Can Lead Nitrates Be Absorbed Through The Skin

Toxicity Profiles

Formal Toxicity Summary for NITRATES

Note: Although the toxicity values presented in these toxicity profiles were right 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
i. INTRODUCTION
two. METABOLISM AND DISPOSITION: two.1 Absorption 2.2 DISTRIBUTION 2.3 METABOLISM 2.four EXCRETION
3. NONCARCINOGENIC HEALTH EFFECTS: three.1 ORAL EXPOSURES iii.2 INHALATION EXPOSURES iii.3 OTHER ROUTES OF EXPOSURE 3.4 TARGET ORGANS/CRITICAL EFFECTS
iv. CARCINOGENICITY: 4.1 ORAL EXPOSURES 4.2 INHALATION EXPOSURES 4.3 OTHER ROUTES OF EXPOSURE 4.iv EPA WEIGHT-OF-Testify four.five CARCINOGENICITY Slope FACTORS
5. REFERENCES

August 1995

Prepared By: Andrew Francis, M.South., DABT, Chemic Risk Evaluation Group, Biomedical Ecology Information Analysis Section, Health Sciences Enquiry Division, ^*, Oak Ridge, Tennessee.

Prepared for: Oak Ridge Reservation Environmental Restoration Program.

*Managed by Martin Marietta Energy Systems, Inc., for the U.Due south. Section 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 environs (Ridder and Oehme 1974). Well-nigh of the excess nitrates in the surround originate from inorganic chemicals manufactured for agronomics. 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 chief toxic effects of the inorganic nitrate ion (NO₃ ^-) result from its reduction to nitrite (NO₂ ^-) by microorganisms in the upper alimentary canal (Johnson and Kross 1990, Bouchard et al. 1992). Nitrite ions can also exist produced with organic nitrate exposure; however, the primary issue of organic nitrate intake is thought to exist 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 claret nitrites (Murad 1990). Nitrates and nitrites are excreted primarily in the urine equally nitrates (Hartman 1982).

The primary toxic effect of inorganic nitrates is the oxidation of the iron in hemoglobin by backlog nitrites forming methemoglobin. Infants less than 6 months old comprise the about 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/Fifty can result in methemoglobinemia, particularly in infants less than ii months of age. No cases of methemoglobinemia were reported with drinking water nitrate nitrogen levels of 10 mg/50 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 tin can likewise result in a vasodilatory effect, which tin can complicate the anoxia resulting from methemoglobinemia (Ridder and Oehme 1974). Decreased motor action 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 h2o. However, exposure of rats to 3000 mg nitrite/L in drinking h2o for two years did not issue in any gross or microscopic changes in brain tissue. The data indicate that these primal nervous system effects are not related to methemoglobin levels (Shuval and Gruener 1972).

The importance of the chief 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, tin also produce methemoglobinemia (Andersen and Mehl 1973). Epidemiological studies accept shown that chronic or subchronic exposure to organic nitrates results in the development of tolerance to the cardiovascular effects of these compounds. This credible biocompensation has acquired serious cardiac bug 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 corporeality of inorganic nitrate in the mother's drinking water (Dorsch et al. 1984). Other studies, still, practise non support these associations, and the presence of unidentified teratogenic factors in the surround 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; withal, fetotoxicity attributed to maternal methemoglobinemia was observed at high doses (4000 mg nitrate/50 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 ten mg/Fifty and a LOAEL of 11-twenty mg/50 in drinking h2o, based on clinical signs of methemoglobinemia in 0-3-calendar month-old infants (Bosch et al. 1950, Walton 1951). It is important to notation, even so, that the effect was documented in the nearly sensitive human population and then 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 grade 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). Homo epidemiological studies, withal, have yielded conflicting evidence. Positive correlations between the concentration of nitrate in drinking h2o 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 testify whatsoever correlation between nitrate levels and cancer incidence (Forman 1985, Al-Dabbagh et al. 1986, Croll and Hayes 1988). Nitrate has non been classified every bit to its carcinogenicity by the EPA, although it is under review (EPA 1994).

ane. 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 disquisitional role in the nitrogen bike of soil and water. Nitrates are produced by natural biological and physical oxidations and therefore are ubiquitous in the surround (Ridder and Oehme 1974). Nearly nitrate compounds are stiff 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 furnishings (Stokinger 1982). Near of the excess nitrates in the surroundings 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 college than the plants can use, the excess nitrates appear in the surface and ground waters and are often establish in drinking water, especially in rural agricultural areas served past wells.

Ammonia from fauna waste and septic tanks can be oxidized to nitrate past soil bacteria under aerobic conditions. This can also be a significant source of nitrate in surface and groundwater peculiarly near areas of concentrated fauna 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 atmospheric precipitation, irrigation, vertical flow, dissolved oxygen concentration, and electron donor availability. The groundwater in the agricultural southeastern United States is non very vulnerable to NO_iii contamination, whereas information technology is a serious problem in parts of the midwest (Spalding and Exner 1993). In improver to drinking water, dietary sources of nitrates include compounds used in meat curing processes and nitrates in vegetables. High concentrations of nitrates in vegetables tin reverberate the overapplication of nitrate-containing fertilizers (Ridder and Oehme 1974, Phillips 1971).

Inorganic nitrate tin 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 furnishings observed with backlog nitrate ingestion (Johnson and Kross 1990, Bouchard et al. 1992).

2. METABOLISM AND DISPOSITION

2.ane. ABSORPTION

Inorganic nitrates are primarily absorbed through the gastrointestinal organization equally a mixture of nitrates and nitrites (Bouchard et al. 1992). Some organic nitrates can also exist absorbed unchanged through the peel, alimentary canal, 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 captivated through the respiratory system. The daily nitrate dose/person via respiration in the Los Angeles surface area has been estimated at most 500 µg nitrate-nitrogen (Fan et al. 1987).

2.2. DISTRIBUTION

Nitrates and nitrites are captivated by the various routes into the general blood apportionment and are transported to all parts of the torso. 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 bulwark and affect the fetus (Shuval and Gruener 1972).

ii.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 broad variations including the number and blazon of microflora present in the saliva and the alimentary canal and the pH of the stomach. Gastric pH is college in infants less than six months former and during some gastrointestinal infections (gastroenteritis), thereby favoring the reduction of nitrates (Bouchard et al. 1992). Nitrites absorbed into the claret are chop-chop oxidized to nitrates. Nitrites take been shown to be oxidized to nitrates at the charge per unit of more 50% in ten minutes at a concentration of 2 to 3 nanomoles/L of blood in mice and rabbits. A catalase-hydrogen peroxide system has been proposed every bit the oxidation mechanism (Parks et al. 1981).

Organic nitrates, which are captivated 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 period. Well-nigh 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 than prolonged prophylaxis against angina attacks (Murad 1990).

ii.four. 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 Furnishings

iii.1. ORAL EXPOSURES

3.one.1. Acute Toxicity

3.ane.1.1. Human

Nitrites formed from nitrates past the microflora in the salivary ducts and gastrointestinal arrangement 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 past 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 upshot of inorganic nitrate ingestion, and infants less than six months sometime contain the most sensitive population. This sensitivity is due to the presence of more than easily reduced fetal hemoglobin, a college 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 outcome that tin can further complicate the trouble of methemoglobinemia-induced anoxia (Ridder and Oehme 1974).

Bosch et al. (1950) correlated the incidence of baby methemoglobinemia with the nitrate concentration of drinking water from Minnesota wells. The water was institute to contain from 10 to greater than 100 mg nitrate-nitrogen/L. No cases of methemoglobinemia were found with baby formula fabricated with well h2o containing ten mg or less nitrate-nitrogen/Fifty. The infants were less than 2 months of age in 90% of the methemoglobinemia cases. An epidemiological study past Walton (1951) analyzed all recorded cases of babe methemoglobinemia in 37 states. The occurrence of the condition was constitute to be primarily due to the ingestion of baby formula prepared with nitrate contaminated h2o. A total of 214 cases could be compared to nitrate concentrations in drinking h2o. No cases were recorded with drinking water containing x mg nitrate-nitrogen/L or less. V cases were reported in infants exposed to xi-twenty mg/50, 36 cases in those exposed to 21-50 mg/50, 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 fifteen.8 mg nitrate-nitrogen/L (lxx mg nitrate/L) were compared with 758 infants with water supplies averaging 1.two mg nitrate-nitrogen/50 (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 onetime. Infants with diarrhea had slightly increased methemoglobin levels (1.78%) compared to normal healthy infants (1.xvi%), and infants on a nutrition loftier in vitamin C-rich foods were observed to have slightly lower levels (1.19% compared to 1.xxx% methemoglobin). Only 6% of the children in this report were fed powdered formula fabricated with the tap water. Knotek and Schmidt (1964) reported subclinical methemoglobinemia in infants fed on formula made with nitrate-rich tap water. Nitrate-induced babe methemoglobinemia persists today, especially in rural farming areas where reliance on well water is prevalent. Johnson et al. (1987) reported a fatal instance of methemoglobinemia resulting from the feeding of powdered infant formula prepared with well water that was found to incorporate near 150 ppm nitrate nitrogen to an viii-week-old infant.

Organic nitrates are well known for their vasodilatory effects and have been used for the handling 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 idea 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 too 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. Pinnacle effects ordinarily occur in 60-90 minutes afterward oral assistants and last iii-half-dozen hours (Murad 1990).

three.one.ane.2. Creature

Methemoglobinemia, which tin can lead to anoxia and expiry in extreme cases, is the primary acute toxic effect of oral exposure to inorganic nitrates in all animals tested. Ruminant animals are well-nigh susceptible. This result is extremely variable since it depends on a number of factors including the conversion of nitrates to nitrites; the power of the various animals to enzymatically reduce methemoglobin; the corporeality of vitamins A, C, D, and E in the nutrition; and the nutritional land of the brute. Acute nitrate toxicity in cattle has been reported post-obit the ingestion of h2o containing 500 ppm or more nitrate or feed containing 5000 ppm or more than nitrate. Methemoglobinemia is caused past the conversion of the nitrates to nitrites; however, high levels of nitrates take also been reported to result in gastroenteritis, diarrhea, diuresis, and petechial hemorrhages on the pericardium (Ridder and Oehme 1974). Dogs accept sustained a plasma level of 24 mEq nitrate/Fifty (336 mg nitrate-nitrogen/L) following gavage with sodium nitrate in h2o with no evidence of methemoglobinemia. Slight increases in glomerular filtration rates and renal plasma menses 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 take besides been given 20,000 ppm nitrate in their diet without any apparent adverse furnishings (Ridder and Oehme 1974). Rats have shown no effects afterwards a dietary nitrate concentration of 10,000 ppm (PHS 1962). Pigs are even more resistant to nitrate poisoning but take developed methemoglobinemia subsequently 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 LD_l 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 fourth dimension to death. Oral LD_l values take been reported in rats for propylene glycol 1,two-dinitrate (PGDN) (250 mg/kg) and triethylene glycol dinitrate (TEGDN) (thou mg/kg). PGDN also causes ataxia, languor, and respiratory depression in rats. TEGDN can likewise result in rats beingness hyperactive to auditory and tactile stimulation. Moderate increases in alkaline phosphatase and creatine kinase activities were reported post-obit PGDN treatment (Stokinger 1982, Andersen and Mehl 1973).

3.i.2. Subchronic Toxicity

iii.1.two.ane. Human being

Elevated methemoglobin as a result of subchronic exposure to loftier dietary or drinking h2o nitrate levels has been reported in school age children. Methemoglobin levels 2-v times the levels seen in children with drinking water nitrate levels <x 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/50 (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/50 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 germination 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 h2o containing 22-111 mg nitrate-nitrogen/Fifty compared with 38 children consuming water with <x mg nitrate-nitrogen/L. The children were from 1-8 years of age. Testify was presented in this report 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 as well 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-four age group than in the v-8 age grouping. These differences, however, were not considered biologically significant (Craun et al. 1981). Toxic wellness hazards in humans, except for methemoglobinemia, as a result of subchronic loftier inorganic nitrate exposure are undocumented (Moller et al. 1989).

The subchronic assistants of organic nitrates results in the development of tolerance to the cardiovascular furnishings of these compounds. This issue is contained of entry route and creates limitations in the handling of angina symptoms and potentially serious problems for workers in munitions and dynamite industries (encounter Sect. three.2.2.i.) (Stokinger 1982, Elkayam et al. 1992, Colucci et al. 1981).

iii.1.2.2. Brute

Ane trouble 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 ninety-day study in rats. Groups of 10 male and x female 6-week-onetime Wistar rats were given 100, 300, 1000, and 3000 mg potassium nitrite/L in drinking water. Potassium levels were equated in all groups past the addition of potassium chloride. Both tap water and tap h2o 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, x.nine, 31.ane, 114.4, 241.7 mg/kg/day for males and females, respectively. All animals appeared healthy during the entire thirteen-week study. Decreased food consumption and weight proceeds was seen in males at the high dose, and decreased drinking water consumption was reported in both sexes at the 3000 mg/50 dose and at the k mg/50 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 thou 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 metal 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; still, 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 pregnant decrease in motor activity was measured in a special action box designed for this purpose. Lower doses, 100 mg/Fifty, and yard mg/L did non bear witness the sedative effect. The decreased activity remained after methemoglobin levels were reduced to near normal following vitamin C administration, thereby indicating that the sedative issue may be independent of the methemoglobinemia. A subchronic study measuring brain electrical action was designed to study this effect. Recordings were made using implanted electrodes to measure possible central nervous arrangement furnishings in groups of 3-calendar month-old male person rats receiving 0, 100, 300, and 2000 mg/L sodium nitrite in drinking water. Recordings were made earlier the treatment began, during the 2 months of treatment, and for 4� months post-obit abeyance 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 catamenia. Some recovery was noted in the depression dose group; nonetheless, diffused spikes and abrupt waves remained for the entire menstruation. It was concluded that subchronic sodium nitrite ingestion in drinking h2o may result in persistent encephalon electrical changes in rats (Shuval and Gruener 1972).

three.1.3. Chronic Toxicity

iii.ane.3.1. Human

Toxic health hazards in humans, except for methemoglobinemia, every bit a result of chronic high inorganic nitrate exposure are undocumented (Moller et al. 1989).

The chronic assistants of organic nitrates results in the development of tolerance to the cardiovascular furnishings of these compounds. This effect is independent of entry route and creates limitations in the treatment of angina symptoms and potentially serious bug for workers in munitions and dynamite industries (see Sect. 3.ii.2.1.) (Stokinger 1982, Elkayam et al. 1992, Colucci et al. 1981).

iii.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 ii years. No significant differences in bloodshed, growth, or development were reported. A dose-related increment in methemoglobin levels was observed, just no significant differences were noticed in hemoglobin levels. Histological examination revealed no pathological changes in pancreas, adrenal, or encephalon 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 take received 250-350 mg sodium nitrite/kg body weight/24-hour interval (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, only no other handling-related hematologic or histologic effects were observed.

iii.1.four. Developmental and Reproductive Toxicity

three.1.4.1. Man

An epidemiological report by Dorsch et al. (1984) involved 218 babies born in rural south Australia with congenital malformations. The babies were matched individually equally to hospital, maternal age, parity, and date of birth with an equal number of normal babies. The nitrate concentrations in the h2o sources used in the homes during pregnancy were adamant or estimated. Significantly (>95% confidence level) increased relative take chances for malformations of the central nervous system and musculoskeletal organisation in babies was associated with mothers that used drinking h2o containing 5 - >15 ppm nitrate. Individuals using rainwater (<5 ppm nitrates) for drinking water were given a relative adventure of 1.0; those exposed to water containing 5-15 ppm were found to accept a relative risk of ii.8; and the individuals exposed to h2o containing >fifteen ppm nitrates had a relative take a chance of 4. Neural tube defects had the strongest association (relative risk of 3.5). Unidentified teratogenic factors that might be present in the water, nutrition, or surroundings could not be eliminated as causative or contributing factors.

3.one.4.2. Beast

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 h2o. The dams in the 2000 mg/50 grouping adult 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 most 20% less than the control grouping. Fetal blood nitrite levels following doses of 2.v 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 vi female republic of 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, alive births, and fetal deaths during the handling period were reported. A subtract in the number of litters (ii 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 meaning gross or microscopic lesions were reported in the reproductive organs. In a parallel experiment, iii-half dozen female person republic of guinea pigs per group were given 300, 1000, 2000, 3000, 4000, 5000, or 10,000 ppm potassium nitrite in drinking water corresponding to xviii, 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, ii command) 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 handling, and the total number of alive births. The control grouping was assumed to be 100%. This indicator dropped from lxxx% 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 proceeds 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 plainly non greatly affected since conception occurred at all doses. Wide variations were reported in the results of these two experiments, such as no alive births at 5000 or ten,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 Nutrient and Drug Administration. The oral doses for sodium nitrate given through gestation were upward 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 upwards 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, ten, 23, and 23 mg/kg were given throughout gestation to mice, rats, hamsters, and rabbits, respectively. Although there was no teratogenic response in whatever grouping, an indication of slightly delayed skeletal maturation, specially 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 aforementioned 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 command grouping contained 35 females. No significant decreases in body weight or food consumption were reported from nascency through lactation in whatsoever of the treated groups. No malformations or significant furnishings were noted on reproductive performance at any of the doses tested. Offspring bloodshed, however, was increased at the center and high dose up to day 24 afterward nascence, after which no further increase in deaths occurred. The period of increased mortality was concurrent with a transient flow of decreased weight gain and delayed swimming development. There were no effects reported on postal service-weaning development, weight proceeds, food consumption, mortality, xc-day brain and eye weights, and tests of developed behavior (Vorhees et al.1984).

iii.1.5. Reference Dose

3.1.v.1. Subchronic

A subchronic RfD for nitrates is not available.

3.1.5.2. Chronic

ORAL RfD_c: 1.sixty mg/kg/day (EPA 1994)

Doubtfulness FACTOR: 1

MODIFYING Gene: 1

NOAEL: 10 mg nitrate-nitrogen/L of drinking h2o

LOAEL: 11-20 mg nitrate-nitrogen/50 of drinking water

Confidence:

Study: High

Data Base of operations: High

RfD: Loftier

VERIFICATION Appointment: 08/22/90

Master STUDY: Walton, 1000. (1951); Bosch, H.One thousand. et al. (1950)

COMMENTS: The NOAEL was obtained from the amount of nitrate-nitrogen in well water used to gear up formula for infants. Information technology is based on the lack of methemoglobin germination in the most sensitive man group; therefore, no doubtfulness gene was deemed necessary. The calculations are based on the consumption of 0.64 50 of water/mean solar day by a 4-kg infant and are given in mg nitrate-nitrogen (1 mg nitrate-nitrogen = four.4 mg nitrate). Come across Sects. 3.one.ane.1 and 3.one.3.ane for farther word of the primary studies. An RfD for organic nitrates as a group is non available.

3.2. INHALATION EXPOSURES

3.2.i. Acute Toxicity

3.ii.1.ane. Human

Atmospheric nitrates and other nitrogen oxides specially 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 astute inhalation toxicity of inorganic nitrates in humans was non available.

Vasodilatory effects have been observed following inhalation exposure to diverse organic nitrates. Nitroglycerine and ethylene glycol dinitrate exposure (two.0 mg/one thousand³ ethylene glycol dinitrate for 1 to three minutes) resulted in a drop in blood pressure level and severe headaches in four out of v volunteers tested. General fatigue and hurting in the chest, abdomen, and extremities were also reported. Only three out of 7 volunteers experienced mild or transitory headaches at 0.five mg/grand³ ethylene glycol dinitrate (Carmichael and Lieben 1963, Stokinger 1982).

3.two.i.ii. Animal

Information on the acute inhalation toxicity of inorganic nitrates in animals was non available. However, an LD_l of 1047 mg/m³ has been reported in mice for propylene glycol 1,2-dinitrate (PGDN) (Andersen and Mehl, 1973; Stokinger, 1978). In rats, nevertheless, exposure to PGDN for 4 hours to 1350 mg/m³ (200 PPM) produced no deaths or overt signs of toxicity subsequently 14 days following treatment although the methemoglobin values increased from a mean of half-dozen to 23.five% (Jones et al. 1972, Stokinger 1978).

3.2.two. Subchronic Toxicity

3.2.2.ane. Human

Information on the subchronic inhalation toxicity of inorganic nitrates in humans was not available. Still, 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 discipline to sudden and sometimes fatal eye attacks. This effect was documented in at least 38 dynamite workers 30-48 hours later on absence from piece of work during 1926 to 1961 (Carmichael and Lieben 1963, Stokinger 1982).

3.ii.ii.two. Animal

Information on subchronic inhalation toxicity of inorganic nitrates in animals was non 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.v, or 31.4 ppm PGDN (0, 67, 108, and 236 mg/m³, respectively) continuously for 90 days. The animals did non 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.four 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 fourteen 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 jail cell infiltrates and focal necrosis were observed in the livers of all the high dose guinea pigs and in 4/9 of the loftier dose monkeys. Atomic number 26 positive deposits were besides reported in the kidneys and spleens of eye 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 xiv.v ppm (Jones et al. 1972).

3.2.3. Chronic Toxicity

3.two.iii.ane. 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 noncombatant Navy personnel involved in torpedo maintenance procedures. The duration of exposures ranged from months to 11 years. The PGDN concentration during exposure ranged from about 0 to 0.22 ppm with an average concentration of 0.03 ppm. The neurological clutter 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 middle movement velocity and latency were reported. There was no prove; however, that whatsoever permanent neurological impairment resulted from repeated daily exposures for up to xi years (Stokinger 1982) (meet Sect. 3.2.2.ane)

3.2.3.ii. Animal

Data on the chronic inhalation toxicity of nitrates in animals was non available.

iii.2.four. Developmental and Reproductive Toxicity

3.2.4.one. Human

Data on developmental and reproductive toxicity in humans resulting from inhalation exposure to nitrates was non available.

three.2.four.2. Animal

Data on developmental and reproductive toxicity in animals resulting from inhalation exposure to nitrates was not available.

3.2.5. Reference Concentration

iii.2.five.1. Subchronic

A subchronic RfC for inhalation exposure to inorganic nitrate is not available at this fourth dimension.

3.2.five.2 Chronic

A chronic RfC for inhalation exposure to inorganic nitrate is non available at this fourth dimension.

3.3. OTHER ROUTES OF EXPOSURE

iii.3.1. Acute Toxicity

3.3.i.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 nigh user-friendly 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. iii.1.1.1).

3.3.one.2. Creature

Data 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 furnishings have been reported. A dose of three.5 g/kg/day PGDN applied to the backs of rabbits resulted in the death of six of 11 treated animals with a mean time to death of sixteen days (Andersen and Mehl 1973, Stokinger 1982).

3.3.2. Subchronic Toxicity

3.three.ii.1. Human being

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 forth with inhalation assimilation to control worker exposure (Einert et al. 1963, Stokinger 1982) (encounter Sect. iii.two.2.one).

3.3.2.2 Creature

Information on the subchronic toxicity of inorganic nitrates past other routes of exposure in animals was unavailable. Doses of ane, 2, and four g/kg/mean solar day of propylene glycol ane,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 two 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 proceeds by the 20th mean solar day. In the high dose group, 13 of 14 animals died inside the outset 6 days. Internal organs were reported to appear night, blue-grayness (Andersen and Mehl 1973, Stokinger 1982).

3.3.3 Chronic Toxicity

3.three.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.ii.2.1).

three.3.3.2 Animal

Data on the chronic toxicity of nitrates past other routes of exposure in animals was unavailable.

three.3.four. Developmental and Reproductive Toxicity

three.iii.iv.1. Human

Data on the developmental and reproductive toxicity of nitrates past other routes of exposure in humans was unavailable.

three.3.4.2 Animal

Data on the developmental and reproductive toxicity of nitrates by other routes of exposure in humans was unavailable.

three.4. TARGET ORGANS/Disquisitional Effects

three.4.i. Oral Exposures

3.4.1.1. Primary Target Organ(due south)

ane. 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 too be the result of organic nitrate ingestion.

2. Cardiovascular organisation: vasodilatory effect on blood vessels. Organic nitrates are used as safety agents for angina patients. Inorganic nitrate is much less effective just has as well been observed to cause vasodilation, which can complicate the adverse effects of methemoglobinemia.

three.four.1.2. Other Target Organ(s)

Fetus: Studies indicate a possible fetotoxic effect at very high doses of inorganic nitrate. In that location are conflicting studies on this upshot, which may involve the in vivo production of Due north-nitroso compounds.

3.4.2. Inhalation Exposures

3.4.2.i. Primary Target Organ(s)

Cardiovascular organisation: The vasodilatory event of organic nitrates is contained of entry route.

3.4.2.2. Other Target Organ(s)

Claret: Methemoglobinemia can occur with organic nitrate inhalation.

3.4.iii Other Routes of Exposure

iii.4.iii.1 Master target organ

Cardiovascular organisation: The vasodilatory effect of organic nitrates is contained of the entry route, which tin include dermal or sublingual routes.

3.iv.3.2 Other target organ

Blood: Methemoglobinemia tin can occur with organic nitrate following sublingual or dermal absorption.

4. CARCINOGENICITY

four.1. ORAL EXPOSURES

4.1.one. Human being

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 course carcinogenic N-nitroso compounds (Bouchard et al. 1992, Taylor and Lijinsky 1975). Human population studies have yielded conflicting results. Studies in Columbia and Allborg, Kingdom of 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 boondocks 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 establish exposed to loftier 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 h2o high in nitrate to an increased incidence of adult brain tumors. More than recently, population studies in Germany failed to bear witness whatsoever 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 trouble. Possible complications in human being 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 Eastward; and possible exogenous sources of nitrosamines (Bouchard et al. 1992).

iv.ane.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).

four.2. INHALATION EXPOSURES

4.ii.i. Human

Information on the inhalation carcinogenicity of inorganic or organic nitrate in humans was unavailable.

four.two.2. Animal

Data on the inhalation carcinogenicity of inorganic or organic nitrate in animals was unavailable.

iv.iii. OTHER ROUTES OF EXPOSURE

Data on the carcinogenicity of inorganic or organic nitrate in animals or humans with other routes of exposure was unavailable.

4.iv. EPA WEIGHT-OF-Prove

iv.4.one. Oral

CLASSIFICATION: Unavailable, currently under review (EPA 1994).

4.iv.2. Inhalation

Classification: The carcinogenicity of nitrate in humans by the inhalation road has not been assessed.

4.5. CARCINOGENICITY SLOPE FACTORS

Carcinogenicity assessment is pending (EPA 1994).

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