Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 171
5 Methyl Bromide1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory 1 This document was prepared by the AEGL Development Team composed of Sylvia Talmage (Summitec Corporation), Julie M. Klotzbach (Syracuse Research Corporation), Chemical Manager George Rodgers (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Envi- ronmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are sci- entifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 171
OCR for page 172
172 Acute Exposure Guideline Levels effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic re- sponses, could experience the effects described at concentrations below the cor- responding AEGL. SUMMARY Methyl bromide is a colorless, nonflammable gas, with no taste or odor properties at low concentrations. Methyl bromide is currently used as a fumigant for buildings and soil and as a methylation agent in industry. Methyl bromide is an effective herbicide, rodenticide, nematicide, insecticide, bactericide, and fun- gicide. In the past, it was used as a refrigerant and fire extinguisher. Worldwide consumption of methyl bromide in 1996 was approximately 68 thousand metric tons. It is available as a liquefied gas in steel cylinders or cans. Although numerous reports of accidental exposure of humans to methyl bromide that resulted in neurotoxicity or deaths are available in the literature, reliable information on exposure concentrations was not available. Acute, re- peat-exposure, subchronic, and chronic studies, primarily with rats and mice, were available. Human case reports and controlled animal studies document that the central nervous system (CNS) is the primary target of methyl bromide. Neu- rotoxic symptoms can be delayed for several hours. Extremely high concentra- tions also produce lung edema. The mechanism-of-action of monohalomethanes is not completely understood, but could involve metabolism via the glutathione- S-transferase (GST) pathway to products that alkylate or inactivate cellular pro- teins. Species with higher cellular concentrations of GST appear to be more sen- sitive to the effects of methyl bromide than those with lower concentrations. The same is true for humans because of genetic polymorphisms of GST in the human population.
OCR for page 173
173 Methyl Bromide Data from animal studies were available on lethal and sublethal concentra- tions, neurotoxicity, developmental and reproductive effects, genotoxicity, and potential carcinogenicity. Although genotoxicity studies show that alkylation of DNA and proteins occurs, carcinogenicity has not been established in chronic studies with rats and mice. The dose-response curve for lethality is steep and the margin of safety between no-effect and lethal values is small. Data from rat and mouse studies show that the concentration-response curve for 50% lethality (LC50 values) over exposure durations of 3.5-480 min can be determined with the equation C1.2 × t = k. Methyl bromide has no odor or irritation properties at concentrations be- low those that define the AEGL-2 values. Therefore, AEGL-1 values were not established. The AEGL-2 values are based on the no-observed-adverse-effect level (NOAEL) for neurotoxicity, as evidenced by a lack of clinical signs in studies with rats and dogs. The weight-of-evidence from those studies indicates that 200 ppm of methyl bromide for 4 h is the threshold concentration for neurotoxicity (Hurtt et al. 1988; Hastings 1990; Japanese Ministry of Labour 1992; Newton 1994a). Reversible impairment of olfactory function (lesions of the olfactory epithelium) was observed in the rat (Hurtt et al. 1988; Hastings 1990; Japanese Ministry of Labour 1992). These lesions are specific to the nasal olfactory epi- thelium of the rat, based on nasal air flow patterns (Bush et al. 1998; Frederick et al. 1998), so it is unlikely that such lesions would occur in primates at the same exposure concentration and duration. Because uptake of methyl bromide is greater in rodents than in humans (based on comparative respiratory rates and comparisons with methyl chloride) and because GST concentrations in rodents are greater than in humans (resulting in more rapid production of toxic metabo- lites), an interspecies uncertainty factor of 1 was applied. Humans differ in their capacity to metabolize the related chemical methyl chloride; but, toxicologi- cally, the difference is thought to be less than 3-fold (Nolan et al. 1985). There- fore, an intraspecies uncertainty factor of 3 was applied. The resulting 4-h value of 67 ppm was time scaled to the other exposure durations using the equation Cn × t = k, with n = 1.2. The value of n was based on lethality studies in rats. The mechanism for delayed neurotoxic effects (AEGL-2) and death (AEGL-3) are assumed to be the same. Because the time-scaled 8-h AEGL-2 value of 37 ppm is close to the chronic NOAEL of 33 ppm for mice (NTP 1992), is less than the 4-day NOAEL of 55 ppm for clinical signs and tissue lesions in dogs (Newton 1994a), and less than the 36-week NOAEL of 55 ppm for neurobehavioral pa- rameters and nerve conduction velocity in rats (Anger et al. 1981), the 8-h value was set equal to the 4-h AEGL-2 value of 67 ppm. Because of differences in methyl-halide metabolism between mice and other rodents and the greater sensitivity of mice to the structurally-similar chemical methyl chloride (metabolism is also by the glutathione [GHS] path- way), the mouse was not considered an appropriate model from which to derive AEGL values for methyl bromide. The AEGL-3 values were based on the BMCL05 (benchmark concentration, 95% lower confidence limit with 5% re-
OCR for page 174
174 Acute Exposure Guideline Levels sponse) of 701 ppm in a 4-h exposure study of rats (Kato et al. 1986). The BMCL05 was also the highest nonlethal value in the study. An interspecies un- certainty factor of 1 and an intraspecies uncertainty factor of 3 were applied, as was done in the calculation of AEGL-2 values. For time scaling (Cn × t = k), n was set equal to 1.2, based on lethality data in the rat. Because uptake of methyl bromide is greater in rodents than in humans (based on comparative respiratory rates and comparisons with methyl chloride) and because GST concentrations in rodents are higher than in humans (resulting in more rapid production of toxic metabolites), an interspecies uncertainty factor of 1 was considered sufficient. Humans differ in their capacity to metabolize methyl bromide, but toxicologi- cally the difference is not thought to be greater than 3-fold (Nolan et al. 1985). An intraspecies uncertainty factor of 3 is supported by the steep dose-response curve for lethality by methyl bromide, which indicates that there might be little intraspecies variation. Furthermore, a larger uncertainty factor would result in values that would be near the AEGL-2 values. Therefore, an intraspecies uncer- tainty factor of 3 was considered sufficient. The 8-h AEGL-3 value of 130 ppm is supported by a repeat-dose study in which dogs exposed to methyl bromide at 156 ppm for 7 h/day did not exhibit severe clinical signs until the third day of exposure (Newton 1994a). There were no remarkable histopathologic lesions at autopsy. The AEGL values for methyl bromide are presented in Table 5-1. TABLE 5-1 Summary of AEGL Values for Methyl Bromide End Point Classification 10 min 30 min 1h 4h 8h (Reference) NRa NRa NRa NRa NRa AEGL-1 (nondisabling) AEGL-2 940 ppm 380 ppm 210 ppm 67 ppm 67 ppm NOAEL for (disabling) (3,657 (1,478 (817 (261 (261 clinical signs mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) in rats and dogs (Hurtt et al. 1988; Hastings 1990; Japanese Ministry of Labour 1992; Newton 1994a) AEGL-3 3,300 ppm 1,300 ppm 740 ppm 230 ppm 130 ppm BMCL05 in (lethal) (12,837 (5,057 (2,879 (895 (506 rats (Kato et mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) al. 1986) a Numerical values are not recommended because the data indicate that toxic effects might occur below the odor threshold for methyl bromide. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects. Abbreviations: BMCL05, benchmark concentration, 95% lower confidence limit with 5% response; NOAEL, no-observed-adverse-effect level; NR, not recommended.
OCR for page 175
175 Methyl Bromide 1. INTRODUCTION Methyl bromide is a colorless, highly volatile gas that exists as a liquid be- low 3.6°C. It is heavier than air. Methyl bromide is nonflammable over a wide range of concentrations in air, and poses practically no fire hazard. These physi- cal properties result in excellent penetration properties and make it a good fumi- gant. Additional chemical and physical properties are listed in Table 5-2. Methyl bromide is ubiquitous in the environment, because it is generated naturally by oceans, biomass burning, and plants. For industrial purposes, methyl bromide is produced by direct bromination of methane and by the hydrobromina- tion of methanol (Davis et al. 1977; O’Neil et al. 2001; Ioffe and Kampf 2002). Sulfur or hydrogen sulfide may be added as reducing agents to the methanol and sodium bromide. Anthropogenic methyl bromide is used mainly as a fumigant. It is an effective herbicide, rodenticide, nematicide, insecticide, bactericide, and fun- gicide, and has been used commercially in the United States for most of the twen- tieth century for the fumigation of soil, structures (such as warehouses), and food commodities, as well as for quarantine purposes (Duafala and Gillis 1999). Ap- proximately 77% is used in preplanting fumigation of soil (IPCS 1995). In 1995, between 25,000 and 27,000 tons of methyl bromide were applied as a fumigant in the United States. Methyl bromide is also used as an intermediate for the manufac- ture of pharmaceuticals, in ionization chambers, for degreasing wool, and for ex- tracting oils from nuts, seeds, and flowers (O’Neil et al. 2001; Ioffe and Kampf 2002). In the past, methyl bromide was used in fire extinguishers, as a refrigerant, and even as an anesthetic agent in dentistry (Alexeeff and Kilgore 1983). In 1996, world consumption of methyl bromide was 68.4 thousand metric tons (Ioffe and Kampf 2002). The U.S. Environmental Protection Agency (EPA 2011) lists the production range of methyl bromide as 16.4 million pounds in 2003 and 1.8 in 2010. Production has decreased because of environmental con- cerns about depletion of the ozone layer by such chemicals. Methyl bromide is easily liquefied, and is commercially available as a liq- uefied gas contained in steel cylinders or cans, usually under its own pressure of about two atmospheres (Braker and Mossman 1980; IPCS 1995; Duafala and Gillis 1999). Nitrogen or carbon dioxide may be added before shipment to per- mit rapid ejection at low temperatures. Formulations for soil fumigation contain chloropicrin (2%) or amyl acetate (0.3%) as warning agents. 2. HUMAN TOXICITY DATA 2.1. Odor Threshold Methyl bromide has almost no odor or irritating effect, even at physiologi- cally hazardous concentrations (Reid 2001). Reported odor thresholds vary from 20 to 1,000 ppm (Van den Oever et al. 1982; Sittig 1985; Ruth 1986). The odor of methyl bromide has been described as sweetish and similar to chloroform
OCR for page 176
176 Acute Exposure Guideline Levels (O’Neil et al. 2001), musty or fruity at concentrations above 1,000 ppm (Mar- raccini et al. 1983; ATSDR 1992), or faintly acrid at around 500 ppm (Hustinx et al. 1993). Methyl bromide has a burning taste, and contact with the skin may cause frostbite (O’Neil et al. 2001). When methyl bromide is used as a structural fumigant, it may react with sulfur-containing materials in buildings to produce a persistent odor (Anger et al. 1986). The addition of 2% chloropicrin as a warning agent (a potent lacrimator sensed at 1.3 ppm) to some preparations of methyl bromide intended for fumiga- tion (IPCS 1995; Reid 2001) is of limited safety efficacy, because chloropicrin vapor typically disappears before the methyl bromide vapor dissipates. 2.2. Toxicity and Neurotoxicity The toxicity of methyl bromide has been reviewed by EPA (1980, 1992), Alexeeff and Kilgore (1983), ATSDR (1992), IPCS (1995), Yang et al. (1995), Reid (2001), OECD SIDS (2002), and HSDB (2010). A review of the literature published in 1983 documented 115 fatalities, 523 systemic illnesses, and 242 skin and eye injuries on a worldwide basis (Alexeeff and Kilgore 1983). TABLE 5-2 Chemical and Physical Properties of Methyl Bromide Parameter Value Reference Synonyms Bromomethane, monobromomethane, O’Neil et al. 2001 methyl fume, isobrome CAS registry no. 74-83-9 O’Neil et al. 2001 Chemical formula CH3Br O’Neil et al. 2001 Molecular weight 94.95 O’Neil et al. 2001 Physical state Colorless gas (above 4°C) O’Neil et al. 2001 Melting point -93.7°C Reid 2001 Boiling point 3.56°C Reid 2001 Density O’Neil et al. 2001 Vapor 3.97 g/L at 20°C (air = 1) Liquid 1.73 g/mL at 4°C (water = 1) Solubility 1.75 g/100 g in water at 20°C, 748 mm Hg O’Neil et al. 2001 Vapor pressure 1,420 mm Hg at 20°C O’Neil et al. 2001 Flammability limits Practically nonflammable; flame Reid 2001 propagation range is 13.5-14.5% by volume in air; ignition temperature is 537°C; burns in O2 1 ppm = 3.89 mg/m3 at 25°C Conversion factors Reid 2001 1 mg/m3 = 0.257 ppm
OCR for page 177
177 Methyl Bromide Most cases of accidental exposures have involved manufacturing or pack- aging operations, use of fire extinguishers containing methyl bromide, or fumi- gation activities. Exposures at high concentrations may occur during fumigation activities, especially when methyl bromide is first released to the environment after fumigation ends, or when fumigated areas are not properly ventilated. When methyl bromide is used as a storage fumigant, its concentrations usually range from 4,112 to 25,700 ppm for 2-3 days; higher concentrations are required to kill eggs and pupae. Accidental inhalation exposure incidents have occurred during atmospheric inversions, which prevent methyl bromide gas from rising and dispersing into the troposphere, or when children, adults, or animals enter sealed, fumigated structures. Most human exposure data on methyl bromide are from its use as an agricultural fumigant. It is applied to soil under plastic sheets or used in space fumigation under tarpaulins. It is also applied to a variety of agricultural commodities in specially designed fumigation chambers. Worker exposure may result from leaks in the plastic sheets or tarpaulin or from failure to allow adequate time for the methyl bromide to dissipate following fumigation (NIOSH 1984). The data from these accidental exposures are generally old, and concentration measurements were either not made or conducted using outdated analytic techniques. Regardless, estimates of concentrations leading to human deaths range from 1,600 to 60,000 ppm, depending on duration of exposure (ATSDR 1992). The primary target of toxicity in humans accidentally or occupationally exposed to methyl bromide is the CNS (Alexeeff and Kilgore 1983; O’Neil et al. 2001). Symptoms of overexposure by inhalation to methyl bromide are head- ache, visual disturbance, vertigo, nausea, vomiting, anorexia, irritation of the respiratory system, abdominal pain, malaise, muscle weakness, incoordination, slurring of speech, staggering gait, hand tremor, convulsions, mental confusion, dyspnea, pulmonary edema, coma, and death from respiratory or circulatory collapse (O’Neil et al. 2001). Severe exposures may result in bronchial or pul- monary inflammation and pulmonary edema, which may not appear for 24 h or more after exposure. Death may occur from respiratory or cardiovascular failure. Exposure to methyl bromide has been known to adversely affect the kidneys, eyes, liver, and skin. Methyl bromide is an insidiously-acting chemical because of its lack of odor or immediate irritating properties at low concentrations (Reid 2001), and because signs of exposure are often delayed. In severe cases of poi- soning, recovery can be protracted, with persisting neurologic problems. Inhalation is the most significant route of exposure to methyl bromide, al- though skin absorption does occur. Standard protective clothing did not protect fumigators wearing respirators from developing skin lesions during two 20-min exposures at concentrations estimated to be about 9,000 ppm (Zwaveling et al. 1987; Hezemans-Boer et al. 1988). Absorption of methyl bromide was indicated by bromide concentrations in the blood. Numerous case reports of methyl bromide exposure are described in the literature. In these reports, concentrations are either unknown or were measured or calculated after the incident. Analytic methods used in older studies, such as
OCR for page 178
178 Acute Exposure Guideline Levels colorimetry, have limited sensitivity. For example, Watrous (1942) describes both mild symptoms and more severe symptoms of nausea, vomiting, headache, and skin lesions in workers exposed for up to 2 weeks. Measurements of methyl bromide were generally less than 35 ppm, but exposures were based on a color detection method (methanol torch) with a lower detection limit of 35 ppm. Ana- lytic methods for detecting higher concentrations involved flame colorimetry, an imprecise method. The exposures were complicated by accidents and routine dermal contact with the cooled liquid. In a factory where fire extinguishers were filled with methyl bromide, one death occurred (accompanied by convulsions) and another employee suffered less severe effects (Tourangeau and Plamondon 1945). Measurements taken at 30 min and 1 h had methyl bromide at concentra- tions of 297-390 ppm in front of the hood, where filling took place. Three addi- tional nonfatal cases are described as examples below. Two of these cases also measured or estimated concentrations after the event. These cases are followed by a description of study of neurologic changes in methyl bromide applicators. Because over 50 cases of methyl-bromide poisoning were reported in date processing and packaging plants in Southern California, Ingram (1951) and Johnstone (1945) conducted a series of surveys in 40 plants. Fumigation took place in a chamber that opened directly into the employee’s workroom. Appro- priate amounts of methyl bromide were released from 50-pound drums or by using 2-pound or 1-pound cans. Exhaust systems were generally inadequate to dissipate the fumes following fumigation. Tests in these plants showed methyl bromide at concentrations up to 100 ppm in the general workroom air, up to 500 ppm near the walls of ineffectively sealed chambers, and over 1,000 ppm at the breathing zone of workers entering the fumigation chamber. Semiquantitative measurements were made with a halide torch, and average concentrations over time were measured colorimetrically with a halogenated-hydrocarbon apparatus. Hustinx et al. (1993) described an accidental exposure during greenhouse fumigation. Nine individuals were inadvertently exposed while working in an enclosed area adjacent to the area being fumigated. The areas were separated by a poorly sealed partition. Three weeks earlier, the portion of the greenhouse in which the accident occurred had been fumigated with methyl bromide at 200 g/m2 (five times greater than the legally allowable concentration of 40 g/m2). At that time, two of the five workers in the nonfumigated section experienced nau- sea, vomiting, and dizziness. During fumigation, the highest methyl bromide concentration (25 ppm) was measured near the partition in the nonfumigated portion of the greenhouse. Measurements were made with Drager gas detectors (lower detection limit of 3-5 ppm). On the day before the accident (3 weeks after fumigation of the first greenhouse section), all nine workers were in the nonfu- migated portion of the greenhouse for an average of 6 h (range of 4-8 h). Most workers experienced nausea and headache that day, and two of them stayed home the following day. The next day, fumigation was carried out in the previ- ously nonfumigated section of the greenhouse, while the laborers worked in the section that had been fumigated 3 weeks earlier. After spending 2 h at work, all but one of the remaining seven workers experienced sudden and almost simulta-
OCR for page 179
179 Methyl Bromide neous nausea, dizziness, and vomiting (the one exception experienced only a slight burning sensation in the throat). All seven workers left the greenhouse and went home. Within 2 h, two workers developed twitching of all limbs followed by generalized and continuous seizure activity, necessitating the induction of a sodium thiopental coma to stop the seizures. Methyl bromide concentrations ranged from 200 ppm near the partition to 150 ppm at the far end of the nonfu- migated section 5 h after the accident, suggesting that the actual exposure was ≥200 ppm. Three days after admission to the hospital, chest x-rays revealed uni- lateral infiltration and pleural effusion, which subsided over the next 10-14 days. The thiopental coma was withdrawn after 3 weeks from the two severely af- fected patients, who then manifested persistent signs of axonal neuropathy. These signs improved only slightly over 6 months. Both workers had exhibited similar rises in serum alanine aminotransferase, aspartate aminotransferase, and lactic acid dehydrogenase activities, which peaked on the sixth day after admis- sion and returned to normal before the thiopental treatment was discontinued, suggesting the increased activities reflected a methyl-bromide-related hepatic effect. The other seven patients experienced remarkably uniform signs, which included headache, nausea, and a “floating” sensation. Within 19 days after the accident, all residual complaints had disappeared in these seven patients. An unused, dry set of drainage pipes that crossed the entire length of both green- house sections was identified as the most likely major cause of the spread of methyl bromide to the nonfumigated section. In the third case report, two fumigation workers entered a fumigated build- ing in which the measured concentration (gas chromatography) was 4,370 ppm (Deschamps and Turpin 1996; Garnier et al. 1996). The workers wore cartridge respirators, which are saturable within a few minutes at that concentration (autonomous air flow masks are obligatory under these circumstances). The workers failed to wait until the concentration had decreased to the recommended level of 5 ppm. Both workers opened windows and doors in the nine-floor build- ing over a period of 45 min to 1 h. During the 100-mile journey home, both workers experienced dizziness, fatigue, nausea, vomiting, chest pain, and short- ness of breath. They were admitted to a hospital where the condition of the one improved rapidly. The other patient experienced convulsions, ataxia, and kidney failure. His tremors and ataxia were still present 5 months later (he experienced permanent neurologic damage). Bromide concentrations in the blood measured 40-48 h after admittance to the hospital were 47 and 156 mg/L in the first and second patient, respectively. Inspection of the charcoal cartridges of the respira- tors showed a concentration bromide greater than 10 mg/g; the highest concen- tration was found in the cartridge of the most injured worker. Verberk et al. (1979) described bromine in the blood, electroencephalo- graphic (EEG) disturbances, liver function (serum transaminases), serum pro- teins, and neurologic changes in 33 men engaged in soil disinfection inside greenhouses. Duration of employment ranged from a few months to 11 years. The amount of methyl bromide applied within the past year ranged from 1,500 to 6,000 kg. The relationship between different factors was based on a product-
OCR for page 180
180 Acute Exposure Guideline Levels moment correlation coefficient or Student’s t-test. No relationship was found between bromine concentration in blood and subjective symptoms, general neu- rologic deficits, or serum proteins. Slight EEG changes and a small increase in serum transaminases were related to blood concentrations of bromine. The au- thors considered the effects marginal. 2.3. Developmental and Reproductive Toxicity No studies were found on reproductive or developmental effects in hu- mans after inhalation of methyl bromide. 2.4. Genotoxicity Liquid methyl bromide tested positive for sister chromatid exchanges (SCE) in in vitro tests with human lymphocytes (Tucker et al. 1986; Garry et al. 1990). When people who are GSH conjugators and nonconjugators were tested, methyl bromide tested positive for SCE in lymphocytes from GSH nonconjuga- tors but not in lymphocytes from GSH conjugators (Hallier et al. 1990). See Section 4.4.2 for an explanation of human variability in GSH conjugation. 2.5. Carcinogenicity EPA has classified methyl bromide as a Group D carcinogen, “not classi- fiable as to human carcinogenicity” (EPA 1992). On the basis of animal studies, the National Institute for Occupational Safety and Health characterizes methyl bromide as a “potential occupational carcinogen” (NIOSH 2010). The Interna- tional Agency for Research on Cancer (IARC 1999) has determined that there is limited evidence for carcinogenicity in animals and inadequate evidence in hu- mans. The overall evaluation states that methyl bromide “is not classifiable as to its carcinogenicity to humans” (Group 3). The American Conference of Gov- ernmental Industrial Hygienists (ACGIH 2004) classifies methyl bromide as A4, “not classifiable as a human carcinogen.” Alavanja et al. (2003) investigated the link between exposure to 45 com- mon agricultural pesticides and the eventual development of prostate cancer in a cohort of 55,332 initially healthy male pesticide applicators in Iowa and North Carolina. The data were collected by self-administered questionnaires that were completed at enrollment (1993-1997). The incidence of cancer in the general population was determined through cancer registries between the time of en- rollment through the end of 1999, and a prostate cancer standardized incidence ratio was computed for the cohort. Odds ratios were determined for individual pesticides and for pesticide use patterns identified by the use of factor analysis. Over a period of 4 years, 566 of the men developed prostate cancer, a number greater than the total number of expected prostate cancer cases (494.5; odds ra-
OCR for page 181
181 Methyl Bromide tio of 1.14), based on state age-adjusted incidence rates. Among the 45 pesti- cides studied, only methyl bromide use showed a statistically significant expo- sure-response trend. The data suggested that if methyl bromide is responsible for the increased incidence of prostate cancer, this effect occurs only in those indi- viduals with relatively frequent exposure. Limitations of this study acknowl- edged by the authors include the fact that the method of data collection was sub- ject to significant recall bias, particularly in participants who had been exposed to the pesticides many years prior to the study. In addition, no direct measure- ments of pesticide exposure were obtained for the study. The follow-up period for the study was relatively short (an average of 4.3 years), precluding the evaluation of time-dependent exposures and risk. Finally, the authors acknowl- edged that the finding of increased risk of prostate cancer from the combined effect of exposure to several pesticides and a family history of prostate cancer was somewhat unexpected, and that the study must be replicated before any rec- ommendations can be made. 2.6. Summary Methyl bromide has been responsible for many occupational poisoning in- cidents, reflecting its wide use as a fumigant. Although many occupational and accidental exposures to methyl bromide have occurred, few cases have accu- rately documented exposure concentrations or durations. Methyl bromide is practically odorless, even at lethal concentrations. Descriptive symptoms indi- cate methyl bromide acts on the CNS (e.g., headache, visual disturbance, mental disturbance, nausea, vomiting) and directly on the lungs (lung edema). Case reports indicate that daily exposure to methyl bromide at 35 ppm (with possible dermal contact) and acute exposures to several hundred ppm can cause mild to severe symptoms. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality Early studies with several species of mammals were carried out by Irish et al. (1940) and Sayers et al. (1929). These reports lack details, used obsolete ana- lytic methods, and used visual inspection rather than standard neurotoxicity tests to assess behavioral deficits. The studies are described here for completeness, but were not considered in the determination of AEGL values. Rats and rabbits were given single exposures to methyl bromide at a series of concentrations which resulted in either 100% mortality or 100% survival (Irish et al. 1940). The postexposure observation period was 4 weeks. Exposure of rats to methyl bro- mide at 13,000, 5,200, 2,600, 520, 260, 220, or 100 ppm resulted in 100% mor- tality in 6, 24, and 42 min and 6, 22, 26, and >26 h, respectively. Survival was 100% when exposures at the respective concentrations were 3, 6, and 25 min
OCR for page 222
222 Acute Exposure Guideline Levels Nolan, R.J., D.L. Rick, T.D. Landry, L.P. McCarty, G.L. Agin, and J.H. Saunders. 1985. Pharmacokinetics of inhaled methyl chloride (CH3Cl) in male volunteers. Fundam. Appl. Toxicol. 5(2):361-369. Norris, J.C., C.D. Driscoll, and J.M. Hurley. 1993. Methyl Bromide: Ninety-day Vapor Inhalation Neurotoxicity Study in CD rats. Project No. 92N1172. Bushy Run Re- search Center, Export, PA. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. NTP (National Toxicology Program). 1992. Toxicology and Carcinogenesis Studies of Methyl Bromide (CAS Reg. No. 74-83-9) in B6C3F1 Mice (Inhalation Studies). Technical Report No. 385. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC [online]. Available: http://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr385.pdf [accessed Jan. 30, 2012]. OECD SIDS (Organization for Economic Co-operation and Development, Screening Information Data Set). 2002. Methyl Bromide (CAS No. 74-83-9). SIDS Initial Assessment Report. United Nations Environment Programme [online]. Available: http://www.chem.unep.ch/irptc/sids/OECDSIDS/Methyl_bromide.pdf [accessed Jan. 31, 2012]. O’Neil, M.J., A. Smith, and P.E. Heckelman, eds. 2001. The Merck Index: An Encyclo- pedia of Chemicals, Drugs, and Biologicals, 13th Ed. Whitehouse Station, NJ: Merck. Parkinson, A. 2001. Biotransformation of xenobiotics. Pp. 133-224 in Casarett & Doull’s Toxicology, The Basic Science of Poisons, 6th Ed., C. Klaassen, ed. New York: McGraw Hill. Peter, H., S. Deutschmann, C. Reichel, and E. Hallier. 1989. Metabolism of methyl chlo- ride by human erythrocytes. Arch. Toxicol. 63(5):351-355. Raabe, O.G. 1986. Inhalation Uptake of Selected Chemical Vapors at Trace Levels. UCD-472-507. A3-132-33. Laboratory for Energy-Related Health Research, Uni- versity of California, Davis, CA. Submitted to the Biological Effects Research Section, California Air Resources Board, Sacramento, CA [online]. Available: http://www.arb.ca.gov/research/apr/past/a3-132-33.pdf [accessed Jan. 30, 2012]. Raabe, O.G. 1988. Inhalation Uptake of Xenobiotic Vapors by People: Final Report. UCD-472-509, A5-155- 33. Laboratory for Energy-Related Health Research, Uni- versity of California, Davis, CA. Submitted to the Biological Effects Research Section, California Air Resources Board, Sacramento, CA[online]. Available: http://www.arb.ca.gov/research/apr/past/a5-155-33.pdf [accessed Jan. 30, 2012]. Redford-Ellis, M., and A.H. Gowenlock. 1971. Studies on the reaction of chloromethane with human blood. Acta Pharmacol. Toxicol. 30(1):36-48. Reed, C.J., B.A. Gaskell, K.K. Banger, and E.A. Lock. 1995. Olfactory toxicity of methyl iodide in the rat. Arch. Toxicol. 70(1):51-56. Reid, J.B. 2001. Saturated methyl halogenated aliphatic hydrocarbons. Pp. 12-26 in Patty’s Toxicology, 5th Ed., Vol. 5. New York: John Wiley & Sons. Reigart, J.R., and J.R. Roberts. 1999. Recognition and Management of Pesticide Poison- ings, 5th Ed. EPA 735-R-98-003. U.S. Environmental Protection Agency, Wash-
OCR for page 223
223 Methyl Bromide ington, DC [online]. Available: http://www.epa.gov/oppfead1/safety/healthcare/ handbook/handbook.pdf [accessed Jan. 30, 2012]. Reitz, R.H., A.L. Mendrala, and F.P. Guengerich. 1989. In vitro metabolism of methyl- ene chloride in human and animal tissues: Use in physiologically based pharma- cokinetic models. Toxicol. Appl. Pharmacol. 97(2):230-246. Reuzel, P.G.J., C.F. Kuper, H.C. Dreef-van der Meulen, and V.M.H. Hollanders. 1987. Chronic (29-month) Inhalation Toxicity and Carcinogenicity Study of Methyl Bromide in Rats. Report No. V86.469/221044. Zeist, The Netherlands: TNO- CIVO Toxicology and Nutrition Institute. Reuzel, P.G.J., H.C. Dreef-van der Meulen, V.M.H. Hollanders, C.F. Kuper, V.J. Feron, and C.A. van der Heijden. 1991. Chronic inhalation toxicity and carcinogenicity study of methyl bromide in Wistar rats. Food Chem. Toxicol. 29(1):31-39. Roycroft, J.H., R.H. Jascot, E.C. Grose, and D.E. Gardner. 1981. The effects of inhala- tion exposure of methyl bromide in the rat. Toxicologist 1(1):79[Abstract 285]. Russo, J.M., W.K. Anger, J.V. Setzer, and W.S. Brightwell. 1984. Neurobehavioral as- sessment of chronic low-level methyl bromide exposure in the rabbit. J. Toxicol. Environ. Health 14(2-3):247-255. Ruth, J.H. 1986. Odor thresholds and irritation levels of several chemical substances: A review. Am. Ind. Hyg. Assoc. J. 47(3):A142-A151. Sayers, R.R., W.P. Yant, B.G.H. Thomas, and L.B. Berger. 1929. Physiological Response Attending Exposure to Vapors of Methyl Bromide, Methyl Chloride, Ethyl Bro- mide, and Ethyl Chloride. U.S. Public Health Service Public Health Bulletin 185. Washington, DC: U.S. Government Printing Office. Schaefer, G.J. 2002. A 6-Week Inhalation Toxicity Study of Methyl Bromide in Dogs. Report WIL-440001, WIL Research Laboratories, Inc., Ashland, OH. Schwob, J.E., S.L. Youngentob, G. Ring, C.L. Iwema, and R.C. Mezza. 1999. Reinnerva- tion of the rat olfactory bulb after methyl bromide-induced lesion: Timing and ex- tent of reinnervation. J. Comp. Neurol. 412(3):439-457. Sikov, M.R., W.C. Cannon, D.B. Carr, R.A. Miller, L.F. Montgomery, and D.W. Phelps. 1981. Teratologic Assessment of Butylene Oxide, Styrene Oxide and Methyl Bro- mide. DHHS Publication (NIOSH) 81-124. PB 81-168-510. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, OH. Sittig, M. 1985. Pp. 587-588 in Handbook of Toxic and Hazardous Chemicals and Car- cinogens, 2nd Ed. Park Ridge, NJ: Noyes Publications. Thomas, D.A., and K.T. Morgan. 1988. Olfactory toxicity: Studies of methyl bromide. CIIT Activities 8(1):3-7. Thomas, D.A., S.A. Lacy, and K.T. Morgan. 1989. Studies on the mechanism s of methyl bromide induced olfactory toxicity. Toxicologist 9:37. Tourangeau, F.J., and S.R. Plamondon. 1945. Cases of exposure to methyl bromide va- pours. Can. J. Pub. Health 36:362-367. Tucker, J.D., J. Xu, J. Stewart, P.C. Baciu, and T.M. Ong. 1986. Detection of sister chromatid exchanges induced by volatile genotoxicants. Teratog. Carcinog. Mutagen. 6(1):15-21. Van den Oever, R., D. Roosels, and D. Lahaye. 1982. Actual hazard of methyl bromide fumigation in soil disinfection. Br. J. Ind. Med. 39(2):140-144. Verberk, M.M., T. Rooyakkers-Beemster, M. de Vlieger, and A.G. van Liet. 1979. Bro- mine in blood, EEG and transaminases in methyl bromide workers. Br. J. Ind. Med. 36(1):59-62.
OCR for page 224
224 Acute Exposure Guideline Levels Warholm, M., A.K. Alexandrie, J. Hogberg, K. Sigvardsson, and K. Rannug. 1994. Po- lymorphic distribution of glutathione transferase activity with methyl chloride in human blood. Pharmacogenetics 4(6):307-311. Watrous, R.M. 1942. Methyl bromide - local and mild systemic toxic effects. Ind. Med. 11:575-578. WHO (World Health Organization). 2000. Methyl Chloride. Concise International Chemi- cal Assessment Document No. 28. Geneva, Switzerland: World Health Organization [online]. Available: http://whqlibdoc.who.int/publications/2000/9241530286.pdf [ac- cessed Jan. 31, 2012]. Yamano, Y. 1991. Experimental study on methyl bromide poisoning in mice. Acute inha- lation study and the effect of glutathione as an antidote [in Japanese]. Sangyo Igaku 33(1):23-30. Yang, R.S., K.L. Witt, C.J. Alden, and L.G. Cockerham. 1995. Toxicology of methyl bromide. Rev. Environ. Contam. Toxicol. 142:65-85. Zwart, A. 1988. Acute Inhalation Study of Methyl Bromide in Rats. CIVO Report No. V88. 127/27, CIVO Institutes, TNO, Zeist, The Netherlands. 17 pp (as cited in IPCS 1995). Zwart, A., J.H. Arts, W.F. ten Berge, and L.M. Appelman. 1992. Alternative acute inha- lation toxicity testing by determination of the concentration-time-mortality rela- tionship: Experimental comparison with standard LC50 testing. Regul. Toxicol. Pharmacol. 15(3):278-290. Zwaveling, J.H., W.L. de Kort, J. Meulenbelt, M. Hezemans-Boer, W.A. van Vloten, and B. Sangster. 1987. Exposure of the skin to methyl bromide: A study of six cases occupationally exposed to high concentrations during fumigation. Hum. Toxicol. 6(6):491-495.
OCR for page 225
225 Methyl Bromide APPENDIX A TIME-SCALING CALCULATION FOR METHYL BROMIDE Best Fit Concentration x Time Curve 4.5 4 Log Concentration (ppm) 3.5 3 2.5 2 0.5 1 1.5 2 2.5 3 Log Time (minutes) FIGURE A-1 Regression line of LC50 data in rats. Source: Data from Bakhishev 1973; Honma et al. 1985; Kato et al. 1986; Zwart 1988). Data: Time (min) Concentration (ppm) Log time Log concentration 3.5 19,460 0.5441 4.2891 30 2,830 1.4771 3.4518 60 1,880 1.7782 3.2742 240 780 2.3802 2.8921 480 302 2.6812 2.4800 480 334 2.6812 2.5237 Regression Output: Intercept 4.7129 Slope -0.8115 R Squared 0.9914 Correlation -0.9957 Degrees of Freedom 4 Observations 6 n = 1.23 k = 642,119
OCR for page 226
226 Acute Exposure Guideline Levels APPENDIX B DERIVATION OF AEGL VALUES FOR METHYL BROMIDE Derivation of AEGL-1 Values AEGL-1 values are not recommended because toxic effects might occur below the odor threshold for methyl bromide. Absence of AEGL-1 values does not imply that exposures below the AEGL-2 values are without adverse effects. Derivation of AEGL-2 Values Key studies: Hurtt, M.E., D.A. Thomas, P.K. Working, T.M. Monticello, and K.T. Morgan. 1988. Degeneration and regeneration of the olfactory epithelium following inhalation exposure to methyl bromide: pathology, cell kinetics, and olfactory function. Toxicol. Appl. Pharmacol. 94(2):311-328. Hastings, L. 1990. Sensory neurotoxicology: Use of the olfactory system in the assessment of toxicity. Neurotoxicol. Teratol. 12(5):455-459. Japanese Ministry of Labour. 1992. Toxicology and Carcinogenesis Studies of Methyl Bromide in F344 Rat and BDF Mice (Inhalation Studies). Industrial Safety and Health Association, Japanese Bioassay Laboratory, Tokyo (as cited in IPCS 1995). Newton, P.E. 1994a. An Up-and-Down Acute Inhalation Toxicity Study of Methyl Bromide in the Dog. Study No. 93-6067. Pharmaco LSR, East Millstone, NJ. Toxicity end points: Clinical signs of neurotoxicity, NOAEL is 200 ppm for 4 h C1.2 × t = k, based on rat lethality data Time scaling: k = (200 ppm ÷ 3)1.2 × 240 min k = 37,059.7 ppm-min Uncertainty factors: 1 for interspecies differences 3 for intraspecies differences
OCR for page 227
227 Methyl Bromide Modifying factor: Not applied Calculations: C1.2 = 37,059.7 ppm-min ÷ 10 min 10-min AEGL-2: C = 940 ppm C1.2 = 37,059.7 ppm-min ÷ 30 min 30-min AEGL-2: C = 380 ppm C1.2 = 37,059.7 ppm-min ÷ 60 min 1-h AEGL-2: C = 210 ppm C1.2 = 37,059.7 ppm-min ÷ 240 min 4-h AEGL-2: C = 67 ppm 8-h AEGL-2: Set equal to the 4-h AEGL-2 of 67 ppm (If based on a chronic NOAEL of 33 ppm for mice (NTP 1992), a 4-day NOAEL of 55 ppm for clinical signs and tissue lesions in dogs (Newton 1994a), and the 36-week NOAEL of 55 ppm for neurobehavioral parameters and nerve conduction velocity in rats (Anger et al. 1981), the time-scaled value would be 37 ppm.) Derivation of AEGL-3 Values Key study: Kato, N., S. Morinobu, and S. Ishizu. 1986. Subacute inhalation experiment for methyl bromide in rats. Ind. Health 24(2):87-103. Toxicity end point: BMCL05 of 701 ppm in the rat C1.2 × t = k, based on rat lethality data. Time scaling: k = (701 ppm ÷ 3)1.2 × 240 min k = 166,927.3 ppm-min Uncertainty factors: 1 for interspecies differences 3 for intraspecies variability Modifying factor: Not applied Calculations: C1.2 = 166,927.3 ppm-min ÷ 10 min 10-min AEGL-3: C = 3,300 ppm
OCR for page 228
228 Acute Exposure Guideline Levels 30-min AEGL-3: C = 166,927.3 ppm-min ÷ 30 min C = 1,300 ppm 1-h AEGL-3 C = 166,927.3 ppm-min ÷ 60 min C = 740 ppm 4-h AEGL-3: C = 166,927.3 ppm-min ÷ 240 min C = 230 ppm 8-h AEGL-3: C = 166,927.3 ppm-min ÷ 480 min C = 130 ppm
OCR for page 229
229 Methyl Bromide APPENDIX C CATEGORY GRAPH OF TOXICITY DATA AND AEGL VALUES FOR METHYL BROMIDE 100000 10000 No Effect Discomfort ppm 1000 Disabling AEGL-3 Some Lethality 100 AEGL-2 Lethal 10 0 60 120 180 240 300 360 420 480 Minutes FIGURE C-1 Category graph of toxicity data on methyl bromide compared with AEGL values. All of the toxicity data pertain to laboratory animals; no clinical data were avail- able.
OCR for page 230
230 Acute Exposure Guideline Levels APPENDIX D ACUTE EXPOSURE GUIDELINE LEVELS FOR METHYL BROMIDE Derivation Summary for Methyl Bromide AEGL-1 VALUES AEGL-1 values are not recommended because toxic effects might occur below the odor threshold for methyl bromide. Absence of AEGL-1 values does not imply that exposures below the AEGL-2 values are without adverse effects. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 940 ppm 380 ppm 210 ppm 67 ppm 67 pm Key references: (1) Hurtt, M.E., D.A. Thomas, P.K. Working, T.M. Monticello, and K.T. Morgan. 1988. Degeneration and regeneration of the olfactory epithelium following inhalation exposure to methyl bromide: Pathology, cell kinetics, and olfactory function. Toxicol. Appl. Pharmacol. 94(2):311-328. (2) Hastings, L. 1990. Sensory neurotoxicology: Use of the olfactory system in the assessment of toxicity. Neurotoxicol. Teratol. 12(5):455-459. (3) Japanese Ministry of Labour. 1992. Toxicology and Carcinogenesis Studies of Methyl Bromide in F344 Rat and BDF Mice (Inhalation Studies). Industrial Safety and Health Association, Japanese Bioassay Laboratory, Tokyo (as cited in IPCS 1995). (4) Newton, P.E. 1994a. An Up-and-Down Acute Inhalation Toxicity Study of Methyl Bromide in the Dog. Study No. 93-6067. Pharmaco LSR, East Millstone, NJ. Test species/Strain/Number: (1) dog/beagle/1 (with support from higher and lower exposures; (2) rat/not specified/30; (3) rat/F-344/10 male and 10 female; and (4) rat/male F-344/15 Exposure route/Concentrations/Durations: Inhalation, (1) 233 ppm for 5 h; (2) 200 ppm for 4 h; (3) 225 ppm for 4 h; and (4) 200 ppm for 6 h Effects: (1) No toxic signs or brain lesions; (2) no clinical signs; (3) reversible metaplasia of the olfactory epithelium; and (4) no clinical signs, reversible olfactory epithelium degeneration. End point/Concentration/Rationale: Threshold for neurotoxic signs is 200 ppm for 4 h. Neurotoxicity (e.g., ataxia) would inhibit the ability to escape. Olfactory lesions were considered specific to the rat. (Continued)
OCR for page 231
231 Methyl Bromide AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 940 ppm 380 ppm 210 ppm 67 ppm 67 pm Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: 1, based on studies with methyl chloride, uptake is greater in rodents than in humans; GST concentrations are greater in rodents than humans, resulting in faster production of toxic metabolites. Intraspecies: 3, differences in metabolism among humans are no greater than 3-fold (Nolan et al. 1985). Modifying factor: Not applied Animal-to-human dosimetric adjustment: Not applied Time scaling: C1.2 × t = k, based on lethality studies with the rat. Data adequacy: Although there are no controlled clinical studies, the database of experimental animal studies is robust. Studies of dogs exposed to methyl bromide at 156 ppm (no clinical signs for first 2 days) or 268 ppm (severe signs during first day) indicate that 200 ppm for 4 h would be near the threshold for neurotoxicity in dogs (Newton 1994a). AEGL-3 VALUES 10 min 30 min 1h 4h 8h 3,300 ppm 1,300 ppm 740 ppm 230 ppm 130 ppm Key Reference: Kato, N., S. Morinobu, and S. Ishizu. 1986. Subacute inhalation experiment for methyl bromide in rats. Ind. Health 24(2):87-103. Test species/Strain/Number: Male rat/Sprague-Dawley/5 or 10 Exposure route/Concentrations/Durations: Inhalation at 502, 622, 667, 701, 767, 808, 832, or 896 ppm for 4 h Effects: clinical signs were not described 502 ppm no morality 622 ppm no mortality 667 ppm no mortality 701 ppm no mortality 767 ppm 30% mortality 799 ppm 60% mortality 808 ppm 70% mortality 817 ppm 80% mortality 832 ppm 100% mortality 896 ppm 100% mortality LC50 = 780 ppm (95% confidence limits of 760-810 ppm) LC01 = 701 ppm BMCL05 = 701 ppm (Continued)
OCR for page 232
232 Acute Exposure Guideline Levels AEGL-3 VALUES Continued 10 min 30 min 1h 4h 8h 3,300 ppm 1,300 ppm 740 ppm 230 ppm 130 ppm End point/Concentration/Rationale: BMCL05, 701 ppm, threshold for lethality Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: 1, based on studies with methyl chloride, uptake is greater in rodents than in humans; GST concentrations are greater in rodents than humans, resulting in faster production of toxic metabolites. Intraspecies: 3, differences in metabolism among humans are no greater than 3-fold (Nolan et al. 1985). Use of an intraspecies uncertainty factor of 3 is supported by the steep dose-response curve for lethality which indicates that there might be little intraspecies variation (see Chapter 6). Furthermore, larger reduction of the AEGL-3 values would result in values near the AEGL-2 values. Modifying factor: Not applied Animal-to-human dosimetric adjustment: Not applied Time scaling: C1.2 × t = k, based on several lethality studies with the rat Data adequacy: Although reliable human data are lacking, the database of animal studies is robust, consisting of acute, repeat-exposure, subchronic, chronic, neurotoxicity, genotoxicity, and carcinogenicity studies.