6

Methyl Isothiocyanate
1

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 Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established 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 distinguished 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 effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.

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1 This document was prepared by the AEGL Development Team composed of Robert Young (Oak Ridge National Laboratory), Heather Carlson-Lynch (SRC, Inc.), Chemical Manager Susan Ripple (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental 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 scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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6 Methyl Isothiocyanate1 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 effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. 1 This document was prepared by the AEGL Development Team composed of Robert Young (Oak Ridge National Laboratory), Heather Carlson-Lynch (SRC, Inc.), Chemical Manager Susan Ripple (National Advisory Committee [NAC] on Acute Exposure Guide- line Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protec- tion Agency). The NAC reviewed and revised the document and AEGLs as deemed nec- essary. 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 scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 166

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Methyl Isothiocyanate 167 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 respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY Methyl isothiocyanate (MITC) is a colorless crystalline solid that occurs primarily as a decomposition product of pesticides applied as soil fumigants. MITC injected into soil rapidly vaporizes. A level of distinct odor awareness (LOA) of 27 ppm for MITC was calculated. The database for MITC includes a controlled human clinical study that evaluated odor threshold and ocular irritation, acute and repeated-exposure inha- lation studies in rats, and oral studies of reproductive and developmental toxicity in rats and rabbits. MITC is a potent, direct-acting irritant to the eyes and respir- atory tract. Death results from acute pulmonary congestion and hemorrhage. Developmental studies indicate that MITC was not teratogenic but caused de- layed growth at maternally toxic concentrations. Although MITC is an alkylat- ing agent, most genotoxicity studies reported negative results. Carcinogenicity studies of MITC administered orally to rats and mice did not find a significant neoplastic response. AEGL-1 values are based on a study of human volunteers (Russell and Rush 1996). This study met the criteria for using data on human subjects out- lined in the Standing Operating Procedures for AEGLs (NRC 2001, Section 2.3.2). Slight and transient ocular irritation was reported by subjects exposed to MITC at a concentration of 0.8 ppm. Blinking rate was slightly increased, but there was no tearing or redness of the eye. Thus, 0.8 ppm was considered the highest concentration without notable discomfort and was used as the point of departure for deriving AEGL-1 values. An intraspecies uncertainty factor of 3 was applied, because MITC appears to have a direct-acting irritant mechanism

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168 Acute Exposure Guideline Levels of toxicity and metabolic and physiologic differences are unlikely to play a ma- jor role (NRC 2001). Also, the range of human sensitivity to ocular irritants is approximately two-fold (Kjaergaard et al. 1992). Because 0.8 ppm was tested for up to 4 h, that concentration was used for all the AEGL-1 exposure dura- tions. Furthermore, there is adaptation to the slight irritation that defines the AEGL-1. The AEGL-1 values are supported by no-effect concentrations in re- peated-exposure studies with rodents (Rosskamp et al. 1978; Klimisch 1987). No acute clinical studies or acute toxicology studies in laboratory animals were identified that were relevant deriving AEGL-2 values. The degree of ocular irritation observed in the study by Russell and Rush (1996) was not of sufficient severity to impair escape. In the absence of data that address AEGL-2 end points, the AEGL-3 for MITC values were divided by 3 to derive the respective AEGL-2 values. This approach is appropriate for chemicals with evidence of a steep concentration-response curve (NRC 2001). The point of departure for AEGL-3 values was the highest nonlethal con- centration of 94 ppm in a study of rats exposed for 4 h (Jackson et al. 1981). Interspecies and intraspecies uncertainty factors of 3 each are generally applied to chemicals that are direct-acting irritants (NRC 2001). However, such an ap- proach in this instance would result in values inconsistent with the human volun- teer study by Russell and Rush (1996). Therefore, interspecies and intraspecies uncertainty factors of 1 and 3, respectively, were applied. Time-scaling was per- formed using the equation Cn × t = k, with default values of n = 3 for extrapola- tion to shorter durations and n = 1 for extrapolating to longer durations (NRC 2001). The 10-min AEGL-3 value was set equal to the 30-min AEGL-3 value because of uncertainties associated with extrapolating a 4-h point of departure to a 10-min value. AEGL values for MITC are presented in Table 6-1. 1. INTRODUCTION MITC is a colorless crystalline solid that is used as a soil fumigant (Lam et al. 1993; HSDB 2012). It is produced by the action of carbon disulfide on me- thylamine or by reacting sodium methyldithiocarbamate with ethyl chlorocar- bonate (HSDB 2012). Metam sodium (sodium N-methyldithiocarbamate), which decomposes to MITC, is the third most commonly used agricultural pesticide in the United States (Pruett et al. 2001); however, production data were not locat- ed. MITC injected into soil immediately vaporizes (Nihon Schering 1990). Metam sodium and dazomet are propesticides (compounds that are con- verted to pesticides) which hydrolyze in soil to MITC as the ultimate toxicant (Lam et al. 1993). Upon dilution with water, metam sodium decomposes to MITC which evolves as a gas of hydrogen sulfide and lesser amounts of methyl- amine and carbon disulfide. Ditrapex® and Trapex® contain 20% MITC (Nihon Schering 1990). Ditrapex® contains 40% 1,2-dichloropropene, a nematicide. MITC is phytotoxic and planting is delayed until the soil fumigant has decom- posed completely.

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Methyl Isothiocyanate 169 TABLE 6-1 AEGL Values for Methyl Isothiocyanatea End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 0.27 ppm 0.27 ppm 0.27 ppm 0.27 ppm 0.27 ppm No evidence of (nondisabling) (0.81 (0.81 (0.81 (0.81 (0.81 notable discomfort mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (ocular irritation) at several time points in humans (Russell and Rush 1996) AEGL-2 21 ppm 21 ppm 17 ppm 10 ppm 5.3 ppm One-third of (disabling) (63 (63 (51 (30 (16 AEGL-3 values mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 63 ppm 63 ppm 50 ppm 31 ppm 16 ppm Nonlethal (lethal) (190 (190 (150 (94 (47 concentration in rats mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Jackson et al. 1981) a A level of distinct odor awareness (LOA) of 27 ppm was calculated for MITC (see Appendix A). The LOA is defined as the concentration above which it is predicted that more than half of the exposed population will experience at least a distinct odor intensity, and about 10% of the population will experience strong odor intensity. Calculation of the LOA does not imply that exposure below the LOA is without effects. MITC belongs to the chemical class mustard oils. It has been considered as a possible military poison (Verschueren 2001). The toxicity of MITC was reviewed by Nihon Schering (1990), NRA (1997), and Rubin et al. (2003). MITC has a pungent, horseradish-like odor at room temperature; its vapors irri- tate mucous membranes and it is a potent lacrimator (Nihon Schering 1990). The chemical and physical properties of MITC are presented in Table 6-2. 2. HUMAN TOXICITY DATA 2.1. Odor Threshold and Odor Awareness MITC has a pungent horseradish-like odor at room temperature (Nihon Schering 1990). Odor thresholds reportedly range from approximately 0.1 ppm (Nesterova 1969) to 5 ppm (Verschueren 2001). The odor threshold determined in a controlled clinical study was 1.7 ppm (Russell and Rush 1996; EPA 2006a). Using the data of Russell and Rush (1996), a level of distinct odor awareness (LOA) of 27 ppm was calculated for MITC (see Appendix A). The LOA repre- sents the concentration above which it is predicted that more than half of the exposed population will experience at least a distinct odor intensity, and about 10% of the population will experience a strong odor intensity. The propesticide metam sodium hydrolyzes into MITC and hydrogen sul- fide, and the odor of hydrogen sulfide might be present at metam sodium appli- cation sites.

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170 Acute Exposure Guideline Levels TABLE 6-2 Chemical and Physical Properties of Methyl Isothiocyanate Parameter Value Synonyms Isothiocyanatomethane; methyl mustard oil; Trapex CAS registry no. 556-61-6 Chemical formula C2H3NS Molecular weight 73.12 Physical state Colorless crystals Melting point 36°C Boiling point 119°C Density/specific gravity (water =1) 1.0691 at 37°C Solubility in water 7.6 g/L at 25°C Vapor density (air =1) 2.53 Vapor pressure 3.54 mm Hg at 25°C Saturated vapor concentration (calculated ~27,000 ppm (~82,000 mg/m3) from vapor pressure) Flammability limits Lower 2.5%; Upper 30%/MITC-Fume Conversion factors (calculated) 1 ppm = 2.99 mg/m3 1 mg/m3 = 0.33 ppm Source: HSDB 2012. 2.2. Accidents and Community Exposures In 1991, a railroad tank car in California derailed and spilled 19,000 gal- lons of metam sodium into the Sacramento River (Alexeeff et al. 1994). The hydrolysis product MITC was released to the air. Many individuals downriver of the incident reported odors. Over 240 individuals complained of ocular and throat irritation, dizziness, and shortness of breath. Ambient air concentrations, measured on the fourth day after the accident (12-h integrated samples) ranged from 0.2 to 37 ppb. Average concentrations reported on the fifth through tenth day ranged from below the limit of detection (<1 ppb) to 2.6 ppb. Estimates of peak concentrations during the first two days were 140-1,600 ppb for exposures of a few minutes to 1 h; these estimates were for areas within 500 meters of the river. Cone et al. (1994) assessed the occurrence of persistent respiratory disor- ders among adults exposed as a result of the metam sodium spill. Exposures were most likely to a mixture of metam sodium hydrolysis products which in- clude MITC, hydrogen sulfide gas, methylamine, and carbon disulfide. Among a group of 197 persons referred for health evaluation, 20 were identified as having persistent irritant-induced asthma and 10 were identified as having persistent exacerbation of pre-existing asthma. Cases of irritant-induced asthma met the

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Methyl Isothiocyanate 171 following criteria: onset of upper respiratory symptoms within 24 h of exposure; onset of lower respiratory symptoms within 1 week and persisting for more than 3 months; no prior history of respiratory illness (confirmed by medical records); location and activity consistent with exposure during and for 1 week after the spill; and nonspecific airway hyper-responsiveness demonstrated by methacho- line challenge. Most (17/20) of the irritant-induced asthma cases met the criteria for reactive airway distress syndrome (RADS). O’Malley et al. (2004) documented illnesses among residents of a com- munity near a potato field where metam sodium was applied with a sprinkler. Air concentrations of MITC were estimated with air models using application information and meteorological data. Concentrations were estimated to range from 0.5 ppm to just over 1 ppm (1-h time-weighted averages). Peak concentra- tions at 1 and 3 min were estimated to be 4 and 7 ppm, respectively. No data were reported regarding concentrations of other hydrolysis products of metam sodium, which includes a mixture of known irritants. Residents were inter- viewed to obtain information on symptoms and proximity to the potato field during pesticide application. Among those closest to the application site (≤0.5 miles), symptoms consisted of irritation of the eyes or upper respiratory tract (burning of eyes, nose, or throat) in 51/135, non-specific systemic symptoms such as headache, nausea, diarrhea, abdominal pain, or malaise in 22/135, “sys- temic irritant” response (not otherwise specified) in 45/135, and respiratory irri- tation (but not asthma or lower respiratory irritation) in 6/135. Frequency of complaints decreased with distance from the application site. O’Malley et al. (2005) reported illnesses related to soil incorporation (shank application) of metam sodium near a rural community in California. Sev- eral hours after application of 25,000 pounds of metam sodium to a 100-acre field, 250 nearby residents experienced ocular and upper-respiratory irritation, non-specific systemic symptoms, and lower-respiratory-tract complaints. Some residents sought medical treatment. After the incident, residents were inter- viewed directly or via medical records in order to correlate symptoms with area and activity. The most serious illnesses were associated with individuals who had pre-existing lung diseases, such as asthma and emphysema. MITC concen- trations were estimated based on field treatment, projected emissions, and weather conditions. Modeling results indicted 1-h MITC concentrations in the affected areas of 0.8-1.0 ppm, with peak concentrations between 2.4 and 3.2 ppm. Bretaudeau Deguigne et al. (2011) described a series of 106 case reports of exposure to metam sodium at a poison control center in France. Most (96) cases were accidentally exposed via inhalation, and the most commonly reported symptoms attributed to MITC exposure were irritation of the eyes (76/96 inhala- tion exposures) and throat and nose (65/96). Exposure concentrations were not reported. Of the 96 exposed, only four had cough or dyspnea; the investigator reported that there were no cases of persistent irritant-induced asthma or exacer- bation of asthma.

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172 Acute Exposure Guideline Levels 2.3. Clinical Studies In order to determine the thresholds for odor detection and ocular irrita- tion, healthy adult volunteers were exposed to measured concentrations of MITC in a laboratory setting (Russell and Rush 19962; reviewed in EPA 2006a). This study met the criteria for use of data from human subjects discussed in the Standing Operating Procedures for AEGLs (NRC 2001, Section 2.3.2). In the olfactory threshold study, 33 individuals (16 males, 17 females; age range of 18- 34 years) were exposed to three reference control odorants: pyridine, acetic acid, and n-butyl alcohol, as well as MITC. The odorants were dispensed in a con- trolled double-blind fashion through one of three presentation ports. A techni- cian chose the odorant and the subject was responsible for determining from which port the odorant was dispersed. There was a 30-sec rest period between odorant presentations. Each volunteer was tested over a range of concentrations for each odorant until a threshold, determined under a standard procedure, was satisfactorily ascertained. The observed odor threshold for MITC ranged from 0.2 to 8 ppm, with a geometric mean of 1.7 ppm. The ocular irritation study was conducted with 70 adult volunteers (38 males, 32 females; age range of 18-67 years). Four exposure durations of 1 min, 14 min, 4 h, and 8 h were used. In the 1-min trial, subjects were exposed to MITC at concentrations up to 3.3 ppm. In the 14-min trial, 9-10 subjects were exposed at 0 (air only), 0.6, 1.9, or 3.3 ppm. In the 4-h trial, there was both an air and acetic acid control; concentration of MITC tested were 0.23 ppm (12 subjects) or 0.8 ppm (9 subjects). In the 8-h study, 12 subjects were exposed to air only, seven were exposed to acetic acid, and 16 subjects were exposed to MITC at 0.22 ppm. Subjects were permitted two 15-min rest periods and a lunch break during the 8-h study. An olfactometer was used to dispense the test materials through a manifold system. A total hydrocarbon analyzer was used to monitor the flow of test material through the tubing; samples were collected on carbon tube samplers, desorbed, and measured with gas chromatography. The subjects were exposed via goggles. No additional details of the methods were available. Subjective irritation was measured on a Likert scale in which irritation was rated from no irritation to a feeling the subject would like to end the expo- sure; the mid-point was described as similar to that of cutting a single mild on- ion. Subjective irritation, blink rates, and tearing were assessed at several time points. Baseline responses were determined pre-exposure and from exposure to the air control. Visual acuity and ocular morphology were assessed at the begin- ning and end of each exposure (methods not provided). The results of this study are summarized in Table 6-3. The no-observed-effect levels (NOELs) for the 1- 2 Russell and Rush (1996) is an unpublished report prepared by the University of Cali- fornia and Western Research Center and submitted to U.S. EPA’s Office of Chemical Safety and Pollution Prevention. The report is not publicly available. A U.S. EPA AEGL staff member with FIFRA clearance reviewed the original report and confirmed the de- tails provided in the U.S. EPA (2006a) Data Evaluation Record for the study.

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Methyl Isothiocyanate 173 and 14-min exposures were 3.3 and 0.6, respectively. The NOEL range for the two longer duration exposures was 0.22-0.23 ppm. The lowest-observed-effect level (LOELs) for the 14-min and 1- through 8-h intervals were 1.9 and 0.8 ppm, respectively. During the first hour of the 4-h trial at 0.8 ppm, subjective irritation was rated at 25 ± 14% on a scale of 1 to 100. During the second hour of the 4-h trial at 0.8 ppm, blink rates increased from 3 ± 9/min in the control group to 16 ± 11/min in the 0.8-ppm group. Thereafter, blink rate did not in- crease with exposure duration. No statistically significant positive tearing re- sponses were observed; photographs of the participant’s eyes failed to show notable, exposure-related changes. Comments from the subjects indicated that recovery began immediately after removal of the goggles and was complete within 20 min at the highest concentration. 2.4. Community Exposures Lee et al. (2002) reported ambient concentrations of MITC (and other pes- ticides or pesticide breakdown products) in California during months associated with pesticide application. With 2 weeks of air monitoring data, generally col- lected from samplers placed atop the roofs of community building, mean con- centrations of MITC were 2.1 µg/m3 (0.7 ppb) in urban communities (range not reported) and 4.9 µg/m3 (1.6 ppb) in rural communities (range up to 18 µg/m3 [6 ppb]). The 15-day maximum concentration was 8.4 µg/m3 (2.8 ppb). The publi- cation reported little information on the areas sampled. TABLE 6-3 Ocular Irritation in Human Subjects Exposure Duration NOELa (ppm) LOEL (ppm) Description 1 min 3.3 – 4 min 0.60 1.9 Subjective ocular irritationb 14 min 0.60 1.9 Subjective ocular irritation 1h 0.23 0.8 Subjective ocular irritation 1.5 h 0.22 – 2h 0.23 0.8 Subjective ocular irritation, increased blink rate. 3h 0.23 0.8 Subjective ocular irritation, increased blink rate. 3.5 h 0.22 – 4h 0.23 0.8 Subjective ocular irritation 6h 0.22 – 8h 0.22 – a The 0.22- and 0.23-ppm concentrations were tested on different days. b Ocular irritation did not include redness or tearing. Source: Rubin et al. 2003.

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174 Acute Exposure Guideline Levels Merriman and Hebert (2007) reported the results of an air monitoring study measuring MITC concentrations in the air of an agricultural region of Washington State during the fall season when metam sodium fumigation is typi- cally done. Five residential sites and one commercial site were selected for mon- itoring. Twenty-four-hour samples comprised of two 12-h day and night sub- samples were collected over the course of 1 month (September 26 to October 25, 2005); a total of 201 samples were collected. The frequency of measurements above the detection limit (0.01 ppb) was 199/201. The maximum 12-h time- weighted average concentration of MITC was 67 µg/m3 (22 ppb); the average over the 30-day sampling period was 10 µg/m3 (3.3 ppb). 2.5. Developmental and Reproductive Toxicity No studies of developmental or reproductive toxicity of MITC in humans were found. 2.6. Genotoxicity Negative results were obtained with MITC at concentrations of 3.0 or 5.0 µg/mL in an in vitro cytogenetic chromosome aberration test using cultured hu- man lymphocytes (Rubin et al. 2003). MITC induced micronuclei and DNA strand breaks in cultured human hepatoma cells at concentrations that were cyto- toxic (Kassie et al. 2001). 2.7. Chronic Toxicity and Carcinogenicity No studies of the chronic toxicity or potential carcinogenicity of MITC in humans were found. 2.8. Summary In studies with human volunteers, the odor threshold for MITC ranged from 0.2 to 8 ppm, with a geometric mean of 1.7 ppm (Russell and Rush 1996). Volunteers were exposed to referent odorants including n-butyl alcohol. In a study with 70 volunteers, ocular irritation was examined at discrete time inter- vals (Russell and Rush 1996). No ocular irritation was observed in association with MITC at 3.3 ppm (the highest concentration tested) for 1 min, 0.6 ppm for 14 min, or 0.22-0.23 ppm for 1-8 h. When exposed at 1.9 ppm for 14 min or at 0.8 ppm for 1-8 h, subjects reported ocular irritation slightly less than that asso- ciated with cutting a single mild onion. MITC failed to induce signs of genotox- icity in an in vitro test for chromosome damage in cultured human lymphocytes (Rubin et al. 2003), and induced strand breaks in human hepatoma cells at cyto- toxic concentrations (Kassie et al. 2001).

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Methyl Isothiocyanate 175 No human studies addressing the potential for reproductive and develop- mental toxicity or chronic toxicity and carcinogenicity were found. 3. ANIMAL TOXICITY DATA Data on MITC were reviewed by Nihon Schering (1990), Alexeeff et al. (1994), NRA (1997), HSDB (2012), and Rubin et al. (2003). MITC is a primary ocular irritant when instilled into the eye of rabbits (100 mg), causing severe inflammation with corneal opacity, iritis, and conjunctival swelling (Nihon Schering 1990). In studies with several species, cats were the most sensitive species, exhibiting irritation of the ocular mucosa (Nesterova 1969). No details of those studies were available. 3.1. Acute Lethality Clark and Jackson (1977) exposed groups of five male and five female Sprague-Dawley CFY rats whole-body to five concentrations of MITC ranging from 600 to 3,100 mg/m3 (200 to 1,037 ppm) for 1 h. The test material adminis- tered in the study was a pesticide formulation that contains MITC as an active ingredient. The conversion used to estimate the MITC concentration in the chamber (the concentration reported by secondary sources) was not clearly ex- plained in the original report. Hyperactivity that began within 5 min of exposure was observed in all MITC-treated groups. Ocular irritation, dyspnea, and hypo- activity were observed during the remainder of the exposure period. Most rats exposed at 3,100 mg/m3 (1,037 ppm) died; death was preceded by convulsions. No deaths occurred at 630 mg/m3 (210 ppm). The 1-h LC50 was 1,900 mg/m3 (635 ppm). Necropsy of animals that died revealed pulmonary congestion and hemorrhage of the lungs. Jackson et al. (1981; reviewed in EPA 2006b)3 exposed groups of five male and five female Sprague-Dawley rats to six different concentrations of MITC for 4 h (concentrations not specified). The test material was MITC. Clini- cal signs noted during exposure included closure of the eyes, lacrimation, and peripheral vasodilation in all rats and a hunched posture in the majority of the animals. Peripheral vasodilation persisted for several hours after exposure. Opacity of the eyes was observed in rats exposed at ≥500 mg/m3 (≥167 ppm). No mortality or gross pathologic changes were observed at 282 mg/m3 (94 ppm), but lung weight was increased and lung rales were observed on day 1 and reoccurred on day 6 post-exposure. The calculated 4-h LC50 was 180 ppm for 3 Jackson et al. (1981) is an unpublished report prepared by Huntingdon Research Center and submitted to U.S. EPA’s Office of Chemical Safety and Pollution Prevention. The report is not publicly available. A U.S. EPA AEGL staff member with FIFRA clear- ance reviewed the original report and confirmed the details provided in the U.S. EPA (2006b) Weight-of-Evidence Discussion for the study.

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176 Acute Exposure Guideline Levels both sexes. Necropsy and histopathologic examination of the animals that died revealed congestion, edema, bronchiolitis, interstitial pneumonitis, and intra- alveolar hemorrhage of the lungs, accompanied by increased lung weight and focal hepatic necrosis. Distention of the stomach and intestines was attributed to swallowing air (gasping) prior to death. Ullman (1985) reported 100% mortality in Wistar rats within 30 min of exposure to MITC at 10 ppm. These results conflict with those of the other acute toxicity studies, as well as with the repeated-exposure studies with the same strain of rats (see Section 3.3). Nesterova (1969) reported no deaths in rats (strain unidentified) exposed to MITC at 26 ppm for 4 h, whereas 80-100% of mice died at 25-26 ppm. No details of the methods of the Nesterova (1969) were reported. With the exception of these two studies, the acute lethality data for MITC are presented in Table 6-4. 3.2. Nonlethal Acute Toxicity No acute toxicity studies other than those summarized in Section 3.1 were found. 3.3. Repeated Exposure Studies Groups of five male and five female SPF Wistar/Chubb:THOM rats were exposed whole-body to MITC for 6 h/day, 5 days/week for 28 days (Klimisch 1987; EPA 2006b). Measured concentrations of MITC were 0, 1.7, 6.8, and 34 ppm. Beginning on the third exposure day and continuing throughout the study, rats exposed at 6.8 or 34 ppm exhibited eyelid closure, somnolence, and ruffled fur during each daily exposure. No clinical signs were observed in the 1.7-ppm group. Additional clinical signs observed in the 34-ppm group included reddish nasal discharge, salivation, ocular discharge, and dyspnea. Except for ruffled fur and respiratory distress in the 34-ppm group, clinical signs resolved between exposures. Body weight and several clinical-chemistry parameters were reduced in the high-exposure group at sacrifice. Histopathologic examination revealed rhinitis in the nasal cavity, atrophy of the olfactory epithelium, metaplasia of the nasal respiratory epithelium, tracheal epithelial proliferation, bronchial pneumo- nia and bronchial and bronchiolar epithelial proliferation, and emphysema. The no-observed-adverse-effect level was 1.7 ppm. TABLE 6-4 Acute Lethality Data on Methyl Isothiocyanate Concentration Exposure Species (ppm) Duration Effect Reference Rat 210 1h No mortality Clark and Jackson, 1977 635 1h LC50 Rat 94 4h No mortality Jackson et al. 1981 180 4h LC50

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Methyl Isothiocyanate 189 Cone, J.E., L. Wugofski, J.R., Balmes, R. Das, R. Bowler, G. Alexeeff, and D. Shuster- man. 1994. Persistent respiratory health effects after a metam sodium pesticide spill. Chest 106(2):500-508. Dourson, M.L., M.J. Kohrman-Vincent, and B.C. Allen. 2010. Dose response assessment for effects of acute exposure to methyl isothiocyanate (MITC). Regul. Toxicol. Pharmacol. 58(2):181-188. EPA (U.S. Environmental Protection Agency). 2006a. Data Evaluation Record: M.J. Rus- sell and T.J. Rush (1996) Methyl Isothiocyanate: Determination of Human Olfactory Detection Threshold and Human No Observable Effect Level for Eye Irritation. Re- port No. RP 96-049B, Sensory Testing Laboratory, University of California, Davis [online]. Available: http://www.epa.gov/osa/hsrb/files/meeting-materials/may-2-3-20 06-public-meeting/mitc_der.pdf [accessed Aug. 21, 2013]. EPA (U.S. Environmental Protection Agency). 2006b. Human Studies Review Board: Weight of Evidence Discussion for Methyl Isothiocyanate [MITC]). Memorandum from Anna Lowit, Toxicologist, Health Effects Division, to Tina Levine, Director, Health Effects Division, Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC. April 13, 2006 [online]. Avail- able: http://www.epa.gov/osa/hsrb/files/meeting-materials/may-2-3-2006-public-mee ting/7-MITC-weight_of_evidence.pdf [accessed Aug. 21, 2013]. Finar, I.L. 1986. Aliphatic compounds of sulphur, phosphorus, silicon and boron. Chapter 14 in Organic Chemistry, Vol. 1. The Fundamental Principles, 6th Ed. New York, NY: Longman. Hawkins, D., L.F. Elsom, and G. Girkin. 1987. The Biokinetics and Metabolism of 14C- Metam Sodium in the Rat. Metam-Sodium Task Force. Study No. BASF 88/0030. Huntington Research Centre, Ltd (as cited in Rubin et al. 2003). Hellwig, J. and B. Hildebrand. 1987. Report on the Study of the Prenatal Toxicology of MITC in Rats after Oral Administration (Gavage). Project No. 34R0231/8537, BASF Aktiengesellschaft, Department of Toxicology, Federal Republic of Germa- ny. September 2, 1987 (as cited in NRA 1997). HSDB (Hazardous Substances Data Bank). 2012. Methyl Isothiocyanate (CAS Reg. No. 556-61-6). TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/ htmlgen?HSDB [accessed Aug. 21, 2013]. Irvine, L.F.H. 1983. Methyl Isothiocyanate (MITC): Oral (Gavage) Teratology Study in the Rat. Hazleton and Schering Report 3191-14/10; Schering Report T53 (as cited in NRA 1997). Irvine, L.F.H. 1984. Methyl Isothiocyanate (MITC): Oral (Gavage) Teratology Study in the New Zealand White Rabbit. Hazleton and Schering Report No. 3687-14/30. Schering Report T74 (as cited in NRA 1997). Jackson, G.C., G.C. Clark, D.E. Prentice, R.M. Read, C. Gopinath, and C. Cherry. 1981. Methyl Isothiocyanate: Acute Inhalation Toxicity in Rats. 4 Hour Exposure. RZ No. 81/082, 378/801109 Huntingdon Research Centre, Huntingdon, England. Submitted to U.S. EPA’s Office of Chemical Safety and Pollution Prevention. Kassie, F., B. Laky, E. Nobis, M. Kundi, and S. Knasmuller. 2001. Genotoxic effects of methyl isothiocyanate. Mutat. Res. 490(1):1-9. Keil, D.E., E.L. Padgett, D.B. Barnes, and S.B. Pruett. 1996. Role of decomposition products in sodium methyldithiocarbamate-induced immunotoxicity. J. Toxicol. Environ. Health 47(5):479-492.

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190 Acute Exposure Guideline Levels Kjaergaard S., O.F. Pedersen, and L. Molhave. 1992. Sensitivity of the eyes to airborne irritant stimuli: Influence of individual characteristics. Arch. Environ. Health 47(1): 45-50. Klimisch, H.J. 1987. Study of the Subchronic Inhalation Toxicity of Methyl Isothiocya- nate in Wistar Rats (4 Weeks Study). BASF Project 87/0244: 4OI0231/8539. BASF Aktiengesellschaft, Ludwigshafen, Federal Republic of Germany (as cited in EPA 2006b). Ladd, R., and P.S. Smith. 1976. Teratogenic Study with Methylisothiocyanate in Albino Rabbits. Report No. 651-07457, Schering Report T23, Industrial Bio-Test Labora- tories Inc., IL (as cited in NRA 1997). Lam, W.W., J.H. Kim, S.E. Sparks, G.B. Quistad, and J.E. Casida. 1993. Metabolism in rats and mice of the soil fumigants metham, methyl isothiocyanate, and dazonet. J. Agric. Food Chem. 41(9):1487-1502. Lee, S., R. McLaughlin, M. Harnly, R. Gunier, and R. Kreutzer. 2002. Community expo- sures to airborne agricultural pesticides in California: Ranking of inhalation risks. Environ. Health Perspect. 110(12):1175-1184. Mennicke, W.H., K. Gorler, and G. Krumbiegel. 1983. Metabolism of some naturally occurring isothiocyanates in the rat. Xenobiotica 13(4):203-207. Merriman, J.H., and V.R. Hebert. 2007. Methyl isothiocyanate residential community air assessment for South Franklin County, Washington. Bull. Environ. Contam. Toxi- col. 78(1):19-23. Nesterova, M.F. 1969. Standards for carbathion in working zone air [in Russian]. Gig. Sanit. 34(5):191-196. Nihon Schering. 1990. Summary of toxicity data on methyl isothiocyanate (MITC). J. Pestic. Sci. 15:297-304. NRA (National Registration Authority). 1997. Metham Sodium, Dazomet and Methyli- sothiocyanate (MITC), Volume III, NRA Special Review Series 97.2. Canberra, Australia: National Registration Authority. 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. O’Malley, M., T. Barry, M. Verder-Carlos, and A. Rubin. 2004. Modeling of methyl isothiocyanate air concentrations associated with community illnesses following a metam sodium sprinkler application. Am. J. Ind. Med. 46(1):1-15. O’Malley, M., T. Barry, M. Ibarra, M. Verder-Carlos, and L. Mehler. 2005. Illnesses related to shank application of metam-sodium, Arvin, California, July 2002. J. Agromedicine 10(4):27-42. Pflaum, J., W. Thompson, C. Salamon, S. Smith, D. Arnold, R.J. Arceo, and G.E. Gor- don. 1978. Three-generation Reproductive Study with Methyl Isothiocyanate in Albino Rats. Report No. 623-07393, Schering Report T24. Industrial Bio-Test La- boratories Inc., IL (as cited in NRA 1997). Pruett, S.B., D.B. Barnes, Y.C. Han, and A.E. Munson. 1992. Immunological characteris- tics of sodium methyldithiocarbamate. Fundam. Appl. Toxicol. 18(1):40-47. Pruett, S.B., L.P. Myers, and D.E. Keil. 2001. Toxicity of metam sodium. J. Toxicol. Environ. Health B Crit. Rev. 4(2):207-222.

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Methyl Isothiocyanate 191 Rosskamp. G., G. Schobel, A. Bhargava, P. Staben, and G. Schuppler. 1978. Methyl Isothiocyanate: ZK 3.318: A 12-13 Week Inhalation Study in the Rat, Project ID 374/77. Schering AG (as cited in EPA 2006b). Rubin, A.L., M. Silva, J. Gee, T. Moore, and T. Thongsinthusak. 2003. Risk Characteriza- tion Document: Methyl Isothiocyanate (MITC) Following the Agricultural Use of Metam Sodium. Medical Toxicology Branch, Department of Pesticide Regulation, California Environmental Protection Agency, Sacramento, CA. July 25, 2003 [online]. Available: http://www.cdpr.ca.gov/docs/risk/rcd/mitc_sb950.pdf [accessed Aug. 20, 2013]. Russell, M.J., and T.I. Rush. 1996. Methyl Isothiocyanate: Determination of Human Olfac- tory Detection Threshold and Human No Observable Effect Level for Eye Irritation. Report No. RR 96-049B, Sensory Testing Laboratory, University of California, Da- vis, CA. Submitted to U.S. EPA’s Office of Chemical Safety and Pollution Preven- tion. Sato, R. 1980. Two-year Chronic Toxicity and Oncogenicity Study with Methyl Isothio- cyanate in Albino Mice (106 Week Final Report). Schering Study No. T52. Nip- pon Experimental Medical Research Institute Co (as cited in Rubin et al. 2003). ten Berge, W.F., A. Zwart, and L.M. Appleman. 1986. Concentration-time mortality re- sponse relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 13(3):301-309. Ullman, L. 1985. 4-Hour Vapor Inhalation Toxicity (LC50) Study with Methylsenfoel (MITC) in Rats. Degassa AG. Study No. 042660. Research and Consulting Com- pany, AG (as cited in Rubin et al. 2003). van Doorn, R., M. Ruijten and T. van Harreveld. 2002. Guidance for the Application of Odor in Chemical Emergency Responses, Version 2.1, August 29, 2002. Presented at the NAC/AEGL Meeting, September 2002, Washington, DC. Verschueren, K. 2001. Methylisothiocyanate. Pp. 1507-1508 in Handbook of Environ- mental Data on Chemicals, Vol. 2, 4th Ed. New York: John Wiley & Sons.

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192 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF THE LEVEL OF DISTINCT ODOR AWARENESS FOR METHYL ISOTHIOCYANATE The level of distinct odor awareness (LOA) represents the concentration above which it is predicted that more than half of the exposed population will ex- perience at least a distinct odor intensity, and about 10% of the population will experience a strong odor intensity. The LOA should help chemical emergency responders in assessing the public awareness of the exposure from odor percep- tion. The LOA derivation follows the guidance of van Doorn et al. (2002). The odor detection threshold (OT50) for MITC was reported to be 1.7 ppm (Russell and Rush 1996). This value is the geometric mean of detection thresh- olds that ranged from 0.2 to 8 ppm among a panel of 33 individuals. The concentration (C) leading to an odor intensity (I) of distinct odor de- tection (I = 3) is derived using the Fechner function: I = kw × log (C ÷ OT50) + 0.5 For the Fechner coefficient, the default of kw = 2.33 was used due to the lack of chemical-specific data: 3 = 2.33 × log (C ÷ 1.7) + 0.5, which can be rearranged to log (C ÷ 1.7) = (3 - 0.5) ÷ 2.33 = 1.07, and results in C = (101.07) × 1.7 = 20 ppm The resulting concentration is multiplied by an empirical field correction factor. The factor takes into account that in everyday life, factors such as sex, age, sleep, smoking, upper airway infections, allergy, and distraction, may in- crease the odor detection threshold by up to a factor of 4. In addition, it takes into account that odor perception is very fast (about 5 seconds) which leads to the perception of concentration peaks. A factor of one-third is applied to adjust for peak exposure. Adjustment for distraction and peak exposure lead to a cor- rection factor of 4 ÷ 3 = 1.33. LOA = C × 1.33 = 20 ppm × 1.33 = 27 ppm The LOA for MITC is 27 ppm.

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Methyl Isothiocyanate 193 APPENDIX B DERIVATION OF AEGL VALUES FOR METHYL ISOTHIOCYANATE Derivation of AEGL-1 Values Key study: Russell, M.J., and T.I. Rush. 1996. Methyl Isothiocyanate: Determination of Human Olfactory Detection Threshold and Human No Observable Effect Level for Eye Irritation. Report No. RR 96-049B, Sensory Testing Laboratory, University of California, Davis, CA. Unpublished report submitted to U.S. EPA’s Office of Chemical Safety and Pollution Prevention. Toxicity end point: Lowest-observed-effect level (0.8 ppm) for ocular irritation in the clinical study was a NOAEL for ocular irritation according to the definition of the AEGL-1 value; exposure durations of 1-480 min. Time scaling: None, because NOAELs for each exposure duration were used. Uncertainty factors: 3 for intraspecies variability; based on direct-acting irritant mechanism of toxicity in which metabolic and physiologic differences are unlikely to play a major role (NRC 2001), and based on data showing approximately 2-fold range of human sensitivity to ocular irritants (Kjaergaard et al. 1992). Modifying factor: Not applicable Calculations: 10-min AEGL-1: C = 0.8 ÷ 3 ppm = 0.27 ppm 30-min AEGL-1: C = 0.8 ÷ 3 ppm = 0.27 ppm 1-h AEGL-1: C = 0.8 ÷ 3 ppm = 0.27 ppm 4-h AEGL-1: C = 0.8 ÷ 3 ppm = 0.27 ppm 8-h AEGL-1: C = 0.8 ÷ 3 ppm = 0.27 ppm

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194 Acute Exposure Guideline Levels Derivation of AEGL-2 Values In the absence of data for deriving AEGL-2 values for MITC and because MITC has a steep exposure-response curve in lethality studies (Clark and Jack- son 1977; Jackson et al. 1981), AEGL-2 values were calculated by dividing the AEGL-3 values by 3 (NRC 2001). 10-min AEGL-2: 63 ppm ÷ 3 = 21 ppm 30-min AEGL-2: 63 ppm ÷ 3 = 21 ppm 1-h AEGL-2: 50 ppm ÷ 3 = 17 ppm 4-h AEGL-2: 31 ppm ÷ 3 = 10 ppm 8-h AEGL-2: 16 ppm ÷ 3 = 5.3 ppm Derivation of AEGL-3 Values Key study: Jackson, G.C., G.C. Clark, D.E. Prentice, R.M. Read, C. Gopinath, and C. Cherry. 1981. Methyl Isothiocyanate: Acute Inhalation Toxicity in Rats. 4 Hour Exposure. RZ No. 81/082, Huntingdon Research Centre, Huntingdon, England. Unpublished report submitted to U.S. EPA’s Office of Chemical Safety and Pollution Prevention. Toxicity end points: NOAEL of 94 ppm for lethality in rats during 4-h exposure Time scaling: Cn × t = k; default values of n = 3 and n = 1 for scaling to shorter and longer exposure durations, respectively (NRC 2001). 30-min and 1-h values: (94 ppm ÷ 3)3 × 240 min = 7.383 × 106 ppm-min 8-h value: (94 ppm ÷ 3)1 × 240 min = 7,520 ppm-min Uncertainty factors: 3 for intraspecies variability; humans are not expected to vary greatly in their response to a direct-acting irritant (NRC 2001). Application of a higher uncertainty factor would result in concentrations inconsistent with human clinical studies.

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Methyl Isothiocyanate 195 Modifying factor: None Calculations: 10-min AEGL-3: Set equal to 30-min AEGL-3 = 63 ppm 30-min AEGL-3: C3 × 30 min = 7.383 × 106 ppm-min C = 63 ppm 1-h AEGL-3: C3 × 60 min = 7.383 × 106 ppm-min C = 50 ppm 4-h AEGL-3: C = 94 ppm ÷ 3 C = 31 ppm 8-h AEGL-3: C1 × 480 min = 7,520 ppm-min C = 16 ppm

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196 Acute Exposure Guideline Levels APPENDIX C ACUTE EXPOSURE GUIDELINE LEVELS FOR METHYL ISOTHIOCYANATE Derivation Summary AEGL-1 VALUES 10 min 30 min 1h 4h 8h 0.27 ppm 0.27 ppm 0.27 ppm 0.27 ppm 0.27 ppm (0.81 mg/m3) (0.81 mg/m3) (0.81 mg/m3) (0.81 mg/m3) (0.81 mg/m3) Key Reference: Russell, M.J., and T.I. Rush. 1996. Methyl Isothiocyanate: Determination of Human Olfactory Detection Threshold and Human No Observable Effect Level for Eye Irritation. Report No. RR 96-049B, Sensory Testing Laboratory, University of California, Davis, CA. Unpublished report submitted to U.S. EPA’s Office of Chemical Safety and Pollution Prevention. Test species/Gender/Number): Human volunteers, male and female, 9-16 per group Exposure route/Concentration/Duration: Inhalation; 0, 0.60, 1.9, or 3.3 ppm for 1 or 14 min; 0, 0.23, or 0.8 ppm for 4 h; 0 or 0.22 ppm for 8 h Effects: No ocular irritation Mild ocular irritation 1 min 3.3 ppm — 14 min 0.60 ppm 1.9 ppm 1h 0.23 ppm 0.8 ppm 4h 0.23 ppm 0.8 ppm 8h 0.22 ppm — End point/Concentration/Rationale: Ocular irritation was mild (less than that associated with cutting one mild onion) and, thus, did not represent the notable discomfort that constitutes an AEGL-1 effect (NRC 2001). Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: 1, because human data were used Intraspecies: 3, based on direct-acting irritant mechanism of toxicity in which metabolic and physiologic differences are unlikely to play a major role (NRC 2001), and based on data showing an approximately 2-fold range of human sensitivity to ocular irritants (Kjaergaard et al. 1992). Modifying factor: None Animal-to-human dosimetric adjustment: Not applicable Time scaling: None; the POD was tested for durations of 1-4 h with no increase in severity of effect; therefore, the irritant effects of MITC are not expected to become more severe with increasing duration at this concentration. Data adequacy: The study was well conducted and used an adequate numbers of healthy individuals. Ocular irritation is considered the most sensitive end point in studies with MITC.

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Methyl Isothiocyanate 197 AEGL-2 VALUES 10 min 30 min 1h 4h 8h 21 ppm 21 ppm 17 ppm 10 ppm 5.3 ppm (63 mg/m3) (63 mg/m3) (51 mg/m3) (30mg/m3) (16 mg/m3) Data adequacy: Data on MITC were inadequate for deriving AEGL-2 values. When data are lacking and the concentration-response curve is steep, AEGL-2 values may be de- rived by dividing the AEGL-3 values by 3 (NRC 2001). A steep concentration-response curve has been demonstrated for MITC. In a 1-h study with rats (Clark and Jackson 1977), the highest nonlethal concentration of 210 ppm is about one-third the LC50 of 635 ppm. In a 4-h study with rats (Jackson et al. 1981), the highest nonlethal concentration of 94 ppm is about one-half the LC50 of 180 ppm. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 63ppm 63 ppm 50 ppm 31 ppm 16 ppm (190 mg/m3) (190 mg/m3) (150 mg/m3) (94 mg/m3) (47 mg/m3) Key reference: Jackson, G.C., G.C. Clark, D.E. Prentice, R.M. Read, C. Gopinath, and C. Cherry. 1981. Methyl Isothiocyanate: Acute Inhalation Toxicity in Rats. 4 Hour Exposure. RZ No. 81/082, Huntingdon Research Centre, Huntingdon, England. Unpublished report submitted to U.S. EPA’s Office of Chemical Safety and Pollution Prevention. Test species/Strain/Number: Rat; Sprague-Dawley; groups of 5 per sex Exposure route/Concentration/Duration: Inhalation ; six concentrations for 4 h Effects: No mortality at 94 ppm; LC50 = 180 ppm End point/Concentration/Rationale: 94 ppm, highest 4-h nonlethal concentration Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: 1 Intraspecies: 3, considered sufficient to protect the sensitive population with respiratory diseases; application of larger uncertainty factors would conflict with results of clinical studies. Modifying factor: None Animal-to-human dosimetric adjustment: Not applicable Time scaling: Cn × t = k; default values of n = 3 and n = 1 for scaling to shorter and longer exposure durations, respectively (NRC 2001). Due to uncertainty in extrapolating a 4-h point of departure to a 10-min value, the 10-min AEGL-3 was set equal to the 30-min AEGL-3 value. Data adequacy: The 4-h study used multiple concentrations and an adequate numbers of animals. The values are supported by repeated-exposure studies performed in different laboratories.

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198 Ac cute Exposure Guideline Levels AP PPENDIX D CATEGOR PLOT FOR METHYL I RY R ISOTHIOCYA ANATE FIGUR D-1 Categor plot of anima and human d RE ry al data and AEGL values for meth hyl isothioc cyanate. TABLE D-1 Data Us in the Category Plot for M E sed Methyl Isothioc cyanate Source Species S ppm Minutes Categ gory Comments s AEGL-1 0.27 10 AEGGL AEGL-1 0.27 30 AEG GL AEGL-1 0.27 60 AEG GL AEGL-1 0.27 240 AEG GL AEGL-1 0.27 480 AEG GL AEGL-2 21 10 AEG GL AEGL-2 21 30 AEG GL AEGL-2 17 60 AEG GL AEGL-2 10 240 AEG GL AEGL-2 5.3 480 AEG GL AEGL-3 63 10 AEG GL AEGL-3 63 30 AEG GL AEGL-3 50 60 AEG GL (Continue ed)

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Methyl Isothiocyanate 199 TABLE D-1 Continued Source Species ppm Minutes Category Comments AEGL-3 31 240 AEGL AEGL-3 16 480 AEGL Russell and Rush 1996 Human 3.3 1 0 No ocular irritation Human 0.60 14 0 No ocular irritation Human 0.23 60 0 No ocular irritation Human 0.23 120 0 No ocular irritation Human 0.23 180 0 No ocular irritation Human 0.23 240 0 No ocular irritation Human 0.22 360 0 No ocular irritation Human 0.22 480 0 No ocular irritation Human 1.9 14 1 Subjective ocular irritation Human 0.8a 120 1 Subjective ocular irritation; increased blink rate Human 0.8a 180 1 Subjective ocular irritation; increased blink rate Human 0.8a 240 1 Subjective ocular irritation Clark and Jackson 1977 Rat 210 60 2 1-h highest nonlethal value Rat 635 60 SL 1-h LC50 Jackson et al. 1981 Rat 94 240 2 4-h highest nonlethal value Rat 180 240 SL 4-h LC50 Categories: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal. a Note: the discomfort associated with human exposure at 0.8 ppm (Russell and Rush 1996) was below the threshold for notable discomfort that constitutes an AEGL-1 effect.