Toxicity Profiles
Toxicity Summary for NITRATES
NOTE:
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- EXECUTIVE SUMMARY
- 1. INTRODUCTION
- 2. METABOLISM AND DISPOSITION
- 2.1 ABSORPTION
2.2 DISTRIBUTION
2.3 METABOLISM
2.4 EXCRETION
- 3. NONCARCINOGENIC HEALTH EFFECTS
- 3.1 ORAL EXPOSURES
3.2 INHALATION EXPOSURES
3.3 OTHER ROUTES OF EXPOSURE
3.4 TARGET ORGANS/CRITICAL EFFECTS
- 4. CARCINOGENICITY
- 4.1 ORAL EXPOSURES
4.2 INHALATION EXPOSURES
4.3 OTHER ROUTES OF EXPOSURE
4.4 EPA WEIGHT-OF-EVIDENCE
4.5 CARCINOGENICITY SLOPE FACTORS
- 5. REFERENCES
AUGUST 1995
Prepared By: Andrew Francis, M.S., DABT, Chemical Hazard Evaluation Group,
Biomedical 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
Nitrates are produced by natural biological and physical oxidations and therefore are ubiquitous
in the environment (Ridder and Oehme 1974). Most of the excess nitrates in the environment
originate from inorganic chemicals manufactured for agriculture. Organic molecules containing
nitrate groups are manufactured primarily for explosives or for their pharmacological effects
(Stokinger 1982). Exposure to inorganic nitrates is primarily through food and drinking water,
whereas exposure to organic nitrates can occur orally, dermally, or by respiration (Stokinger 1978).
The primary toxic effects of the inorganic nitrate ion (NO3-) result from its reduction to nitrite (NO2-)
by microorganisms in the upper gastrointestinal tract (Johnson and Kross 1990, Bouchard et al.
1992). Nitrite ions can also be produced with organic nitrate exposure; however, the primary effect
of organic nitrate intake is thought to be dependent on the production of an active nitric oxide (NO-)
radical (Waldman and Murad 1987). Organic nitrates are metabolized in the liver resulting in an
increase in blood nitrites (Murad 1990). Nitrates and nitrites are excreted primarily in the urine as
nitrates (Hartman 1982).
The primary toxic effect of inorganic nitrates is the oxidation of the iron in hemoglobin by
excess nitrites forming methemoglobin. Infants less than 6 months old comprise the most sensitive
population (Hartman 1982, Bouchard et al. 1992). Epidemiological studies have shown that baby
formula made with drinking water containing nitrate nitrogen levels over 10 mg/L can result in
methemoglobinemia, especially in infants less than 2 months of age. No cases of
methemoglobinemia were reported with drinking water nitrate nitrogen levels of 10 mg/L or less
(Bosch et al. 1950, Walton 1951, Shuval and Gruener 1972). A secondary target for inorganic nitrate
toxicity is the cardiovascular system. Nitrate intake can also result in a vasodilatory effect, which
can complicate the anoxia resulting from methemoglobinemia (Ridder and Oehme 1974). Decreased
motor activity was reported in mice given up to 2000 mg nitrite/L in drinking water, and persistent
changes in EEG recordings were observed in rats exposed to 100 to 2000 mg nitrite/L in drinking
water. However, exposure of rats to 3000 mg nitrite/L in drinking water for 2 years did not result in
any gross or microscopic changes in brain tissue. The data indicate that these central nervous system
effects are not related to methemoglobin levels (Shuval and Gruener 1972).
The importance of the primary and secondary targets are reversed with organic nitrates, several
of which have long been used for their vasodilatory effects in the treatment of angina pectoris in
humans (Murad 1990). Large doses of organic nitrates, however, can also produce
methemoglobinemia (Andersen and Mehl 1973). Epidemiological studies have shown that chronic
or subchronic exposure to organic nitrates results in the development of tolerance to the
cardiovascular effects of these compounds. This apparent biocompensation has caused serious
cardiac problems in munitions workers exposed to organic nitrates when they are suddenly removed
from the source of exposure (Carmichael and Lieben 1963).
An epidemiological study correlated the number of congenital malformations of the central
nervous system and musculoskeletal system of babies with the amount of inorganic nitrate in the
mother's drinking water (Dorsch et al. 1984). Other studies, however, do not support these
associations, and the presence of unidentified teratogenic factors in the environment could not be
ruled out. Inorganic nitrate and nitrite have been tested for teratogenicity in rats, guinea pigs, mice,
hamsters, and rabbits. No teratogenic responses were reported; however, fetotoxicity attributed to
maternal methemoglobinemia was observed at high doses (4000 mg nitrate/L in drinking water)
(Sleight and Atallah 1968, Shuval and Gruener 1972, FDA 1972a, b, c).
A Reference Dose (RfD) of 1.60 mg/kg/day (nitrate nitrogen) for chronic oral exposure was
calculated from a NOAEL of 10 mg/L and a LOAEL of 11-20 mg/L in drinking water, based on
clinical signs of methemoglobinemia in 0-3-month-old infants (Bosch et al. 1950, Walton 1951). It
is important to note, however, that the effect was documented in the most sensitive human
population so no uncertainty or modifying factors were used (EPA 1994).
The possible carcinogenicity of nitrate depends on the conversion of nitrate to nitrite and the
reaction of nitrite with secondary amines, amides, and carbamates to form N-nitroso compounds that
are carcinogenic (Bouchard et al. 1992). Experiments with rats have shown that when given both
components, nitrite and heptamethyleneimine, in drinking water, an increase in the incidence of
tumors occurs (Taylor and Lijinsky 1975). Human epidemiological studies, however, have yielded
conflicting evidence. Positive correlations between the concentration of nitrate in drinking water and
the incidence of stomach cancer were reported in Columbia and Denmark (Cuello et al. 1976,
Fraser et al. 1980). However, studies in the United Kingdom and other countries have failed to show
any correlation between nitrate levels and cancer incidence (Forman 1985, Al-Dabbagh et al. 1986,
Croll and Hayes 1988). Nitrate has not been classified as to its carcinogenicity by the EPA, although
it is under review (EPA 1994).
1. INTRODUCTION
Nitrate (NO3-) (CAS No. 014797-55-8) is an inorganic anion resulting from the oxidation of
elemental nitrogen. It is an essential nutrient for plant protein synthesis and plays a critical role in
the nitrogen cycle of soil and water. Nitrates are produced by natural biological and physical
oxidations and therefore are ubiquitous in the environment (Ridder and Oehme 1974). Most nitrate
compounds are strong oxidizing agents and some can react violently with oxidizable substances and
may explode if exposed to heat or shock (Sax and Lewis 1989).
Organic molecules containing nitrate groups are manufactured primarily for explosives or for
their pharmacological effects (Stokinger 1982). Most of the excess nitrates in the environment
originate from inorganic chemicals manufactured for agriculture. Farmers often apply fertilizer in
the form of ammonium or sodium nitrate in excess to their crops. When the concentration of nitrates
in the soil is higher than the plants can use, the excess nitrates appear in the surface and ground
waters and are often found in drinking water, especially in rural agricultural areas served by wells.
Ammonia from animal waste and septic tanks can be oxidized to nitrate by soil bacteria under
aerobic conditions. This can also be a significant source of nitrate in surface and groundwater
especially near areas of concentrated animal populations, such as feedlots and dairy barns (Bouchard
et al. 1992). The groundwater contamination also depends on the type and thickness of the soil, the
amount of precipitation, irrigation, vertical flow, dissolved oxygen concentration, and electron donor
availability. The groundwater in the agricultural southeastern United States is not very vulnerable
to NO3 contamination, whereas it is a serious problem in parts of the midwest (Spalding and
Exner 1993). In addition to drinking water, dietary sources of nitrates include compounds used in
meat curing processes and nitrates in vegetables. High concentrations of nitrates in vegetables can
reflect the overapplication of nitrate-containing fertilizers (Ridder and Oehme 1974, Phillips 1971).
Inorganic nitrate can be reduced to nitrite (NO2-) by the microflora in saliva and the
gastrointestinal tract. Nitrite is thought to be responsible for most of the toxic effects observed with
excess nitrate ingestion (Johnson and Kross 1990, Bouchard et al. 1992).
2. METABOLISM AND DISPOSITION
2.1. ABSORPTION
Inorganic nitrates are primarily absorbed through the gastrointestinal system as a mixture of
nitrates and nitrites (Bouchard et al. 1992). Some organic nitrates can also be absorbed unchanged
through the skin, gastrointestinal tract, mucous membranes, and lungs (Stokinger 1982). Nitrates and
nitrogen oxides, which can be oxidized to nitrates, occur as organic products of photochemical smog
and as inorganic aerosols in the atmosphere (NAS 1981). These substances can be absorbed through
the respiratory system. The daily nitrate dose/person via respiration in the Los Angeles area has been
estimated at about 500 µg nitrate-nitrogen (Fan et al. 1987).
2.2. DISTRIBUTION
Nitrates and nitrites are absorbed by the various routes into the general blood circulation and
are transported to all parts of the body. Radioactive tracer experiments have shown that nitrates are
distributed evenly among body organs, and the rate of distribution is dependent on blood flow (Parks
et al. 1981). Animal experiments have shown that nitrites can cross the placental barrier and affect
the fetus (Shuval and Gruener 1972).
2.3. METABOLISM
Nitrates are reduced to nitrites by the microflora in saliva and the gastrointestinal system
(Hartman 1982, Ridder and Oehme 1974, Bouchard et al. 1992). The in vivo reduction of nitrates
to nitrites depends on conditions that are subject to wide variations including the number and type
of microflora present in the saliva and the gastrointestinal tract and the pH of the stomach. Gastric
pH is higher in infants less than 6 months old and during some gastrointestinal infections
(gastroenteritis), thereby favoring the reduction of nitrates (Bouchard et al. 1992). Nitrites absorbed
into the blood are rapidly oxidized to nitrates. Nitrites have been shown to be oxidized to nitrates
at the rate of more than 50% in 10 minutes at a concentration of 2 to 3 nanomoles/L of blood in mice
and rabbits. A catalase-hydrogen peroxide system has been proposed as the oxidation mechanism
(Parks et al. 1981).
Organic nitrates, which are absorbed intact and are used to relieve angina attacks, undergo
reductive hydrolysis by the action of hepatic glutathione-organic nitrate reductase, forming a more
water soluble organic molecule and inorganic nitrites. The kinetics of this reduction is dependent
upon the organic nitrate molecule, the route of entry, and the hepatic blood flow. Most
pharmacological doses of organic nitrate can undergo denitration during one circulation through the
liver. Oral doses, some of which are absorbed into the portal circulation, are formulated to saturate
the hepatic enzymes to facilitate a more prolonged prophylaxis against angina attacks (Murad 1990).
2.4. EXCRETION
Nitrates and nitrites are excreted in the urine primarily as inorganic nitrates. Small quantities
of nitrates are excreted in the saliva, where they are subject to reduction to nitrites by
microorganisms in the salivary ducts resulting in the recycling of a mixture of nitrates and nitrites
in the gastrointestinal system (Hartman 1982).
3. NONCARCINOGENIC HEALTH EFFECTS
3.1. ORAL EXPOSURES
3.1.1. Acute Toxicity
3.1.1.1. Human
Nitrites formed from nitrates by the microflora in the salivary ducts and gastrointestinal system
are primarily responsible for the toxic effects observed after nitrate ingestion (Fan et al. 1987,
Bouchard et al. 1992). Inorganic nitrates, if not reduced to nitrites, are not toxic at concentrations
found in drinking water, vegetables, and cured meats. Their physicochemical effects have been
compared to the effects of sodium chloride in humans (Fan et al. 1987).
An excess of nitrites produced by the reduction of organic or inorganic nitrates can oxidize the
iron in hemoglobin from ferrous to ferric, forming methemoglobin (Craun et al. 1981, Hartman 1982,
Bouchard et al. 1992). This is the primary toxic effect of inorganic nitrate ingestion, and infants less
than 6 months old comprise the most sensitive population. This sensitivity is due to the presence of
more easily reduced fetal hemoglobin, a higher population of reducing bacteria in the stomach due
to a higher gastric pH, lower enzymatic capacity to reduce methemoglobin, and a predisposition to
gastrointestinal infections that tend to favor populations of reducing bacteria (Bouchard et al. 1992).
Nitrites also have a vasodilatory effect that can further complicate the problem of
methemoglobinemia-induced anoxia (Ridder and Oehme 1974).
Bosch et al. (1950) correlated the incidence of infant methemoglobinemia with the nitrate
concentration of drinking water from Minnesota wells. The water was found to contain from 10 to
greater than 100 mg nitrate-nitrogen/L. No cases of methemoglobinemia were found with baby
formula made with well water containing 10 mg or less nitrate-nitrogen/L. The infants were less than
2 months of age in 90% of the methemoglobinemia cases. An epidemiological study by Walton
(1951) analyzed all recorded cases of infant methemoglobinemia in 37 states. The occurrence of the
condition was found to be primarily due to the ingestion of baby formula prepared with nitrate
contaminated water. A total of 214 cases could be compared to nitrate concentrations in drinking
water. No cases were recorded with drinking water containing 10 mg nitrate-nitrogen/L or less. Five
cases were reported in infants exposed to 11-20 mg/L, 36 cases in those exposed to 21-50 mg/L, and
173 cases in infants exposed to greater than 50 mg/L nitrate-nitrogen. Additional studies have
supported these observations.
Methemoglobin levels in 1702 infants with water supplies averaging 15.8 mg nitrate-nitrogen/L
(70 mg nitrate/L) were compared with 758 infants with water supplies averaging 1.2 mg
nitrate-nitrogen/L (5 mg nitrate/L) (Shuval and Gruener 1972). No cases of methemoglobinemia
were reported, and only slight differences in methemoglobin levels were observed. No changes were
observed in infants more than 90 days old. Infants with diarrhea had slightly increased
methemoglobin levels (1.78%) compared to normal healthy infants (1.16%), and infants on a diet
high in vitamin C-rich foods were observed to have slightly lower levels (1.19% compared to 1.30%
methemoglobin). Only 6% of the children in this study were fed powdered formula made with the
tap water. Knotek and Schmidt (1964) reported subclinical methemoglobinemia in infants fed on
formula made with nitrate-rich tap water. Nitrate-induced infant methemoglobinemia persists today,
especially in rural farming areas where reliance on well water is prevalent. Johnson et al. (1987)
reported a fatal case of methemoglobinemia resulting from the feeding of powdered infant formula
prepared with well water that was found to contain about 150 ppm nitrate nitrogen to an 8-week-old
infant.
Organic nitrates are well known for their vasodilatory effects and have been used for the
treatment of angina pectoris. Although nitrite release from organic nitrates accounts for the
formation of methemoglobin, the vasodilatation effect of organic nitrates does not depend on the
liberation of the nitrite groups (Stokinger 1982). The production of an active nitric oxide radical is
thought to lead to the dephosphorylation of the light chain of myosin and the relaxation of smooth
muscle (Fung et al. 1992, Murad 1990, Waldman and Murad 1987). Headache, dizziness, and
weakness may also be experienced and is associated with the cardiovascular effects. Organic nitrates
can also produce a drug-induced rash in susceptible people. The usual oral dose of most organic
nitrates for the relief of angina symptoms is about 10-40 mg, 2 to 4 times daily. Specific organic
nitrates that are given orally for their vasodilation effects include nitroglycerin, isosorbide dinitrate,
erythrityl tetranitrate, and pentaerythritol tetranitrate. Peak effects usually occur in 60-90 minutes
after oral administration and last 3-6 hours (Murad 1990).
3.1.1.2. Animal
Methemoglobinemia, which can lead to anoxia and death in extreme cases, is the primary acute
toxic effect of oral exposure to inorganic nitrates in all animals tested. Ruminant animals are most
susceptible. This effect is extremely variable since it depends on a number of factors including the
conversion of nitrates to nitrites; the ability of the various animals to enzymatically reduce
methemoglobin; the amount of vitamins A, C, D, and E in the diet; and the nutritional state of the
animal. Acute nitrate toxicity in cattle has been reported following the ingestion of water containing
500 ppm or more nitrate or feed containing 5000 ppm or more nitrate. Methemoglobinemia is caused
by the conversion of the nitrates to nitrites; however, high levels of nitrates have also been reported
to result in gastroenteritis, diarrhea, diuresis, and petechial hemorrhages on the pericardium (Ridder
and Oehme 1974). Dogs have sustained a plasma level of 24 mEq nitrate/L
(336 mg nitrate-nitrogen/L) following gavage with sodium nitrate in water with no evidence of
methemoglobinemia. Slight increases in glomerular filtration rates and renal plasma flow were
observed, and hyperexcretion of chloride leading to hypochloremia, alkalosis, and digestive
disturbances were reported. Dehydration occurred in some dogs as a result of the gastrointestinal
problems and a diuretic effect of nitrates (Greene and Hiatt 1954). Dogs have also been given
20,000 ppm nitrate in their diet without any apparent adverse effects (Ridder and Oehme 1974). Rats
have shown no effects after a dietary nitrate concentration of 10,000 ppm (PHS 1962). Pigs are even
more resistant to nitrate poisoning but have developed methemoglobinemia after ingesting food or
drinking water containing nitrites converted from nitrates by microflora in the food or water before
ingestion (toxic dose listed as 88 mg nitrite/kg body weight) (Ridder and Oehme 1974). Potassium
nitrate oral LD50 values of 3750 mg/kg for rats and 1901 mg/kg for rabbits and sodium nitrate oral
LD50 values of 2680 mg/kg for rabbits have been reported (Sax and Lewis 1989).
Organic nitrates can also produce methemoglobinemia in animals, which contributes to the
overall toxic response resulting in reduced average time to death. Oral LD50 values have been
reported in rats for propylene glycol 1,2-dinitrate (PGDN) (250 mg/kg) and triethylene glycol
dinitrate (TEGDN) (1000 mg/kg). PGDN also causes ataxia, lethargy, and respiratory depression in
rats. TEGDN can also result in rats being hyperactive to auditory and tactile stimulation. Moderate
increases in alkaline phosphatase and creatine kinase activities were reported following PGDN
treatment (Stokinger 1982, Andersen and Mehl 1973).
3.1.2. Subchronic Toxicity
3.1.2.1. Human
Elevated methemoglobin as a result of subchronic exposure to high dietary or drinking water
nitrate levels has been reported in school age children. Methemoglobin levels 2-5 times the levels
seen in children with drinking water nitrate levels <10 mg nitrate-nitrogen/L were reported in groups
of school children (total number 517) in the Soviet Union consuming water with 180 and
204 mg nitrate-nitrogen/L (Diskalenko 1968). In another study of 21 children 12-14 years old, there
was a 7-fold increase in methemoglobin levels observed between the children exposed to a drinking
water nitrate-nitrogen concentration of 23 mg/L compared to 2 mg/L (Subbotin 1961,
Craun et al. 1981). Wide individual variations in responses to high dietary or drinking water nitrate
levels are reported. Methemoglobin formation depends on the microflora conversion of nitrates to
nitrites, the age and nutritional state of the individual, and the amount of vitamin C in the diet (Craun
et al., 1981).
No increase in methemoglobin was observed in a group of 64 Illinois children consuming
drinking water containing 22-111 mg nitrate-nitrogen/L compared with 38 children consuming water
with <10 mg nitrate-nitrogen/L. The children were from 1-8 years of age. Evidence was presented
in this study that indicated the length of exposure was less important than the concentration of nitrate
in the water during the previous 24 hours before sampling blood for methemoglobin and also less
important than the age of the children. The methemoglobin levels in the highest dose groups
(201-500 mg nitrate estimated intake/ previous 24 hours) were significantly higher in the 1-4 age
group than in the 5-8 age group. These differences, however, were not considered biologically
significant (Craun et al. 1981). Toxic health hazards in humans, except for methemoglobinemia, as
a result of subchronic high inorganic nitrate exposure are undocumented (Moller et al. 1989).
The subchronic administration of organic nitrates results in the development of tolerance to the
cardiovascular effects of these compounds. This effect is independent of entry route and creates
limitations in the treatment of angina symptoms and potentially serious problems for workers in
munitions and dynamite industries (see Sect. 3.2.2.1.) (Stokinger 1982, Elkayam et al. 1992,
Colucci et al. 1981).
3.1.2.2. Animal
One problem with inorganic nitrate studies in animals is the different rates of conversion of
nitrate to nitrite seen in animals when compared to humans. Rats have a much lower nitrate to nitrite
conversion rate than humans, which complicates interpretation and extrapolation of results. For this
reason, Til et al. (1988) examined the toxicity of nitrite in a 90-day study in rats. Groups of 10 male
and 10 female 6-week-old Wistar rats were given 100, 300, 1000, and 3000 mg potassium nitrite/L
in drinking water. Potassium levels were equated in all groups by the addition of potassium chloride.
Both tap water and tap water plus potassium chloride control groups were used. The estimated
average intake of potassium nitrite was reported as 0, 8.9, 24.6, 77.5, 199.2 and 0, 10.9, 31.1, 114.4,
241.7 mg/kg/day for males and females, respectively. All animals appeared healthy during the entire
13-week study. Decreased food consumption and weight gain was seen in males at the high dose,
and decreased drinking water consumption was reported in both sexes at the 3000 mg/L dose and
at the 1000 mg/L dose in males. Methemoglobin was significantly (P <0.01) increased in both sexes
at the high dose. Slight changes in erythrocyte parameters were also noticed, including decreased
hemoglobin concentration and packed-cell volume and erythrocyte counts in the 1000 and
3000 mg/L groups. The high dose also resulted in an increase in plasma urea levels in males and a
slight decrease in plasma alkaline phosphatase activity in both sexes although significantly only in
females. The relative weights of the kidneys were increased in both sexes at the 3000 mg/L dose;
however, histopathological examinations were negative. Thorough autopsies on all animals were
performed, and the histopathological examinations revealed a dose-related hypertrophy of the
adrenal zona glomerulosa in both sexes. The hypertrophy was correlated with previously reported
changes in urinary steroid excretion in rabbits and humans following nitrite ingestion and with the
vasodilating properties of nitrite.
A sedative effect was reported in groups of 57 black 6J male mice given drinking water
containing 1500 and 2000 mg nitrite/L. A significant decrease in motor activity was measured in a
special activity box designed for this purpose. Lower doses, 100 mg/L, and 1000 mg/L did not show
the sedative effect. The decreased activity remained after methemoglobin levels were reduced to near
normal following vitamin C administration, thereby indicating that the sedative effect may be
independent of the methemoglobinemia. A subchronic study measuring brain electrical activity was
designed to study this effect. Recordings were made using implanted electrodes to measure possible
central nervous system effects in groups of 3-month-old male rats receiving 0, 100, 300, and
2000 mg/L sodium nitrite in drinking water. Recordings were made before the treatment began,
during the 2 months of treatment, and for 4½ months following cessation of the treatments.
Alterations in the EEG recordings were observed in all treated groups. The changes persisted in the
three highest groups during the observation period. Some recovery was noted in the low dose group;
however, diffused spikes and sharp waves remained for the entire period. It was concluded that
subchronic sodium nitrite ingestion in drinking water may result in persistent brain electrical changes
in rats (Shuval and Gruener 1972).
3.1.3. Chronic Toxicity
3.1.3.1. Human
Toxic health hazards in humans, except for methemoglobinemia, as a result of chronic high
inorganic nitrate exposure are undocumented (Moller et al. 1989).
The chronic administration of organic nitrates results in the development of tolerance to the
cardiovascular effects of these compounds. This effect is independent of entry route and creates
limitations in the treatment of angina symptoms and potentially serious problems for workers in
munitions and dynamite industries (see Sect. 3.2.2.1.) (Stokinger 1982, Elkayam et al. 1992,
Colucci et al. 1981).
3.1.3.2. Animal
Groups of 8 male rats were given 0, 100, 1000, 2000, or 3000 mg sodium nitrite/L in drinking
water for 2 years. No significant differences in mortality, growth, or development were reported. A
dose-related increase in methemoglobin levels was observed, but no significant differences were
noticed in hemoglobin levels. Histological examination revealed no pathological changes in
pancreas, adrenal, or brain tissue. However, pathological changes were reported with increased
frequency at the higher doses in the lungs and heart. The observed changes included dilated bronchi,
fibrosis and emphysema in the lungs, and fibrosis and degenerative foci in the heart. The coronary
arteries in the high dose group were reported to be much thinner and dilated than expected in animals
of their age. The high dose group was estimated to have received 250-350 mg sodium nitrite/kg body
weight/day (60 mg nitrite-nitrogen/kg/day) (Shuval and Gruener 1972).
Druckrey et al. (1963) gave rats 100 mg sodium nitrite/kg/day (20 mg nitrite-nitrogen/kg/day)
in a lifetime drinking water study. Elevated methemoglobin was reported in treated animals, but no
other treatment-related hematologic or histologic effects were observed.
3.1.4. Developmental and Reproductive Toxicity
3.1.4.1. Human
An epidemiological study by Dorsch et al. (1984) involved 218 babies born in rural south
Australia with congenital malformations. The babies were matched individually as to hospital,
maternal age, parity, and date of birth with an equal number of normal babies. The nitrate
concentrations in the water sources used in the homes during pregnancy were determined or
estimated. Significantly (>95% confidence level) increased relative risk for malformations of the
central nervous system and musculoskeletal system in babies was associated with mothers that used
drinking water containing 5 - >15 ppm nitrate. Individuals using rainwater (<5 ppm nitrates) for
drinking water were given a relative risk of 1.0; those exposed to water containing 5-15 ppm were
found to have a relative risk of 2.8; and the individuals exposed to water containing >15 ppm nitrates
had a relative risk of 4. Neural tube defects had the strongest association (relative risk of 3.5).
Unidentified teratogenic factors that might be present in the water, diet, or environment could not
be eliminated as causative or contributing factors.
3.1.4.2. Animal
Groups of 12 pregnant rats were given 2000 or 3000 mg/L sodium nitrite in drinking water. A
control group of seven pregnant rats were given tap water. The dams in the 2000 mg/L group
developed methemoglobinemia and decreased hemoglobin compared to controls and nonpregnant
rats. No deformities were reported in any of the groups, and the birth weight of the pups was
comparable to the controls. The pups of the treated groups had decreased growth rates, the fur was
thin and lacked luster, and survival was decreased (mortality was 6, 30, and 53% for controls, 2000,
and 3000 mg/L, respectively). The pups did not show abnormally high methemoglobin in either of
the treated groups, although hemoglobin levels were about 20% less than the control group. Fetal
blood nitrite levels following doses of 2.5 to 50 mg/kg sodium nitrate given orally to the dams were
measured in a subsequent experiment. Elevated fetal blood nitrite and methemoglobin levels were
reported after a lag of about 20 minutes. The threshold of transplacental transfer of nitrite was
reported to be at a sodium nitrite dose of 2.5 mg/kg (Shuval and Gruener 1972).
Groups of 3 to 6 female guinea pigs were given 0, 300, 2500, 10,000, or 30,000 ppm potassium
nitrate in drinking water for 143 to 204 days. The daily intake of nitrate nitrogen was calculated to
be 12, 102, 507, and 1130 mg/kg body weight for the 300, 2500, 10,000, and 30,000 ppm doses in
drinking water, respectively. Five animals or less were kept in one cage including one male rabbit
per cage. The daily food and water consumption were measured and the animals were weighed each
week. The number of litters produced, live births, and fetal deaths during the treatment period were
reported. A decrease in the number of litters (2 treated, 8 control) and the number of live births
(2 treated, 31 control) were reported for animals in the 30,000 ppm dose group, which were treated
for 204 days. One animal in this group died with four mummified fetuses in utero. The fetal deaths
were attributed to hypoxia due to maternal methemoglobinemia. Food and water consumption were
comparable in all groups and weight gains were normal. No significant gross or microscopic lesions
were reported in the reproductive organs. In a parallel experiment, 3-6 female guinea pigs per group
were given 300, 1000, 2000, 3000, 4000, 5000, or 10,000 ppm potassium nitrite in drinking water
corresponding to 18, 45, 154, 182, 192, 244, and 577 mg nitrite nitrogen/kg body weight/day,
respectively. Treatment duration varied from 100 days for 4000 ppm to 240 days for 300 ppm. In this
case, the number of litters produced per female (0.7 treated, 2 control) and live births per female (1.7
treated, 7.8 control) were decreased at 4000 ppm, and 4 fetal deaths were reported versus 1 in the
control group. No live births at 5000 or 10,000 ppm were recorded.
Inflammatory cervical and uterine lesions and degenerative placental lesions were reported in
females with dead fetuses. The relative percent reproductive performance was calculated taking into
consideration the number of females, the average number of days under treatment, and the total
number of live births. The control group was assumed to be 100%. This indicator dropped from 80%
at 3000 ppm to 41% at 4000 ppm and to 0.0% at 5000 ppm. Food and water consumption was near
normal at all doses. Decreased weight gain was seen with the highest dose of potassium nitrite.
Methemoglobin levels were about 20% of the available hemoglobin in the 10,000 ppm group
(Sleight and Atallah 1968). Male fertility was apparently not greatly affected since conception
occurred at all doses. Wide variations were reported in the results of these two experiments, such
as no live births at 5000 or 10,000 ppm in one study, but 2 live births at a dose of 30,000 ppm in the
other study.
Sodium and potassium nitrate and nitrite were tested in mice, rats, hamsters, and rabbits for
teratogenicity in studies sponsored by the Food and Drug Administration. The oral doses for sodium
nitrate given through gestation were up to 400 mg/kg for groups of 20 to 26 mice and hamsters and
up to 250 mg/kg for groups of 20 to 26 rats and 10 to 13 rabbits. Potassium nitrate up to 400 mg/kg
for mice, 1980 mg/kg for rats, 280 mg/kg for hamsters and 206 mg/kg for rabbits was given. No
effects were reported in any treated group on nidation, maternal or fetal survival, or incidence of soft
or skeletal tissue abnormalities. Sodium and potassium nitrite at doses up to 23, 10, 23, and 23 mg/kg
were given throughout gestation to mice, rats, hamsters, and rabbits, respectively. Although there
was no teratogenic response in any group, an indication of slightly delayed skeletal maturation,
especially in the ribs and skull, was observed in rats at the highest dose (10 mg/kg) (FDA 1972a, b,
c).
Groups of 22 to 28 female rats were given 0.0125, 0.025, or 0.05% sodium nitrite in their diet
from 14 days before breeding through gestation and lactation. Offspring were given sodium nitrite
at the same dietary level as their parents for up to 90 days of age. Males were also given the same
doses 14 days before breeding. The negative control group contained 35 females. No significant
decreases in body weight or food consumption were reported from birth through lactation in any of
the treated groups. No malformations or significant effects were noted on reproductive performance
at any of the doses tested. Offspring mortality, however, was increased at the middle and high dose
up to day 24 after birth, after which no further increase in deaths occurred. The period of increased
mortality was concurrent with a transient period of decreased weight gain and delayed swimming
development. There were no effects reported on post-weaning development, weight gain, food
consumption, mortality, 90-day brain and eye weights, and tests of adult behavior
(Vorhees et al.1984).
3.1.5. Reference Dose
3.1.5.1. Subchronic
A subchronic RfD for nitrates is not available.
3.1.5.2. Chronic
ORAL RfDc: 1.60 mg/kg/day (EPA 1994)
UNCERTAINTY FACTOR: 1
MODIFYING FACTOR: 1
NOAEL: 10 mg nitrate-nitrogen/L of drinking water
LOAEL: 11-20 mg nitrate-nitrogen/L of drinking water
CONFIDENCE:
Study: High
Data Base: High
RfD: High
VERIFICATION DATE: 08/22/90
PRINCIPAL STUDY: Walton, G. (1951); Bosch, H.M. et al. (1950)
COMMENTS: The NOAEL was obtained from the amount of nitrate-nitrogen in well water
used to prepare formula for infants. It is based on the lack of methemoglobin formation in
the most sensitive human group; therefore, no uncertainty factor was deemed necessary. The
calculations are based on the consumption of 0.64 L of water/day by a 4-kg infant and are
given in mg nitrate-nitrogen (1 mg nitrate-nitrogen = 4.4 mg nitrate). See Sects. 3.1.1.1 and
3.1.3.1 for further discussion of the principal studies. An RfD for organic nitrates as a group
is not available.
3.2. INHALATION EXPOSURES
3.2.1. Acute Toxicity
3.2.1.1. Human
Atmospheric nitrates and other nitrogen oxides especially associated with smog near large
industrial centers are known to contribute to the overall nitrate/nitrite intake of the population in
these areas (Fan et al. 1987). However, specific information on the acute inhalation toxicity of
inorganic nitrates in humans was not available.
Vasodilatory effects have been observed following inhalation exposure to various organic
nitrates. Nitroglycerine and ethylene glycol dinitrate exposure (2.0 mg/m3 ethylene glycol dinitrate
for 1 to 3 minutes) resulted in a drop in blood pressure and severe headaches in four out of five
volunteers tested. General fatigue and pain in the chest, abdomen, and extremities were also
reported. Only three out of seven volunteers experienced mild or transitory headaches at 0.5 mg/m3
ethylene glycol dinitrate (Carmichael and Lieben 1963, Stokinger 1982).
3.2.1.2. Animal
Information on the acute inhalation toxicity of inorganic nitrates in animals was not available.
However, an LD50 of 1047 mg/m3 has been reported in mice for propylene glycol 1,2-dinitrate
(PGDN) (Andersen and Mehl, 1973; Stokinger, 1978). In rats, however, exposure to PGDN for 4
hours to 1350 mg/m3 (200 PPM) produced no deaths or overt signs of toxicity after 14 days
following treatment although the methemoglobin values increased from a mean of 6 to 23.5% (Jones
et al. 1972, Stokinger 1978).
3.2.2. Subchronic Toxicity
3.2.2.1. Human
Information on the subchronic inhalation toxicity of inorganic nitrates in humans was not
available. However, long-term (months to years) inhalation exposure of individuals working in
munitions or dynamite manufacturing leads to an apparent biocompensation of the cardiovascular
effects of organic nitrates. These workers, when removed from the source of the nitrates,
experienced symptoms of angina and were subject to sudden and sometimes fatal heart attacks. This
effect was documented in at least 38 dynamite workers 30-48 hours after absence from work during
1926 to 1961 (Carmichael and Lieben 1963, Stokinger 1982).
3.2.2.2. Animal
Information on subchronic inhalation toxicity of inorganic nitrates in animals was not available.
Studies using monkeys, dogs, rats, and guinea pigs were performed by the U. S. Navy on the organic
nitrate, propylene glycol-1,2-dinitrate (PGDN), a torpedo propellent. Animals were exposed to 0,
9, 14.5, or 31.4 ppm PGDN (0, 67, 108, and 236 mg/m3, respectively) continuously for 90 days. The
animals did not exhibit visible signs of toxicity; however, methemoglobin values were increased in
all species at the high dose and were highest in dogs and monkeys (23.4 and 17%, respectively).
Serum inorganic nitrate was also increased to maximums of 202 µg/ml and 174 µg/ml over the
control values of 12 and 2.4 µg/mL for monkeys and dogs, respectively, after 14 days of exposure
to 31.4 ppm. Hemoglobin and hematocrit values were decreased 63 and 37%, respectively, in dogs.
Hemosiderin deposits were observed in the liver and kidneys of dogs and rats at the high dose.
Vacuolar changes associated with some iron-positive deposits, mononuclear cell infiltrates and focal
necrosis were observed in the livers of all the high dose guinea pigs and in 4/9 of the high dose
monkeys. Iron positive deposits were also reported in the kidneys and spleens of middle and high
dose monkeys and dogs. The monkeys also had elevated serum urea nitrogen and decreased serum
alkaline phosphatase levels, which could be indicative of kidney damage. Hemorrhagic foci were
reported in the lungs of guinea pigs exposed to 14.5 ppm (Jones et al. 1972).
3.2.3. Chronic Toxicity
3.2.3.1. Human
Information on the chronic inhalation toxicity of inorganic nitrates in humans was not available.
The effects of long-term exposure to an organic nitrate, PGDN, on tests involving eye-tracking and
ataxia were performed on 115 active duty and civilian Navy personnel involved in torpedo
maintenance procedures. The duration of exposures ranged from months to 11 years. The PGDN
concentration during exposure ranged from near 0 to 0.22 ppm with an average concentration of
0.03 ppm. The neurological ataxia tests demonstrated no differences from the control group. When
the velocity of eye movements and latency were tested immediately before and after exposure,
significant decreases in eye movement velocity and latency were reported. There was no evidence;
however, that any permanent neurological impairment resulted from repeated daily exposures for
up to 11 years (Stokinger 1982) (see Sect. 3.2.2.1)
3.2.3.2. Animal
Information on the chronic inhalation toxicity of nitrates in animals was not available.
3.2.4. Developmental and Reproductive Toxicity
3.2.4.1. Human
Information on developmental and reproductive toxicity in humans resulting from inhalation
exposure to nitrates was not available.
3.2.4.2. Animal
Information on developmental and reproductive toxicity in animals resulting from inhalation
exposure to nitrates was not available.
3.2.5. Reference Concentration
3.2.5.1. Subchronic
A subchronic RfC for inhalation exposure to inorganic nitrate is not available at this time.
3.2.5.2 Chronic
A chronic RfC for inhalation exposure to inorganic nitrate is not available at this time.
3.3. OTHER ROUTES OF EXPOSURE
3.3.1. Acute Toxicity
3.3.1.1. Human
Information on the acute toxicity of inorganic nitrates in humans by other routes of exposure
was unavailable. Most organic nitrates are effectively absorbed dermally or sublingually. These
routes are often the most convenient route for treatment of angina. The specific efficiency of
absorption varies with the particular organic moiety. For example, ethylene glycol dinitrate and
nitroglycerine are readily absorbed through the skin, but erythritol tetranitrate and pentaerythritol
tetranitrate are not. The cardiovascular effects particular to these compounds are essentially
independent of route (Stokinger 1982) (see Sect. 3.1.1.1).
3.3.1.2. Animal
Information on the acute toxicity of inorganic nitrates in animals by other routes of exposure
was unavailable. Organic nitrates are absorbed through the skin of animals, and severe acute effects
have been reported. A dose of 3.5 g/kg/day PGDN applied to the backs of rabbits resulted in the
death of 6 of 11 treated animals with a mean time to death of 16 days (Andersen and Mehl 1973,
Stokinger 1982).
3.3.2. Subchronic Toxicity
3.3.2.1. Human
Information on the subchronic toxicity of inorganic nitrates by other routes of exposure in
humans was unavailable. In the munitions and dynamite production industries, dermal absorption
of organic nitrates is known to contribute to the total dose and is taken into consideration along with
inhalation absorption to control worker exposure (Einert et al. 1963, Stokinger 1982) (see
Sect. 3.2.2.1).
3.3.2.2 Animal
Information on the subchronic toxicity of inorganic nitrates by other routes of exposure in
animals was unavailable. Doses of 1, 2, and 4 g/kg/day of propylene glycol 1,2-dinitrate were applied
to the backs of 14 rabbits per group for 90 days. Weakness and slight cyanosis was observed for the
first 6 days at the 2 g/kg/day dose, and one rabbit died during this period. Steady improvement in the
surviving animals was seen for the remainder of the treatment period with 15% weight gain by the
20th day. In the high dose group, 13 of 14 animals died within the first 6 days. Internal organs were
reported to appear dark, blue-gray (Andersen and Mehl 1973, Stokinger 1982).
3.3.3 Chronic Toxicity
3.3.3.1 Human
Information on the chronic toxicity of inorganic nitrates by other routes of exposure in animals
was unavailable. Industrial exposure to organic nitrates has occurred from months to years. Dermal
absorption is known to contribute to the total dose and is taken into consideration to control worker
exposure (Einert et al. 1963, Stokinger 1982) (see Sect. 3.2.2.1).
3.3.3.2 Animal
Information on the chronic toxicity of nitrates by other routes of exposure in animals was
unavailable.
3.3.4. Developmental and Reproductive Toxicity
3.3.4.1. Human
Information on the developmental and reproductive toxicity of nitrates by other routes of
exposure in humans was unavailable.
3.3.4.2 Animal
Information on the developmental and reproductive toxicity of nitrates by other routes of
exposure in humans was unavailable.
3.4. TARGET ORGANS/CRITICAL EFFECTS
3.4.1. Oral Exposures
3.4.1.1. Primary Target Organ(s)
1. Blood: formation of methemoglobinemia especially in young children. The effect depends
on conversion of nitrates to nitrites in the gastrointestinal system. Methemoglobinemia is
primarily caused by ingestion of inorganic nitrate but can also be the result of organic
nitrate ingestion.
2. Cardiovascular system: vasodilatory effect on blood vessels. Organic nitrates are used as
prophylactic agents for angina patients. Inorganic nitrate is much less effective but has
also been observed to cause vasodilation, which can complicate the adverse effects of
methemoglobinemia.
3.4.1.2. Other Target Organ(s)
Fetus: Studies indicate a possible fetotoxic effect at very high doses of inorganic nitrate. There
are conflicting studies on this effect, which may involve the in vivo production of N-nitroso
compounds.
3.4.2. Inhalation Exposures
3.4.2.1. Primary Target Organ(s)
Cardiovascular system: The vasodilatory effect of organic nitrates is independent of entry route.
3.4.2.2. Other Target Organ(s)
Blood: Methemoglobinemia can occur with organic nitrate inhalation.
3.4.3 Other Routes of Exposure
3.4.3.1 Primary target organ
Cardiovascular system: The vasodilatory effect of organic nitrates is independent of the entry
route, which can include dermal or sublingual routes.
3.4.3.2 Other target organ
Blood: Methemoglobinemia can occur with organic nitrate following sublingual or dermal
absorption.
4. CARCINOGENICITY
4.1. ORAL EXPOSURES
4.1.1. Human
The possibility of inorganic or organic nitrate functioning as a carcinogen depends on its
conversion to nitrite and the subsequent reaction of nitrite with other molecules, specifically
secondary amines, amides, and carbamates, to form carcinogenic N-nitroso compounds
(Bouchard et al. 1992, Taylor and Lijinsky 1975). Human population studies have yielded
conflicting results. Studies in Columbia and Allborg, Denmark, show positive correlations between
the incidence of stomach cancer and the nitrate content of well water (Cuello et al. 1976,
Fraser et al. 1980).
Aarhus, another town in Denmark of similar size but with relatively low nitrate concentrations
in drinking water, had 25% lower stomach cancer rates in men and 20% lower rates in women
(Fraser et al. 1980). Epidemiological studies in the United Kingdom have shown the overall stomach
cancer deaths decreasing as the nitrate levels were rising and no positive correlation between cancer
rates and areas with high nitrate in the drinking water (Forman 1985). A study of workers in a
fertilizer plant exposed to high concentrations of nitrate had no significantly higher cancer rates than
a control group of workers not exposed to high nitrate intakes (Al-Dabbagh et al. 1986, Croll and
Hayes 1988). In an epidemiological study of cases in Ontario, Burch et al. (1987) linked diets and
drinking water high in nitrate to an increased incidence of adult brain tumors. More recently,
population studies in Germany failed to show any correlation between high nitrate content of
drinking water and the incidence of brain tumors (Steindorf et al., 1994). The conflicting evidence
reflects the complexity of the problem. Possible complications in human studies on nitrate
carcinogenicity include the parameters involved in the conversion of nitrate to nitrite; the presence
and concentrations of the precursor compounds to form the N-nitroso compounds; the presence and
concentrations of substances that can be inhibitory to nitrosation, including vitamins C and E; and
possible exogenous sources of nitrosamines (Bouchard et al. 1992).
4.1.2. Animal
Rats given both nitrite and heptamethyleneimine in drinking water, which can react in vivo to
form a nitrosamine, were shown to have an increased incidence of tumors when compared to controls
missing either component (Taylor and Lijinsky 1975).
4.2. INHALATION EXPOSURES
4.2.1. Human
Information on the inhalation carcinogenicity of inorganic or organic nitrate in humans was
unavailable.
4.2.2. Animal
Information on the inhalation carcinogenicity of inorganic or organic nitrate in animals was
unavailable.
4.3. OTHER ROUTES OF EXPOSURE
Information on the carcinogenicity of inorganic or organic nitrate in animals or humans with
other routes of exposure was unavailable.
4.4. EPA WEIGHT-OF-EVIDENCE
4.4.1. Oral
CLASSIFICATION: Unavailable, currently under review (EPA 1994).
4.4.2. Inhalation
CLASSIFICATION: The carcinogenicity of nitrate in humans by the inhalation route has not
been assessed.
4.5. CARCINOGENICITY SLOPE FACTORS
Carcinogenicity assessment is pending (EPA 1994).
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