REASONABLY ANTICIPATED TO BE CARCINOGEN:
NICKEL AND CERTAIN NICKEL COMPOUNDS

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CARCINOGENICITY

There is sufficient evidence for the carcinogenicity of nickel (7440-02-0)
and the following nickel compounds in experimental animals: nickel acetate
(373-02-4), nickel carbonate (3333-67-3), nickel carbonyl (13463-39-3),
nickel hydroxide (12054-48-7 or 12125-56-3), nickelocene (1271-28-9),
nickel oxide (1313-99-1), and nickel subsulfide (12035-72-2) (IARC V.2,
1973; IARC V.11, 1976; IARC S.4, 1982; IARC S.7, 1987). When injected
intramuscularly, nickel induced incidences of fibrosarcomas in rats and
hamsters of both sexes, local sarcomas in rats of both sexes, and local
tumors with some metastases to pre-vertebral lymph nodes in female rats.
When injected intrapleurally, nickel powder induced round cell and spindle
cell tumors at the injection site in female rats. When administered by
inhalation, nickel induced lymphosarcomas in female mice and anaplastic
intraalveolar carcinomas, including one with extensive pulmonary
adenomatosis, in male and female guinea pigs. Subdermal implantation of
nickel pellets induced sarcomas surrounding the pellet in female and male
rats. When injected intramedullarly into the femur, rats developed
neoplasms at or near the site, including fibrosarcomas (neurogenic in
origin), and one reticulum cell sarcoma with metastases. The same route of
administration induced one metastasizing endothelial fibrosarcoma in a
rabbit (IARC V.11, 1976; IARC V.2, 1973). When administered
intraperitoneally, nickel acetate induced an excess of lung adenomas and
carcinomas in mice (IARC S.4, 1982). When implanted intramuscularly, nickel
carbonate induced sarcomas at the site of the implanted pellet. When
administered nickel carbonyl through inhalation, male rats developed one
pulmonary adenocarcinoma with metastases, extensive squamous metaplasms of
the epithelium, neoplasms of the lung, one mixed adenocarcinoma and
squamous cell carcinoma with metastases to the kidney and mediastinum, and
papillary bronchiolar adenomas. Injection of nickel carbonyl into the tail
vein of rats of both sexes induced malignant tumors including
undifferentiated leukemia, pulmonary lymphomas, and individual incidences
of liver, kidney, and mammary carcinomas. When millipore diffusion chambers
containing nickel hydroxide were implanted in rats, local tumors were
induced. When administered by intramuscular injection, nickelocene induced
fibrosarcomas in rats and hamsters of both sexes. When administered by
intramuscular injection, nickel oxide induced injection site sarcomas in
mice and rats; administration by intramuscular implantation induced
rhabdomyosarcomas and fibrosarcomas in mice and implantation site sarcomas
in rats. When administered by intramuscular implantation, nickel subsulfide
induced rhabdomyosarcomas and fibrosarcomas in mice and rats,
rhabdomyosarcomas with distant metastases and implantation site sarcomas in
rats, and tumors in mice. Palpable local tumors arose at implantation sites
after nickel subsulfide pellets were removed from rats at various times.
Intratracheal injection of nickel subsulfide induced malignant neoplasms of
the lungs, adenocarcinomas, and squamous cell carcinomas, in rats of both
sexes. Intramuscular injection of nickel subsulfide induced injection site
sarcomas and rhabdomyosarcomas in rats and mice and fibrosarcomas and
undifferentiated sarcomas in male rats; in addition, the sarcomas
metastasized to distant sites, e.g., lungs, liver, heart, spleen,
mediastinum, and mesentery and para-aortic lymph nodes (IARC V.2, 1973;
IARC V.11, 1976). Nickel subsulfide induced malignant tumors in rats after
insertion into heterotransplanted tracheas and after intrarenal,
intratesticular, and intraocular administration (IARC S.4, 1982).

An IARC Working Group determined that there is limited evidence for the
carcinogenicity of nickel and certain nickel compounds, and sufficient
evidence for the carcinogenicity of nickel refining in humans (IARC S.4,
1982). A subsequent IARC Working Group determined that there is sufficient
evidence for the carcinogenicity of the group of nickel compounds in
humans. However, the specific carcinogenic substance(s) could not be
identified (IARC S.7, 1987). Several epidemiological studies demonstrated
excess incidences of cancers of the nasal cavity, lung, and possibly the
larynx in workers exposed to nickel or nickel compounds. The cancer hazards
seemed to be associated with the early stage of nickel refining, and with
exposure primarily to nickel subsulfide and nickel oxide (IARC V.2, 1973;
IARC V.11, 1976; IARC S.4, 1982; IARC S.7, 1987). Nickel refining as an
occupational exposure is now listed in the Introduction of this Annual
Report, p. viii (also see p. viii for a discussion on the carcinogenicity
of metals).

PROPERTIES

Nickel occurs as silver metallic cubic crystals. It is soluble in dilute
nitric acid, slightly soluble in hydrochloric acid, insoluble in cold and
hot water, ammonia, acid and sulfuric acid. It is available with a 99.9%
purity and in grades which include electrolytic, ingot, pellets, shot,
sponge, powder, high-purity strip, and single crystals. Nickel reacts
violently with fluorine (F2), ammonium nitrate, hydrazine, ammonia, a
mixture of hydrogen (H2) and dioxane, performic acid, phosphorus, selenium,
sulfur, or a mixture of titanium and potassium chlorate. Nickel acetate
occurs as a green powder that effloresces somewhat in air. It is soluble in
acetic acid and water and insoluble in alcohol. It is available in a grade
with purity > 99.0%. When heated to decomposition, nickel acetate emits
irritating fumes. Nickel carbonate occurs as light green rhombic crystals
or as a brown powder. It is soluble in dilute acids and ammonia and
insoluble in hot water. Nickel carbonate is available with a 99.5% purity
and occurs naturally as the mineral zaratite. Nickel carbonate can react
violently with iodine (I2), hydrogen sulfide, or a mixture of barium oxide
and air. Nickel carbonyl occurs as a colorless, volatile, inflammable
liquid that has a musty odor. It is soluble in aqua regia, alcohol,
ethanol, benzene, and nitric acid, slightly soluble in water, and insoluble
in dilute acids and dilute alkalies. It is available in a technical grade.
Nickel carbonyl explodes when exposed to heat or flame, and it can react
violently with air, oxygen, bromine (Br2), or a mixture of n- butane and
oxygen. When heated or on contact with acid or acid fumes, nickel carbonyl
emits toxic carbon monoxide fumes. Nickel hydroxide occurs as either green
crystals or as an amorphous black powder. It is soluble in acid and
ammonium hydroxide, but is practically insoluble in water. Nickel hydroxide
is available in a grade containing about 60% nickel. Nickelocene occurs as
dark green crystals. It is soluble in common organic solvents and insoluble
in water. Nickelocene is a highly reactive compound which decomposes in
air, acetone, alcohol, and ether. It is available as a grade containing 8
to 10% nickelocene in toluene. Nickel oxide is a green-black powder that
becomes yellow when heated. It is soluble in acids and ammonium oxide and
insoluble in both cold and hot water. It is available in a grade with 99%
purity. Nickel subsulfide is a pale yellowish-bronze, metallic, lustrous
solid. It is soluble in nitric acid and insoluble in cold and hot water.
When heated to decomposition, nickel subsulfide emits toxic fumes of sulfur
oxides (SOx).

USE

In 1987, approximately 39% of the primary nickel consumed went into
stainless and alloy steel production, 28% into nonferrous alloys, and 22%
into electroplating. Ultimate end uses for nickel were: transportation,
24%; chemical industry, 15%; electrical equipment, 9%; construction, 9%;
fabricated metal products, 8%; petroleum, 8%; household appliances, 7%;
machinery, 7%; and other, 13% (USDOI, 1988). The many uses of nickel
include use in alloys (e.g., low-alloy steels, stainless steel, dental
fillings, copper and brass, permanent magnets, and electrical resistance
alloys), electroplated protective coatings, electroformed coatings,
alkaline storage batteries, fuel cell electrodes, and as a catalyst in the
methanation of fuel gases and hydrogenation of vegetable oils. Nickel
acetate is used as a catalyst and in the textiles industry as a mordant.
Nickel carbonate is used in electroplating and in the preparation of nickel
catalysts, ceramic colors, and glazes. Nickel carbonyl is used in the
production of high-purity nickel powder by the Mond process and continuous
nickel coatings on steel and other metals. It also has many small-scale
applications, e.g., vapor seating of nickel and depositing of nickel in
semiconductor manufacturing. Nickel hydroxide finds use in the manufacture
of nickel salts. Nickelocene is used as a catalyst and complexing agent.
Nickel oxide is used in nickel salts, porcelain painting, fuel cell
electrodes, and the manufacture of stainless and alloy steel. There is no
reported use for nickel subsulfide (Sax, 1987; IARC V.2, 1978; IARC V.11,
1976).

PRODUCTION

The United States produced an estimated 8 million lb of nickel from
domestic ore in 1990 (USDOI, 1991). Ferronickel was produced by a smelter
near Riddle, OR. Byproduct crude nickel sulfate was produced by four copper
refineries, two firms that treated secondary copper, and scrap, nickel-base
alloy scrap, and copper scrap. One firm converted particulate wastes from
stainless steel plants and spent catalysts into nickel-bearing pigs for
making stainless steel. Another company processed nickel hydroxide waste
from several hundred metal finishers, and its product was shipped to a
smelter for nickel recovery. The U.S. imported 320 million lb and exported
48 million lb (6 million lb; 42 million lb secondary nickel) in 1990
(USDOI, 1991). In 1989 the U.S. produced 764 thousand lb of nickel from
domestic ore, and imported more than 278 million lb. Nickel exports
exceeded 48 million lb (4.6 million lb primary nickel. 42.7 million lb
secondary nickel) in 1989. More than 308 million lb of nickel were imported
into the U.S. in 1988, and almost 42 million lb (5.4 million lb primary,
nickel; 36.5 million lb secondary nickel) exported. In 1987, there was no
domestic mine production of nickel. Generally, nickel is produced either as
a by-product from copper refining or recycled or reclaimed from secondary
sources. The 110 million lb of nickel produced in 1987 were from secondary
sources. Imports of nickel were 302 million lb and exports were 2 million
lb in 1987. In 1986, the production of nickel was by the following methods:
> 2.3 million lb from mine production, 2.3 million lb from plant production
of domestic ore, and 87.5 million lb from secondary sources. Imports of
nickel in 1986 were 258 million lb and exports were 5.6 million lb. In
1985, mine production of nickel was 12.3 million lb, plant production from
domestic ore was 10.5 million lb, plant production from foreign matte was
62.5 million lb, and secondary production was 107 million lb. Imports of
nickel in 1985 were 315 million lb and exports were 45.5 million lb (USDOI,
1988). In 1985, 25.0 million lb of nickel powders were imported (USDOI
Imports, 1986). In 1984, 29.1 million lb of nickel were produced by mine
production, 19.2 million lb were produced by plant production from domestic
ore, 70.7 million lb were produced by plant production from foreign matte,
and 110 million lb were produced from secondary sources. In 1984, imports
of nickel were 353 million lb and nickel powders were 30.1 million lb, and
exports of nickel were 63.3 million lb (USDOI, 1988; USDOC Imports, 1985).
In 1983, 66.8 million lb of nickel were produced by plant production from
foreign matte and 100 million lb were produced from secondary sources.
About 304.7 million lb of nickel were imported and 46.7 million lb were
exported in 1983. Mine production of nickel was 6.4 million lb, plant
production from domestic ore was 6.9 million lb, plant production from
foreign matte was 83 million lb, and secondary production was 86 million lb
in 1982. Also in 1982, 259.6 million lb of nickel were imported and 74.7
million lb were exported. In 1981, mine production of nickel was 24.2
million lb, plant production from domestic ore was 20.6 million lb, plant
production from foreign matte was 77 million lb, and secondary source
production was 104 million lb. In 1981, 418 million lb and 39.2 million lb
of nickel were imported and exported, respectively. In 1980, 29.3 million
lb of nickel were produced by mine production, 22.5 million lb by plant
production from domestic ore, 66 million lb by plant production from
foreign matte, and 98.6 million lb from secondary sources. In 1980, 378.3
million lb of nickel were imported and 38.9 million lb were exported
(USDOI, 1988; USDOI, 1985). The 1979 TSCA Inventory reported that in 1977,
there were 21 companies producing 106.8 million lb of nickel and 30
companies importing 390.6 million lb (TSCA, 1979). In 1973, 36.6 million lb
of nickel were produced from mine production (IARC V.11, 1976).

In 1985, 10.2 million lb of nickel compounds and 4.3 million lb of
unspecified nickel compounds were imported, and 709,719 lb of unspecified
nickel compounds were exported (USDOC Imports, 1986; USDOC Exports, 1986).
Imports of nickel oxide in 1984 were 11.1 million lb and imports of
unspecified nickel compounds were 195,840 lb (USDOC Imports, 1985). Also
during 1984, exports of unspecified nickel compounds were 409,339 lb (USDOC
Exports, 1985). The 1979 TSCA Inventory reported that in 1977, 15 companies
produced 12.7 million lb and 2 companies imported 500 lb of nickel
carbonate, with some site limitations; 13 manufacturers produced 781,000 lb
of nickel hydroxide, with some site limitations; 27 companies produced 5.3
million lb and 12 companies imported 30.1 million lb of nickel oxide, with
some site limitations; and 4 companies produced 121,200 lb of nickel
subsulfide. The CBI Aggregate was less than 1 million lb for nickel
carbonate and between 1 million and 100 million lb for nickel carbonyl and
nickel subsulfide. Nickel acetate and nickelocene did not appear on the
TSCA Inventory (TSCA, 1979).

EXPOSURE

The primary routes of potential human exposure to nickel and nickel
compounds are ingestion, inhalation, and dermal contact. Possible exposures
can occur because nickel is present in air, water, soil, food, and consumer
products. NIOSH estimated that 250,000 workers in the United States were
potentially exposed to nickel (including elemental nickel and inorganic
nickel compounds) (NIOSHb, 1977a). OSHA estimated that 709,000 workers were
possibly exposed to nickel and its compounds. Significant occupational
exposure to nickel, through inhalation, at or near permissible levels may
occur in a wide variety of occupations including battery makers, ceramic
makers, electroplaters, enamelers, glass workers, jewelers, metal workers,
nickel mine workers, refiners and smelters, paint-related workers, and
welders. Inorganic nickel concentrations in workroom atmospheres usually
range between 0.1 and 1 mg/m3. In addition, exposure may occur to the
workforce from dermal contact with cutting oils contaminated with nickel
and nickel-containing or nickel-plated tools (ATSDR, 1987k). The ACGIH has
established threshold limit values (TLVs) as 8-hr time-weighted averages
(TWAs) of 1 mg/m3 for nickel metal, 0.1 mg/m3 for soluble nickel compounds,
as nickel, and 0.05 ppm and 0.35 mg/m3 for nickel carbonyl, as nickel
(ACGIH, 1986).

The Toxic Chemical Release Inventory (EPA) listed 912 industrial facilities
that produced, processed, or otherwise used nickel in 1988 (TRI, 1990). In
compliance with the Community Right-to-Know Program, the facilities
reported releases of nickel to the environment which were estimated to
total 1.5 million lb. EPA estimated that nearly 720,000 people living
within 12.5 miles of primary sources may possibly be exposed to nickel at
concentrations up to 15.8 µg/m3 (median 0.2 µg/m3). As many as 160 million
people live within 12.5 miles of all sources of nickel and nickel
compounds, and they may possibly be exposed to median concentrations of
0.05 µg/m3. Ambient air concentrations of nickel in the United States are 6
ng/m3 in nonurban areas, and about 20 ng/m3 in urban areas, with higher
values of up to 150 ng/m3 in large cities (New York City) and industrial
areas (Merian, 1984). Also, the entire U.S. population may possibly be
exposed to low levels of nickel (300-600 µg/day) in food and water. The
following are typical concentrations of nickel found in various food
categories: grains, vegetables, and fruits, 0.02- 2.7 µg/g; meats, 0.06-0.4
µg/g; and seafoods, 0.02-20 µg/g. Cow's milk has been found to contain
nickel concentrations of < 100 µg/l, and the typical concentration of
nickel in mother's milk ranges between 20 and 500 µg/l. Dietary nickel
levels can increase because of food processing methods that leach nickel
from nickel-containing alloys. Dietary intake of nickel has been estimated
to range from 100 to 300 µg/day (ATSDR, 1987k). Nickel also is an essential
micronutrient for plants; thus, eating plant material may be another
potential source of exposure. There is a significant vector of exposure to
the general population such as users of nickel-containing kitchen utensils
and tableware (Sax, 1981). In the United States, nickel levels in drinking
water are estimated to be less than 10 µg/l. Cigarette smoke is reported to
contain up to 3 µg nickel/cigarette (OSH, 1982).

Environmental sources of nickel include emissions from coal- and oil-fired
boilers, coke ovens, diesel-fuel burning, and gray- iron foundries. Total
annual emissions from these types of sources was estimated to be 22.4
million lb. Crude oil contains on the average about 5 ppm nickel. In the
United States, it was calculated that 60% of the atmospheric nickel
emissions originate from oil-fired vessels. Soils normally contain 5-500
ppm nickel; soils from serpentine rock may contain as much as 5,000 ppm.
The earth's crust and soils contain about 50 ppm of nickel, mostly in
igneous rocks. Fresh and sea waters contain about 0.3 µg/l of nickel,
ground water almost none. Urban effluents may contain 60 µg/l of nickel, of
which 40% accumulate in sewage sludge. It has been determined that sewage
sludges contain 20-1,000 ppm nickel with an average of 150 ppm. U.S. river
basins contain 3-17 µg/l of nickel (Merian, 1984).

REGULATIONS

In 1980 CPSC preliminarily determined that nickel carbonyl was not present
in consumer products under its jurisdiction. Subsequently, public comment
was solicited to verify the accuracy of this information; no comments were
received. Pending receipt of new information, CPSC plans no action on this
chemical. EPA regulates nickel and nickel compounds under the Clean Water
Act (CWA), Comprehensive Environmental Response, Compensation, and
Liability Act (CERCLA), Resource Conservation and Recovery Act (RCRA), and
Superfund Amendments and Reauthorization Act (SARA). Effluent guidelines
have been established for nickel and nickel compounds under CWA. Reportable
quantities (RQs) have been established for nickel, nickel carbonyl, and
nickel hydroxide under CERCLA. RCRA regulates nickel and nickel compounds
as hazardous wastes. RCRA and SARA subject nickel and nickel compounds to
report/recordkeeping requirements. SARA also establishes threshold planning
quantities. FDA has taken no action on nickel as a carcinogen because the
data available are not adequate to assess its carcinogenicity through
dietary exposure. Nickel is a compound generally recognized as safe (GRAS)
when used as a direct human food ingredient.

OSHA adopted permissible exposure limits (PELs) of 0.007 mg/m3 as an 8-hour
TWA for nickel carbonyl and 1 mg/m3 as an 8-hour TWA for nickel metal and
soluble nickel compounds; OSHA adopted these standards for toxic effects
other than cancer. NIOSH recommended to OSHA that exposure to nickel be
limited to 15 µg/m3 (10-hour TWA) because of observed carcinogenicity of
nickel metal and all inorganic nickel compounds. OSHA regulates nickel and
certain nickel compounds under the Hazard Communication Standard and as
chemical hazards in laboratories.