and a transitory decrease in plasma adrenal cortisol levels following single doses of 25, 37.5 or 50 mg Zn (Brandao-Neto et al., 1990).

One of the most toxic inorganic zinc compounds is the rodenticide zinc phosphide, which releases phosphine gas under acidic conditions in the stomach. Poisonings with this substance can result in vomiting, anorexia, abdominal pain, lethargy, hypotension, cardiac arrhythmias, circulatory collapse, pulmonary edema, seizures, renal damage, leukopenia, and coma and death in days to weeks (Mack, 1989). The estimated fatal dose is 40 mg/kg.

3.1.1.2. Animal

The acute toxic effects of zinc have been observed in animals in the field and laboratory. Sheep consuming zinc (dose not quantifiable) as a result of environmental contamination developed diarrhea, proteinuria, intestinal and adrenal lesions, and pancreatic acinar cell degeneration (Allen et al., 1983). In laboratory studies, hepatic and gastrointestinal lesions and pancreatitis occurred in sheep treated with 33 mg Zn/kg/day (as zinc sulfate) for 13 days (Allen et al., 1983). Pancreatitis, diffuse nephrosis, intestinal hemorrhages, and anemia were observed in ferrets given 850 mg Zn/kg/day (as zinc oxide in the diet) for 9-13 days (Straube et al., 1980). This dose level was lethal to 1 of 3 animals. A dose level of 425 mg Zn/kg/day for 7-21 days also resulted in nephrosis, pancreatitis, and anemia, as well as fatty infiltration of the liver. A dose level of 142 mg Zn/kg/day for up to 6 months had no adverse effects.

Acute lethality values for varous zinc compounds are as follows: 0.25 g/kg LDLo for zinc fluoride (guinea pigs); 1.19 g/kg LD50 for zinc nitrate hexahydrate (rats); 2.2 g/kg LDLo for zinc sulfate heptahydrate (rats); and 2.46 g/kg LDLo for zinc acetate dihydrate (rats) (Stokinger, 1981).

3.1.2. Subchronic Toxicity

3.1.2.1. Human

Gastrointestinal upset is the most common adverse effect from subchronic ingestion of zinc. Twenty-six of 47 individuals developed such symptoms after taking 150 mg Zn/day (2.24 mg/kg/day) for 6 weeks (Samman and Roberts, 1987). Similar symptoms were reported in 10 individuals taking 2.14 mg Zn/kg/day for 43-61 days; however, only one of 80 individuals taking 100 mg Zn/day (1.57 mg Zn/kg/day, as zinc sulfate), for 3-6 months developed such symptoms (Henkin et al., 1976). In another study, no adverse renal, hepatic, or hematological effects were observed in individuals treated with 3.4 mg Zn/kg/day (as zinc sulfate) for 18 weeks (Hallbook and Lanner, 1972).

There is limited evidence that the immune system may be affected by excessive intake of zinc. Chandra (1984) reported that zinc sulfate, in doses equivalent to 4.29 mg Zn/kg/day for 6 weeks, impaired the immune system as measured by the mitogenic response of peripheral blood lymphocytes and the chemotactic and phagocytic responses of polymorphonuclear leukocytes. In vitro studies conducted by Baginski (1990) revealed a diminished phagocytic capacity of polymorphonuclear leukocytes and a promotion of inflammatory reactions due to an increase of toxic oxygen species in the presence of zinc ions.

3.1.2.2. Animal

Zinc-induced gastrointestinal effects have been reported in a number of subchronic animal studies. Rats and mice ingesting zinc sulfate (510 mg Zn/kg/day and 1,120 mg Zn/kg/day, respectively) for 13 weeks developed stomach ulcers (Maita et al., 1981). The latter concentration was lethal to 5 of 12 test animals. Gastrointestinal and hepatic lesions were observed in sheep treated with 18.6 mg Zn/kg/day for 49-72 days (Allen et al., 1983), and inflammation of the gastrointestinal tract and stunted growth occurred in weanling pigs treated with 1,000 mg Zn/kg/day for more than a month (Brink et al., 1959). Pancreatic lesions have been reported in rats receiving 510 mg Zn/kg/day (as zinc sulfate) for 13 weeks (Maita et al., 1981), and in cats receiving 266.6 mg Zn/kg/day (as zinc oxide) for 3-53 weeks (Drinker et al., 1927a).

Anemia has been observed in mice, rats, ferrets, and sheep following oral exposures to zinc oxide, zinc oleate or zinc sulfate (ATSDR, 1989; Fox and Jacobs, 1986; Maita et al., 1981). The anemia may have been due to intestinal hemorrhaging.

Adverse kidney effects have been observed in mice dosed with 1,120 mg Zn/kg/day (as zinc sulfate) in their diet for 13 weeks (Maita et al., 1981); in sheep dosed with 18.6 mg Zn/kg/day (as zinc oxide) for 49-72 days (Allen et al., 1983); and in rats dosed with 640 mg Zn/kg/day (as zinc acetate dihydrate) in drinking water for 3 months (Llobet et al., 1988). Histopathological lesions accompanied by increased liver, kidney, and brain weights were observed in rats fed diets containing 200 or 500 ppm zinc phosphide for 13 weeks (Bai et al., 1980). Dietary levels of 50 and 100 ppm caused no adverse effects except for extensive body hair loss.

Increased adrenal and thymus weights and decreased plasma levels of 11-hydroxysteroids occurred in rats receiving zinc in their drinking water at a level corresponding to 10 mg ZnSO4/day (time period not reported) (Quarterman, 1974). Decreased hexobarbital sleeping time was observed in rats receiving 40 mg Zn/kg/day (as zinc sulfate) for 30 days (Kadiiska et al., 1985). This has been attributed to the induction of hepatic monooxygenases (ATSDR, 1989). Chromosomal aberrations have been observed in the bone marrow cells of mice maintained on a low calcium diet and dosed with 650 mg/kg/day of zinc chloride for one month (Deknudt, 1982). Alopecia has been observed in zinc-treated animals and is thought to be a secondary effect of zinc-induced copper deficiency (Mulhern et al., 1986; ATSDR, 1989).

3.1.3. Chronic Toxicity

3.1.3.1. Human

Chronic oral exposures to zinc can result in sideroblastic or hypochromic microcytic anemia associated with hypoceruloplasminemia, hypocupremia, and neutropenia (U.S. EPA, 1984; Broun et al., 1990). Doses of >= 2 mg Zn/kg/day for 11 mo to 2 years were reported to cause such effects (Prasad et al., 1978; Porter et al., 1977; Hoffman et al., 1988). Shorter exposure periods at the dose levels of 2 mg Zn/kg/day or less did not produce any adverse effects (U.S. EPA, 1984).

3.1.3.2. Animal

Several animal studies have evaluated the chronic toxicity of inorganic zinc compounds. Pancreatic lesions were reported in mice ingesting 38 mg Zn/kg/day (as zinc sulfate) in drinking water for 14 months (Aughey et al., 1977) and in cats ingesting 223.8 mg Zn/kg/day (as zinc oxide) for 10-53 weeks (Drinker et al., 1927a). Anemia was reported in mice receiving a dietary level of 2500 ppm zinc (as zinc oleate) (Walters and Roe, 1965) and in rats dosed with 250 or 500 mg Zn/kg/day (as zinc carbonate) for 39 weeks (Sutton and Nelson, 1937). Rats ingesting up to 25.5 mg Zn/kg/day (as zinc acetate) in drinking water for 47 weeks exhibited no overt toxic effects (Drinker et al., 1927b), nor did rats ingesting zinc oxide (250 mg Zn/kg/day) or zinc dust (125 mg Zn/kg/day) in their diet over three generations; however, in the latter case there was a slight reduction in growth rates in the high-dose group (Heller and Burke, 1927).

3.1.4. Developmental and Reproductive Toxicity

3.1.4.1. Human

Of four women given 1.42 mg Zn/kg/day (as zinc sulfate) during the third trimester of pregnancy, three had premature deliveries and one delivered a stillborn infant (Kumar, 1976).

3.1.4.2. Animal

Teratogenic effects have not been observed in animals dosed orally with zinc; however, high oral doses can affect reproduction and fetal growth. Fetal growth of albino rats was reduced and the incidence of stillbirths increased in tests in which pregnant females were maintained during the gestation period on a diet containing 0.05% zinc (as zinc oxide and equivalent to 250 mg Zn/kg/day) (Ketcheson et al., 1969). Similar changes in fetal growth and decreased fetal copper and iron levels, as well as an increase in fetal resorptions occurred in pregnant rats dosed with 200 mg/kg/day (Schlicker and Cox 1967, 1968). Complete inhibition of reproduction occurred in female rats ingesting 500 mg Zn/kg/day (as zinc carbonate) for 5 months (Sutton and Nelson, 1937). It was reported that these effects may have been associated with a zinc-induced anemia as indicated by reduced hemoglobin and RBC levels.

3.1.5. Reference Dose

The generic oral Reference Dose for zinc and zinc compounds is currently under review by EPA (U.S. EPA, 1991a). The subchronic and chronic RfDs listed below are those currently used (U.S. EPA, 1992). The chronic RfD for zinc phosphide listed below has been verified and included on IRIS (U.S. EPA 1991a).

3.1.5.1. Subchronic

Zinc (metallic)
  • ORAL RfD: 0.2 mg/kg/day (U.S. EPA, 1992)
  • UNCERTAINTY FACTOR: 10
  • LOAEL: 2.14 mg/kg/day.
  • COMMENT: The same study applies to the subchronic and chronic RfD.
Zinc phosphide
  • ORAL RfD: 0.003 mg/kg/day (U.S. EPA, 1991a)
  • UNCERTAINTY FACTOR: 1,000
  • MODIFYING FACTOR: 1
  • LOAEL: 50 ppm diet (3.48 mg/kg/day), rats, 13 weeks.
  • COMMENT: The same study applies to the subchronic and chronic RfD.

3.1.5.2. Chronic

Zinc (metallic)
  • ORAL RfD: 0.2 mg/kg/day (U.S. EPA, 1992)
  • UNCERTAINTY FACTOR: 10
  • LOAEL: 2.14 mg/kg/day.
  • COMMENT: Based on clinical data demonstrating zinc-induced copper deficiency and anemia in patients taking zinc sulfate for the treatment of sickle cell anemia (U.S. EPA, 1992). The Office of Drinking Water also recognizes an oral RfD of 0.2 mg/kg/day (U.S. EPA, 1991b).
Zinc phosphide
  • ORAL RfD: 0.0003 mg/kg/day (U.S. EPA, 1991a)
  • UNCERTAINTY FACTOR: 10,000
  • MODIFYING FACTOR: 1
  • LOAEL: 50 ppm diet (3.48 mg/kg/day), rats.
  • CONFIDENCE: Study: Medium Data Base: Low RfD: Low
  • VERIFICATION DATE: 05/14/96
  • PRINCIPAL STUDIES: Bai et al., 1980
  • COMMENT: Based on a subchronic study of female weanling rats on diets containing 10, 50, 100, 200 or 500 ppm Zn for 13 weeks. The only effect noted at 50 and 100 ppm was hair loss, which returned to normal after week 6. Concentrations of 200 or 500 ppm Zn increased liver, kidney, and brain weight and caused histopathological lesions. The UF of 10,000 includes factors of 10 for interspecies extrapolation, 10 for providing added protection to unusually sensitive individuals, 10 for expanding subchronic to chronic exposures, and 10 for a lack of a NOAEL (U.S. EPA, 1991a).

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

3.2.1.1. Human

Inhalation exposure to high concentrations of some zinc compounds can result in toxic effects to the respiratory system (ATSDR, 1989). Inhalation of zinc oxide fumes has been associated with "metal fume fever" (Bertholf, 1988) characterized by nasal passage irritation, cough, rales, headache, altered taste, fever, weakness, hyperpnea, sweating, pains in the legs and chest, reduced lung volume, and decreased diffusing capacity of carbon monoxide. Hives and angioedema were also reported in one case (Farrell, 1987). General symptoms can appear at concentrations as low as 15 mg/m3. A concentration as high as 600 mg Zn/m3 for only a few minutes can cause effects in several hours. Recovery usually takes 6 to 48 hours (Elinder, 1986). Some exposed individuals exhibit radiographic lung abnormalities (diffuse nodular infiltrates) and reductions in forced expiratory volume and forced vital capacity (Malo et al., 1990). Leukocytosis is a secondary effect that has been reported in cases of "metal fume fever" (Sturgis et al., 1927; Malo et al., 1990).

Inhalation of zinc chloride can cause nose and throat irritation, dyspnea, cough, chest pain, headache, fever, nausea and vomiting, bilateral diffuse infiltrations, pneumothorax, and acute pneumonitis (ITII, 1988; ATSDR, 1989; Nemery, 1990). More severe effects include ulcerative and edematous changes in mucous membranes, subpleural hemorrhage, advanced pulmonary fibrosis, and respiratory distress syndrome. Fatalities have occurred in some accidental exposures (Elinder, 1986; Hjortso et al., 1988). A TCLo of 4,800 mg/m3 for a 30-min exposure has been reported for zinc chloride (Stokinger, 1981).

3.2.1.2. Animal

Decreased lung compliance was observed in guinea pigs exposed to 1 mg zinc oxide/m3 for 1 hr (Amur et al., 1982). Exposure of guinea pigs to 5 mg/m3 for 3 hr/day for six days resulted in decreased lung compliance, decreased diffusing capacity, increased flow resistance, inflammation of the alveoli and alveolar ducts, interstitial thickening, and increased numbers of pulmonary macrophages and neutrophils (Lam et al., 1985). Biochemical and histopathological evidence of pulmonary inflammation was observed in guinea pigs exposed to 5.9 mg zinc oxide/m3, 3 hr daily for 3 days (Conner et al., 1988). Severe lung damage was observed in rats, rabbits and cats acutely exposed to 110-600 mg zinc oxide/m3 (Drinker and Drinker, 1928). The LCT50 (concentration multiplied by exposure time) for zinc chloride has been reported to be 11,800 mg min/m3 in mice (Schenker et al., 1981).

Mice exposed to zinc oxide had an increase in chromosomal aberrations in bone marrow cells (Voroshilin et al., 1978).

3.2.2. Subchronic Toxicity

3.2.2.1. Human

Information on the toxicity of zinc and zinc compounds in humans following subchronic inhalation exposures was not available.

3.2.2.2. Animal

Rats exposed to zinc oxide at 15 mg/m3 for 8 hr daily for up to 84 days showed only minor histological changes in the lung, but pulmonary function tests were indicative of chronic pulmonary inflammation (Elinder, 1986). Rats exposed to 14 mg/m3 of zinc oxide for 4 hr/day, 5 days per week, for 56 days, developed inflammatory changes in the lungs, including infiltration of leukocytes and macrophages (Pistorius, 1976). Histological examination of lungs from rats exposed to zinc stearate at 5 mg/m3 for 3-5 months showed no signs of fibrosis (Elinder, 1986).

3.2.3. Chronic Toxicity

3.2.3.1. Human

Non-cancer health effects have been reported in occupationally exposed workers. Workers exposed to zinc compounds have exhibited gastrointestinal symptoms including anorexia, nausea, vomiting, epigastric discomfort, and weight loss, as well as respiratory distress, leukocytosis, and hypocalcemia (NRC, 1979; Stokinger, 1981; U.S. EPA, 1991a). Since many of these effects are the same as those occurring in cases of "metal fume fever," it is possible that they may have been due, at least in part, to transient elevations in exposure levels.

Some studies have suggested a correlation between concentrations of zinc in the air and changes in serum enzyme activities indicative of liver dysfunction (Guja, 1973; Badawy et al., 1987a). In addition, some workers exposed to zinc have a higher than normal incidence of chromosome anomalies in leukocytes (Badawy et al., 1987b). Concomitant exposure to other toxic substances may have contributed to these effects; however, in vitro studies have shown that zinc chloride can cause chromosome aberrations in human lymphocytes (Elinder, 1986).

3.2.3.2. Animal

Information on the chronic toxicity of inorganic zinc to animals by inhalation was not available.

3.2.4. Developmental and Reproductive Toxicity

Little information is available on the developmental and reproductive toxicity of inorganic zinc to humans or animals. In an occupational exposure study of a group of pregnant women working in metallurgy, Pietrois et al. (1991) found no significant complications or increase in spontaneous abortions in women having significantly higher zinc serum levels than a control group.

3.2.5. Reference Dose/Concentration

U.S. EPA (1992) has not developed subchronic or chronic inhalation reference concentrations for zinc.

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

Exposure to zinc-chromium compounds from galvanized steel was considered to be partially responsible for an outbreak of irritant hand dermatitis, which affected 24 of 41 employees working on a new assembly line of an electronics factory (Bruynzeel et al., 1988).

When administered parenterally, zinc depresses the central nervous system, causing tremors and paralysis of the extremities (Stokinger, 1981).

3.3.1.2. Animal

The subcutaneous LDLo for zinc sulfate heptahydrate is 330 mg/kg in rats, and that for zinc fluoride is 100 mg/kg (Stokinger, 1981). The intravenous LD50 for zinc sulfate is 40 mg/kg in rats, and the i.v. LDLo for zinc chloride is 30 mg/kg.

3.3.2. Subchronic Toxicity

Information on the subchronic toxicity of inorganic zinc compounds to humans or animals by other routes of exposure was not available.

3.3.3. Chronic Toxicity

Information on the chronic toxicity of inorganic zinc compounds to humans or animals by other routes of exposure was not available.

3.3.4. Developmental and Reproductive Toxicity

3.3.4.1. Human

Information on the developmental and reproductive toxicity of inorganic zinc compounds to humans by other routes of exposure was not available.

3.3.4.2. Animal

Parenteral injections of zinc compounds in rodents during gestation have resulted in adverse developmental effects. The offspring of pregnant golden hamsters injected intravenously with a single dose of 2 mg zinc sulfate/kg on the eighth day of gestation exhibited exencephaly and rib fusions (Ferm and Carpenter, 1968). Similar skeletal anomalies including delayed ossification, and ripple ribs were observed in the offspring of mice injected intraperitoneally with single doses of 12.5, 20.5, and 25 mg zinc chloride/kg on day 8, 9, 10, or 11 of gestation (Chang et al., 1977).

3.4. TARGET ORGAN/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organs

  1. Blood: Copper deficiency and hypochromic microcytic anemia in humans chronically exposed. Anemia in animals.
  2. Pancreas: Pancreatitis in humans acutely exposed, and in animals acutely, subchronically, or chronically exposed.
  3. Gastrointestinal Tract: Vomiting, diarrhea, cramps, and possibly bleeding following acute or subchronic exposures in humans and animals.

3.4.1.2. Other Target Organs

  1. Immune System: Possible impairment in humans following subchronic exposures.
  2. Kidney: Renal lesions in animals following acute and subchronic exposures.
  3. Developmental Effects: Reduced fetal growth in animals.
  4. Reproductive Effects: Inhibition of reproduction in animals following subchronic exposures.
  5. Skin: Hair loss in animals following subchronic exposure to zinc phosphide.

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organs

Lung: Pulmonary congestion, leukocytic infiltration (zinc oxide); pneumonitis, ulceration, subpleural hemmorhage, and fibrosis (zinc chloride) in occupationally exposed workers most likely from acute exposures.

3.4.2.2. Other Target Organs

  1. Blood: Leukocytosis, hypocalcemia in humans following acute exposures.
  2. Gastrointestinal Tract: Possible ulcers in occupationally exposed workers.
  3. Liver: Possible changes in hepatic enzymes in occupationally exposed workers.

4. CARCINOGENICITY

There is some evidence that zinc may act antagonistically towards the carcinogenic effects of other compounds. For example, administration of zinc sulfate in drinking water reduced the incidence of 9,10-dimethyl-1,2-benzanthracene-induced tumors in the cheek pouches of golden hamsters (Poswillo and Cohen, 1971).

4.1. ORAL EXPOSURES

4.1.1. Human

An excess rate of gastric cancer was reported for a region of Great Britain having a high zinc to copper ratio in home garden soil (Stocks and Davies, 1964); however, in another study significantly lower gastric cancer rates were reported for areas with a similar zinc-copper soil composition (Phillip et al., 1982).

4.1.2. Animal

The potential carcinogenicity of zinc has been evaluated in only a few animal studies. Walters and Roe (1965) maintained groups of newborn Chester Beatty stock mice for one year on drinking water containing 0, 1000, or 5000 ppm Zn (0, 170, 850 mg Zn/kg/day, as zinc sulfate), or on a diet containing zinc oleate (5000 ppm Zn for 3 months followed by 2500 ppm for 3 months, and then 1250 ppm for the rest of the study period). The incidence of hepatomas, malignant lymphomas, and lung adenomas was not statistically different from control values, although the incidence of hepatomas in mice on the zinc-augmented diet was increased over that in the controls (30.4% vs 12.5%) (U.S. EPA, 1991a).

In a 3-year, 5-generation study on tumor resistant and tumor-susceptible strains of mice, Halme (1961) found that zinc concentrations of 10-20 mg/L in drinking water resulted in increased frequencies of tumors from the F0 to the F4 generation in the resistant strain (from 0.8 to 25.7% vs. 0.0004% in the controls), and higher tumor frequencies in two susceptible strains (43.4% and 32.4% vs. 15% in the controls). Statistical analysis of the data was not reported.

Aughey et al. (1977) reported hypertrophy of the adrenal cortex and pancreatic islets, but no corresponding tumors in C3H mice given drinking water containing 500 mg/L zinc sulfate for 14 months.

4.2.INHALATION EXPOSURES

4.2.1. Human

Several epidemiological studies have examined cancer mortality rates in occupationally exposed workers and in residents in areas with potentially high zinc contamination. No association between cancer mortality and zinc exposure could be established for workers employed in electrolytic zinc and copper refining plants; however, analysis of the data was limited by the small number of deaths in workers exposed to zinc (Logue et al., 1982). Lung cancer mortality was reported to be elevated in residents living in an old lead/zinc mining and smelting area, but there was no association with environmental levels of zinc (Neuberger and Hollowell, 1982). Because many confounding factors (i.e., smoking, occupation, and duration of residence) were not considered, it is unlikely that the study could have detected zinc-related effects (ATSDR, 1989).

4.2.2. Animal

Marrs et al. (1988) evaluated the carcinogenic effects of a zinc oxide/hexachloroethane smoke mixture on several species of animals and found a statistically significant increase in the frequency of alveologenic carcinomas in female mice exposed to 123 mg Zn/m3, 1 hr/day, 5 days/week for 18 months. Carcinogenic effects were not seen when similar studies were conducted on rats and guinea pigs. Evaluation of this study is complicated by the presence of several compounds in the smoke mixture that may have contributed to the carcinogenic effects.

4.3. OTHER ROUTES OF EXPOSURE

Injection of zinc chloride or zinc sulfate in the testes of roosters resulted in the formation of teratomas (Michalowsky, 1926; Falin and Gromtseve, 1939). Similar results were reported in rats (Rivere et al., 1959).

4.4. EPA WEIGHT-OF-EVIDENCE

Classification -- D; not classifiable as to human carcinogenicity (U.S. EPA, 1991b)

Basis -- Inadequate evidence in humans or animals.

4.5. SLOPE FACTORS

The calculation of slope factors is not possible due to the lack of evidence of carcinogenicity.

5. REFERENCES

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