1 NAC Proposed 1: November 2009

2

3

4

5 ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs)

6 FOR

7 METHYL IODIDE

8 (CAS Reg. No. 74-88-4)

9

10 CH3I

11

12

13

14

15 PROPOSED

16

17
METHYL IODIDE NAC Proposed 1: November 2009/ Page 2 of 49

1 PREFACE

2

3 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 

4 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous 

5 Substances (NAC/AEGL Committee) has been established to identify, review and interpret 

6 relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic 

7 chemicals.

8

9 AEGLs represent threshold exposure limits for the general public and are applicable to 

10 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels – AEGL-1, 

11 AEGL-2 and AEGL-3 – are developed for each of five exposure periods (10 and 30 minutes, 1 

12 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects. 

13 The three AEGLs are defined as follows:

14

15 AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per 

cubic meter [ppm or mg/m3 16 ]) of a substance above which it is predicted that the general 

17 population, including susceptible individuals, could experience notable discomfort, irritation, or 

18 certain asymptomatic, non-sensory effects. However, the effects are not disabling and are

19 transient and reversible upon cessation of exposure.

20

AEGL-2 is the airborne concentration (expressed as ppm or mg/m3 21 ) of a substance above 

22 which it is predicted that the general population, including susceptible individuals, could 

23 experience irreversible or other serious, long-lasting adverse health effects or an impaired ability 

24 to escape.

25

AEGL-3 is the airborne concentration (expressed as ppm or mg/m3 26 ) of a substance above 

27 which it is predicted that the general population, including susceptible individuals, could 

28 experience life-threatening health effects or death.

29

30 Airborne concentrations below the AEGL-1 represent exposure levels that could produce 

31 mild and progressively increasing but transient and nondisabling odor, taste, and sensory 

32 irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations 

33 above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity 

34 of effects described for each corresponding AEGL. Although the AEGL values represent 

35 threshold levels for the general public, including susceptible subpopulations, such as infants, 

36 children, the elderly, persons with asthma, and those with other illnesses, it is recognized that 

37 individuals, subject to unique or idiosyncratic responses, could experience the effects described 

38 at concentrations below the corresponding AEGL.

39

40
METHYL IODIDE NAC Proposed 1: November 2009/ Page 3 of 49

1 TABLE OF CONTENTS

2 PREFACE.....................................................................................................................................................2

3 LIST OF TABLES........................................................................................................................................5

4 SUMMARY..................................................................................................................................................6

5 1. INTRODUCTION................................................................................................................................8

6 2. HUMAN TOXICITY DATA...............................................................................................................9

7 2.1. Clinical Studies............................................................................................................................9

8 2.2. Case Studies.................................................................................................................................9

9 3. ANIMAL TOXICITY DATA ............................................................................................................10

10 3.1. Acute Toxicity ...........................................................................................................................10

11 3.1.1. Rats........................................................................................................................................10

12 3.1.2. Mice.......................................................................................................................................11

13 3.2. Repeat-Dose Studies..................................................................................................................12

14 3.3. Neurotoxicity .............................................................................................................................14

15 3.4. Developmental/Reproductive Toxicity ......................................................................................14

16 3.5. Genotoxicity...............................................................................................................................15

17 3.6. Chronic Toxicity/Carcinogenicity..............................................................................................15

18 3.7. Summary....................................................................................................................................16

19 4. SPECIAL CONSIDERATIONS ........................................................................................................16

20 4.1. Metabolism and Disposition ......................................................................................................16

21 4.1.1. Clinical and Laboratory Animal Studies................................................................................16

22 4.1.2. Physiologically-Based Pharmacokinetic (PBPK) Modeling ..................................................17

23 4.2. Mechanism of Toxicity ..............................................................................................................18

24 4.3. Structure-Activity Relationships................................................................................................21

25 4.4. Other Relevant Information .......................................................................................................21

26 4.4.1. Species Variability.................................................................................................................21

27 4.4.2. Susceptible Populations.........................................................................................................23

28 4.4.3. Concentration-Exposure Duration Relationship ....................................................................23

29 4.4.4. Concurrent Exposure Issues ..................................................................................................24

30 5. DATA ANALYSIS FOR AEGL-1.....................................................................................................24

31 5.1. Summary of Human Data Relevant to AEGL-1.........................................................................24

32 5.2. Summary of Animal Data Relevant to AEGL-1 ........................................................................24

33 5.3. Derivation of AEGL-1 ...............................................................................................................24

34 6. DATA ANALYSIS FOR AEGL-2.....................................................................................................25

35 6.1. Summary of Human Data Relevant to AEGL-2.........................................................................25

36 6.2. Summary of Animal Data Relevant to AEGL-2 ........................................................................25

37 6.3. Derivation of AEGL-2 ...............................................................................................................25

38 7. DATA ANALYSIS FOR AEGL-3.....................................................................................................27

39 7.1. Summary of Human Data Relevant to AEGL-3.........................................................................27

40 7.2. Summary of Animal Data Relevant to AEGL-3 ........................................................................27

41 7.3. Derivation of AEGL-3 ...............................................................................................................27
METHYL IODIDE NAC Proposed 1: November 2009/ Page 4 of 49

1 8. SUMMARY OF AEGLs....................................................................................................................28

2 8.1. AEGL Values and Toxicity Endpoints ......................................................................................28

3 8.2. Comparison with Other Standards and Guidelines ....................................................................28

4 8.3. Data Adequacy and Research Needs..........................................................................................30

5 9. REFERENCES...................................................................................................................................30

6 APPENDIX A: DERIVATION OF METHYL IODIDE AEGLS..............................................................39

7 APPENDIX B: CATEGORY GRAPH OF AEGL VALUES AND TOXICITY DATA ..........................50

8 APPENDIX C: DERIVATION SUMMARY FOR METHYL IODIDE AEGLS......................................47

9

10

11
METHYL IODIDE NAC Proposed 1: November 2009/ Page 5 of 49

1 LIST OF TABLES

2

3 S 1. Summary of AEGL Values for Methyl Iodide.......................................................................................................8

4

5 Table 1. Chemical and Physical Properties ...................................................................................................9

6 Table 2. Summary of Acute Inhalation Data in Laboratory Animals .........................................................12

7 Table 3. Summary of Repeat-Dose Studies................................................................................................13

8 Table 4. Comparison of Toxicity Values among the Monohalomethanes..................................................21

9 Table 5. AEGL-1 Values for Methyl Iodide...............................................................................................25

10 Table 6. AEGL-2 Values for Methyl Iodide...............................................................................................25

11 Table 7. AEGL-3 Values for Methyl Iodide...............................................................................................27

12 Table 8. Summary of AEGL Values ..........................................................................................................28

13 Table 9. Standards and Guidelines for Methyl Iodide ................................................................................29

14 Table 10. AEGL Values for Halomethanes................................................................................................30

15

16
METHYL IODIDE NAC Proposed 1: November 2009/ Page 6 of 49

1 SUMMARY

2

3 Methyl iodide (CH3I, CAS No. 74-88-4) is a colorless liquid that turns brown with 

4 exposure to light or moisture due to the liberation of iodine. It has a sweet ethereal odor which 

5 provides poor warning properties. Methyl iodide is a pre-plant biocide used to control insects, 

6 plant parasitic nematodes, soil-born pathogens, and weed seeds. It is also used as a methylating

7 agent in inorganic synthesis; in microscopy, as an embedding material for examining diatoms; 

8 and in testing for pyridine. Production data were not located.

9

10 Acute exposure to methyl iodide produces a number of effects in laboratory animals 

11 including degeneration of the nasal epithelium and neurotoxicity in rats and fetal toxicity in 

12 rabbits. Neurotoxicity has been observed in human accidental exposures. Absorption following 

13 inhalation is rapid; retention in humans averages 72%. Methyl iodide is rapidly metabolized in 

14 blood and tissue resulting in methylation products and release of inorganic iodide. Toxicity 

15 appears linked to metabolism. Halomethanes are usually conjugated via glutathione-S16 transferase (GST) with glutathione (GSH), but the conjugation of methyl iodide with glutathione 

17 may be non-enzymatic. Nasal lesions in rats are attributed to the sustained depletion of GSH 

18 below critical levels due to metabolism. Depletion of GSH, likely renders tissues susceptible to 

19 methylation and/or oxidative stress; in addition DNA repair processes may be inhibited. In the 

20 nasal cavity of the rat, the olfactory epithelium is the target tissue of methyl iodide. Transient 

21 neurotoxicity is attributed to the presence of the parent chemical in nerve cell membranes. 

22 Fetotoxicity in rabbits (early fetal deaths) is attributed to the unregulated uptake of iodine by the 

23 developing thyroid of the fetal rabbit. Accumulation of iodide in the rabbit fetus disrupts the 

24 fetal hypothalamic-pituitary-thyroid axis at a critical time in the development of the fetal thyroid. 

25 Fetal uptake of iodine is regulated in the rat and in humans. The data base for methyl iodide 

26 includes repeat-exposure, genotoxicity, developmental, subchronic, and chronic studies.

27

28 The AEGL-1 values are based on a weight-of evidence approach. A 6-hour exposure to 

29 27 ppm was a NOAEL for clinical signs that indicated neurotoxicity (U.S. EPA 2006). A 1-hour 

30 exposure to 100 ppm was a no-effect concentration for lesions of the nasal passage in rats, and a 

31 2-hour exposure to 100 ppm resulted in minimal lesions of the olfactory epithelium (Reed et al. 

32 1995). Results of studies with longer exposure durations showed that the nasal lesions are 

33 reversible. In a 4-week repeat-exposure study, 25 ppm was a no-effect level for irritation, 

34 neurotoxic signs, and gross pathologic changes in rats (Monsanto Company 1983). In a 13-week 

35 study, 21 ppm was a NOAEL for nasal degeneration in rats (U.S. EPA 2006). 

36

37 Based on the acute studies of U.S. EPA (2006) and Reed et al. (1995) with support from 

38 the repeat-exposure studies of Monsanto Company (1983) and U.S. EPA (2006), a weight-of 

39 evidence approach shows that exposures of rats to 27 ppm for 6 hours and to 100 ppm for 30 or 

40 60 minutes are NOAELs for both neurotoxicity and nasal lesions. The 6-hour 27 ppm 

41 concentration was used as the point of departure for the AEGL-1. Based on a higher blood:air 

42 partition coefficient for methyl iodide in rats compared with humans, resulting in greater uptake, 

43 an interspecies uncertainty factor of 1 was applied. Metabolism via glutathione conjugation is 

44 not expected to vary greatly among humans (Nolan et al. 1985). In addition, conjugation of 

45 methyl iodide with glutathione, the primary route of metabolism, may be non-enzymatic, further 

46 minimizing individual differences. Based on the neurotoxicity endpoint, Sweeney et al. (2009) 

47 estimated that GSH conjugation with methyl iodide in a GSTT-1 null person would be a factor of 
METHYL IODIDE NAC Proposed 1: November 2009/ Page 7 of 49

1 1.4 lower than that derived for a person with full GST activity. Therefore, the intraspecies 

2 uncertainty factor was lowered from the default of 10 to 3. 

3

4 Development of nasal lesions and neurotoxicity are systemic effects; methyl iodide is not 

5 an irritant at these concentrations. Therefore the AEGL-1 values were time-scaled. The 6-hour 

NOAEL for nasal lesions and neurotoxicity value of 9 ppm (27 ppm/3) was time scaled using Cn 6

7 x t = k. Because neurotoxicity is on a continuum with lethality, time scaling was based on the rat 

8 lethality data sets of Eastman Kodak Co. (1987), Reed et al. (1995), and U.S. EPA (2006). The 

time scaling value was 2 (C2 9 x t = k). The 6-hour value was time scaled to 10 minutes because 

10 one of the key studies (Reed et al. 1995) utilized a 0.5-hour exposure. Because the 8-hour time11 scaled value of less than 10 ppm appears unrealistic in light of no-effect concentrations of 10 

12 ppm and 20 ppm in subchronic and chronic studies reported by Blank et al. (1984) and U.S. EPA 

13 (2006), respectively, the 8-hour value was set equal to the 4-hour value of 11 ppm. 

14

15 The AEGL-2 values were based on reversible lesions of the olfactory epithelium of rats, 

16 i.e., a NOAEL for irreversible lesions (Reed et al. 1995). The point of departure was the 6-hour 

17 exposure to 100 ppm. This concentration (100 ppm for 6 hours) had no effect on breathing 

18 frequency in rats (DeLorme et al. 2009), and is the threshold for neurotoxicity that might impede

19 the ability to escape (93 ppm for 6 hours) (U.S. EPA 2006). Based on a higher blood:air partition 

20 coefficient for methyl iodide in rats compared with humans, an interspecies uncertainty factor of 

21 1 was applied. Metabolism via glutathione conjugation is not expected to vary greatly among 

22 humans (Nolan et al. 1985). In addition, conjugation of methyl iodide with glutathione, the 

23 primary route of metabolism, may be non-enzymatic, further minimizing individual differences. 

24 Based on the neurotoxicity endpoint, Sweeney et al. (2009) estimated that GSH conjugation with 

25 methyl iodide in a GSTT-1 null person would be a factor of 1.4 lower than that derived for a 

26 person with full GST activity. Therefore, the intraspecies default uncertainty factor of 10 was 

lowered to 3. Values were time-scaled using C2 27 x t = k. The fetotoxic effects of iodine liberated 

28 from methyl iodide were considered in the derivation of AEGL-2 values. Based on historical 

29 evidence of medical prescription of iodine to pregnant women, the inhaled dose at the 8-hour 

30 AEGL-2 is considered of minimal health risk for the developing fetus. 

31

32 The following data sets were considered in derivation of AEGL-3 values. Mortality rates 

33 for male and female rats inhaling 1190, 1554, or 1973 ppm for 1 hour were 20, 60, and 90%, 

34 respectively (Eastman Kodak Co. 1987). No mortality was observed in rats inhaling 100 ppm for 

35 0.5 to 6 hours (Reed et al. 1995). Mortality rates of male and female rats inhaling 581, 710, 797, 

36 or 1198 ppm for 4 hours were 0, 80, 80, and 100%, respectively (U.S. EPA 2006), and mortality 

37 rates of rats inhaling 27, 93, or 401 ppm for 6 hours were 0, 0, and 4% (U.S. EPA 2006). Using 

38 all data sets, the threshold for lethality was calculated at each AEGL-3 exposure duration using 

39 the probit-analysis based dose-response program of ten Berge (2006). The threshold for lethality 

40 was set at the lower limit of the 95% confidence limit. The data indicated a time-scaling value of 

2 (C2 41 x t = k). Based on a higher blood:air partition coefficient for methyl iodide in rats 

42 compared with humans, resulting in greater uptake, an interspecies uncertainty factor of 1 was 

43 applied. Although humans vary in the rate at which they metabolize halomethanes, the 

44 difference is not expected to be greater than three-fold (Nolan et al. 1985). Furthermore, the 

45 conjugation of methyl iodide with glutathione may be non-enzymatic, further minimizing 

46 differences in metabolism rates. Based on the neurotoxicity endpoint, Sweeney et al. (2009) 

47 estimated that GSH conjugation with methyl iodide in a GSTT-1 null person would be a factor of 

48 1.4 lower than that of a person with full GST activity. Therefore, the intraspecies uncertainty 
METHYL IODIDE NAC Proposed 1: November 2009/ Page 8 of 49

1 factor was lowered from the default of 10 to 3. A total uncertainty factor of 3 was applied to the 

2 time-scaled values of the ten Berge program.

3

4 The calculated values are listed in the table below. 

5

S 1. Summary of AEGL Values for Methyl Iodide

Classification 10-min 30-min 1-h 4-h 8-h

Endpoint 

(Reference)

AEGLB1

(Nondisabling)

54 ppm

(310 mg/m3

)

31 ppm

(180 mg/m3)

22 ppm

(130 mg/m3)

11 ppm

(64 mg/m3)

11 ppm

(64 mg/m3)

Weight of evidence 

NOAEL for clinical 

signs/effects -rat (U.S. 

EPA 2006; Reed et al. 

1995)

AEGLB2

(Disabling)

200 ppm

(1200 mg/m3)

120 ppm

(700 mg/m3)

82 ppm

(480 mg/m3)

41 ppm

(240 mg/m3)

29 ppm

(170 mg/m3)

Reversible lesions of 

the nasal passages –

rat (Reed et al. 1995)

AEGLB3

(Lethal)

670 ppm

(3900 mg/m3)

400 ppm

(2300 mg/m3)

290 ppm

(1700 mg/m3)

150 ppm

(870 mg/m3)

98 ppm

(570 mg/m3)

Lower limit of the 

95% CL based on the 

rat toxicity data of 

Eastman Kodak Co. 

(1987), Reed et al. 

(1995), and U.S. EPA 

(2006), calculated 

using the probitanalysis, doseresponse program of 

ten Berge (2006) 

6

7

8 1. INTRODUCTION

9

10 Methyl iodide (CH3I, CAS No. 74-88-4) is a colorless liquid that turns brown with 

11 exposure to light or moisture due to the liberation of iodine. It has a sweet ethereal odor which 

12 provides poor warning properties. It is applied to soil used to grow crops such a strawberries, 

13 tomatoes, peppers, and ornamentals. Liquid methyl iodide injected into soil rapidly volatilizes. 

14 Methyl iodide is an alternative to methyl bromide, an ozone-depleting fumigant. The vapor 

15 pressure is 375 mm Hg at 20C. Solubility is 1 part in 50 parts of water (O’Neil et al. 2001; 

16 ACGIH 1992; Gargas et al. 2009). Additional chemical and physical properties are listed in 

17 Table 1. 

18

19 The major sources of methyl iodide in the environment are the oceans. Near oceanic 

regions characterized by high biomass productivity, atmospheric levels range from 40-128 ng/m3 20

21 (IARC 1986).

22

23 Methyl iodide is produced commercially by any of the following methods: (1) reaction of 

24 methanol and iodine in the presence of phosphorous, (2) the reduction of an aqueous solution of 

25 iodine with bisulfate to yield hydriodic acid, which reacts with dimethyl sulfate to form methyl 

26 iodide, (3) the reaction of hydrogen gas, elemental iodine, and aqueous methanol, (4) reaction of 

27 methanol, iodine, and diborane (NIOSH 1984; Lauterbach and Ober 2001). Recent production 

28 data were not found. In the past, the major uses of methyl iodide were as a methylation agent in 
METHYL IODIDE NAC Proposed 1: November 2009/ Page 9 of 49

1 inorganic synthesis, in microscopy (because of its high refractive index), as an embedding 

2 material for examining diatoms, and in testing for pyridine (Lauterbach and Ober 2001). Methyl 

3 iodide is a pre-plant biocide used to control insects, plant parasitic nematodes, soil born 

4 pathogens, and weed seeds (U.S. EPA 2006). Although stored as a liquid under pressure, it 

5 volatilizes rapidly following soil injection as a pesticide.

6

TABLE 1. Chemical and Physical Properties

Parameter Value Reference

Synonyms Iodomethane O’Neil et al. 2001

Chemical formula CH3I O’Neil et al. 2001

Molecular weight 141.95 O’Neil et al. 2001

CAS Reg. No. 74-88-4 ACGIH 1992

Physical state Liquid O’Neil et al. 2001

Solubility in water 1 part/50 parts O’Neil et al. 2001

Vapor pressure 375 mm Hg at 20oC ACGIH 1992

Vapor density (air =1) 4.9 HSDB 2007

Liquid density (water =1) 2.28 at 20oC O’Neil et al. 2001

Melting point –66.5oC O’Neil et al. 2001

Boiling point 42.5oC; decomposes at 270oC O’Neil et al. 2001

Flammability limits in air Nonflammable NIOSH 1984

Conversion factors 1 ppm = 5.81 mg/m3

1 mg/m3 = 0.172 ppm

Calculated

7

8

9 2. HUMAN TOXICITY DATA

10 2.1. Clinical Studies

11

12 At high concentrations, methyl iodide has a sweet, ethereal odor. No odor threshold data 

13 were available. A concentration of 3700 ppm was reported as irritating (ACGIH 1992; Ruth 

14 1986), but the source of the data was not provided. Two metabolism studies were conducted 

15 with methyl iodide. These studies are summarized in Section 4.1, Metabolism and Disposition.

16

17 2.2. Case Studies

18

19 Schwartz et al. (2005) reviewed 11 case reports of methyl iodide poisoning. Six of the 

20 patients experienced a chronic neurological syndrome characterized by delayed psychiatric, 

21 behavioral, and cognitive sequelae. Acute symptoms in a fatal case included nausea, vomiting, 

22 diarrhea and oliguria, vertigo, slurred speech, visual disturbances, ataxia, tremor, irritability, 

23 drowsiness, and coma (Garland and Camps 1945). In a non-fatal case (Appel et al. 1975), 

24 symptoms were delayed, but included systemic, motor, and psychotic changes. Recovery of 

25 motor and memory skills was slow, with some symptoms present after 9 months. Air sampling 

26 was reported in only one study (Hermouet et al. 1996). Following repeated exposure of an 

27 unprotected worker which resulted in motor and sensory disturbances, air samples were taken at 

28 the work site where methyl iodide was decanted in open containers. The three sample 

29 concentrations were 16, 22, and 24 ppm (analysis method and air sampling time were not 

30 provided).

31
METHYL IODIDE NAC Proposed 1: November 2009/ Page 10 of 49

1 3. ANIMAL TOXICITY DATA

2

3 Methyl iodide was tested for irritation in a study with rabbits (Monsanto Company 

4 1982a). It was severely irritating to the skin (0.5 mL applied undiluted) and corrosive to the eye

5 (0.1 mL instilled undiluted). Data on methyl iodide toxicity were reviewed by Bolt and 

6 Gansewendt (1993) and U.S. EPA (2006). The studies reviewed by U.S. EPA (2006) were 

7 sponsor-submitted unpublished studies; original documents were not available. Recent, well 

8 characterized studies with laboratory rodents are summarized in Table 2. Older studies that 

9 generally used nominal concentrations are described only in the text. A single acute study that 

10 addressed neurotoxicity is summarized in Table 2 and described in Section 3.4.

11

12 3.1. Acute Toxicity

13 3.1.1. Rats

14

15 Deichmann and Gerarde (1969) reported a 4-hour LC50 in rats of 216 ppm, but details of 

16 the exposure were not provided.

17

18 The approximate lethal concentration (ALC) was determined in male Wistar rats 

19 (Comstock et al. 1950). Measured quantities of the gas were introduced into the chamber air 

20 stream at a constant rate. Rats were tested one at a time for 15 minutes. At 14 days 

21 postexposure, mortalities at concentrations of 1590 and 2760 ppm were 0/1 and 0/1. A rat 

22 exposed to 3790 ppm for 15 minutes died after 11 days. This concentration-exposure duration 

23 was considered the ALC. At higher concentrations, the survival time shortened in a 

24 concentration-dependent manner. The two rats that survived for 14 days post-exposure (15-

25 minute exposures to 1590 or 2760 ppm) showed no remarkable lesions when tissues were 

26 examined grossly and microscopically (MacNamee 1950). Following a 15-minute lethal 

27 exposure to 32,100 ppm, the trachea and lungs were severely eroded, with severe pulmonary 

28 edema and hemorrhage.

29

30 Groups of 5 male and 5 female Crl:CD rats were exposed to measured concentrations of 

31 1190, 1554, or 1973 ppm for one hour (Eastman Kodak Co. 1987) and were observed for 14 days 

32 post-exposure. Concentration-related mortality was observed post-exposure (days 1 and 2) in all 

33 groups: males, 0/5, 2/5, and 4/5; and females, 2/5, 4/5, and 5/5. The 1-hour LC10 was 1347 ppm 

34 for males and 976 ppm for females. The 1-hour LC10 for males and females combined was 1074 

35 ppm with 95% confidence limits of 565-1266 ppm. Concentration-related clinical signs 

36 observed during the exposure included lethargy, gait disturbance, gasping, and excessive tearing. 

37 At necropsy, edema and necrosis of the nasal passages, hemorrhage in the lungs, and enlarged 

38 livers with focal necrosis were observed.

39

40 In a recent study, groups of Sprague-Dawley rats (4 to 5/sex) inhaled 581, 710, 797, or 

41 1198 ppm for 4 hours (U.S. EPA 2006). Animals were observed for 14 days post-exposure and 

42 terminal necropsy findings were recorded. No deaths were recorded at 581 ppm. Clinical signs 

43 at all concentrations included gasping, ataxia, hypoactivity, nasal discharge, labored respiration, 

44 rales and red material around the nose. Deaths occurred within two days at the highest 

45 concentration. Following an initial weight loss, the surviving animals gained weight during the 

46 rest of the study. A few decedents showed several of the following macroscopic lesions: dark 

47 pituitary, dark red lungs, distended gas filled and congested stomach, hemorrhagic thymus, dark 

48 red adrenal glands, and distended intestines.
METHYL IODIDE NAC Proposed 1: November 2009/ Page 11 of 49

1

2 In a study that addressed effects on the nasal cavity, Reed et al. (1995) exposed groups of 

3 three male Alpk:APfsD (Wistar-derived) rats, nose-only, to a measured concentration of 100 

4 ppm methyl iodide for 0.5, 1, 2, 3, 4, or 6 hours. Rats were sacrificed 24 hours later. Additional 

5 groups inhaled 100 ppm for either 3 or 6 hours and were sacrificed either 0 to 6 hours or 2 weeks 

6 later. Microscopic examination of the nasal epithelium showed that the olfactory epithelium was 

7 the target tissue. At 24 hours postexposure, there were no observable changes in the nasal tissues 

8 of the rats administered 100 ppm for 0.5 or 1 hour. With increasing exposure duration, 

9 degeneration of the olfactory epithelium ranged from focal to complete destruction. The basal 

10 cell layer remained intact as did nerve bundles and Bowman’s glands in the lamina propria. The 

11 lesions were characterized as minimal at 100 ppm for two hours, slight at 100 ppm for 3 hours, 

12 moderate at 100 ppm for 4∙hours and marked at 100 ppm for 6 hours. Following the 6-hour 

13 exposure, the lesions included focal degeneration of the transitional epithelium in the anterior 

14 nasal passages while the respiratory epithelium was unaffected. The earliest detected nasal 

15 lesion, vacuolation of the olfactory epithelium, was observed in rats killed immediately after a 3-

16 hour exposure. In rats sacrificed 2 weeks after exposure for 3 or 6 hours, there was almost 

17 complete regeneration of the nasal epithelium. 

18

19 The respiratory frequency was measured in groups of 4 rats exposed to 0, 25, or 100 ppm 

20 and in groups of 4 rabbits exposed to 0 or 20 ppm methyl iodide for 6 hours (DeLorme et al. 

21 2005; 2009). No significant reductions in breathing frequency were observed in either rats or 

22 rabbits. In rats, minute volume increased at 25 ppm but decreased at 100 ppm as did total 

23 volume inhaled. At 20 ppm, rabbits demonstrated a 30% increase over controls in total volume

24 of air inhaled. According to the authors, neither species demonstrated a sensory irritant effect or 

25 decreased inhalation uptake of test atmosphere. 

26

27 3.1.2. Mice

28

29 Buckell (1950) determined the LC50 in an unreported strain of male white mice. 

30 Concentrations ranged from approximately 86 to 14,600 ppm, and were determined by metering 

31 a measured quantity of methyl iodide into the exposure chamber. Exposure durations were not 

32 clearly stated. Air samples were collected in alcoholic potash and liberated iodine was measured 

33 by titration. All mice exposed to approximately 900 ppm or greater died. Obvious signs of 

34 toxicity included irritation of the eyes and increased general activity. Groups of 10 mice were 

35 also exposed to 860 ppm for varying times and then observed for a week. Mortality was 0 after a 

36 20-minute exposure and 100% after an 80-minute exposure. The LC50 time was estimated at 57 

37 minutes, i.e. 57-minute LC50 of 860 ppm.
METHYL IODIDE NAC Proposed 1: November 2009/ Page 12 of 49

1

TABLE 2. Summary of Acute Inhalation Data in Laboratory Animals

Species

Concentration 

(ppm)

Exposure 

Time Effecta Reference

Rat 1190

1554

1973

1074

1458

1 hour

1 hour

1 hour

1 hour

1 hour

20% mortality

60% mortality

90% mortality

Calculated LC10

Calculated LC50

Eastman Kodak Co. 

1987

Rat 581

710

797

1198

691

4 hours

4 hours

4 hours

4 hours

4 hours

0% mortality 

80% mortality

80% mortality

100% mortality

Calculated LC50

Clinical signs of gasping, ataxia, 

hypoactivity, nasal discharge, labored 

respiration, rales and red material 

around the nose at all concentrations

U.S. EPA 2006

Rat 27

93

401

6 hours

6 hours

6 hours

NOAEL for neurotoxicity

Clonic convulsions; decreased body 

temperature, decreased motor activity

Additional neurotoxicity, gasping, 

one death (4% mortality)

U.S. EPA 2006

Rat 100 0.5 hour

1 hour

2 hours

3 hours

4 hours

6 hours

No observable change, nasal passages

No observable change, nasal passages

Minimal lesions, olfactory epithelium

Slight lesion, olfactory epithelium

Moderate lesion, olfactory epithelium

Marked lesion, olfactory epithelium; 

almost complete regeneration after 2 

weeks

Reed et al. 1995

Rat 0, 25, or 100 6 hours No clear effect on respiratory 

parameters

DeLorme et al. 2005

Mouse 860

860

860

20 minutes

80 minutes

57 minutes

0/10 dead

10/10 dead

LC50

Buckell 1950

2

3

4 3.2. Repeat-Exposure Studies

5

6 Repeat-dose studies are summarized in Table 3.

7

8 Groups of 5 male and 5 female Sprague-Dawley rats inhaled 150 ppm methyl iodide for 6 

9 hours/day for 3 days (Monsanto Co. 1982b). Clinical signs included eye irritation and sneezing 

10 in all animals. Tremors were observed in one female on the third day. No deaths were reported.

11

12 Groups of 10 male and 10 female Sprague-Dawley rats inhaled 0, 25, 74, or 140 ppm for 

13 6 hours/day, 5 days/week for 4 weeks (Monsanto Company 1983; Blank et al. 1984). Exposure14 related signs in the 74- and 143-ppm groups included irritation of the eyes, nasal discharge, 

15 tremors, disturbances of the fur, poor general physical condition, and lowered mean body weight 

16 compared with controls. Five animals, 2 males and 3 females in the 140-ppm group died or were 

17 sacrificed moribund during the last week of exposure. No gross lesions were observed. The “no18 effect” level was 25 ppm.
METHYL IODIDE NAC Proposed 1: November 2009/ Page 13 of 49

1

2 Additional groups of 10 male and 10 female Sprague-Dawley rats inhaled 0, 10, 30, or 60 

3 ppm for 14 weeks (Blank et al. 1984). Ocular irritation and lower mean body weight were 

4 observed in the “higher” exposure groups. Microscopic examination of tissues in the 60-ppm 

5 exposure groups failed to reveal gross or microscopic lesions. The NOAEL was 10 ppm. No 

6 further details were reported in the published abstract.

7

8 In a subchronic inhalation toxicity study, described in U.S. EPA (2006), methyl iodide 

9 (99.7% pure) was administered whole-body to groups of 20 male and 20 female Crl:CD (SD)IGS 

10 BR rats for 6 hours/day, 5 days/week for 13 weeks. Analytically-determined concentrations were 

11 0, 5, 21, and 70 ppm. Ten rats/sex/concentration were sacrificed after 4 weeks, and the 

12 remaining rats were sacrificed after 13 weeks. There were no effects of treatment on mortality, 

13 ophthalmology, urinalysis, hematology, organ weights, or gross pathology. There was an initial 

14 decrease in body weight, body weight gain, and food consumption in males that received 70 ppm 

15 for 13 weeks. At 70 ppm, there was degeneration of the olfactory epithelium (not further 

16 described). The NOAEL for olfactory degeneration was 21 ppm.

17

18 In a range-finding study, groups of three New Zealand rabbits inhaled 0, 30, 100, or 300 

19 ppm methyl iodide for 6 hours/day for 5 days (Nemec et al. 2009). No clinical signs were 

20 reported in the group exposed to 30 ppm. At 100 ppm, food consumption and body weight 

21 deficits were observed. At 300 ppm, all rabbits died or were euthanized in extremis prior to 

22 scheduled termination. Toxicity described as behavioral/central nervous system and 

23 cardiopulmonary signs were accompanied by reduced food intake and loss of body weight.

24

TABLE 3. Summary of Repeat-Dose Studies

Species

Concentration 

(ppm)

Exposure 

Time Effect Reference

Rat 150 6 hours/day,

3 days

No deaths, eye irritation and 

sneezing; slight tremors in one of 

5 females

Monsanto Company 

1982b

Rat 0, 25, 74, 140 6 hours/day,

5 days/week,

4 weeks

Exposure–related signs of eye 

irritation, nasal discharge, 

tremors, lower mean body 

weight; mortality 20% at 143 

ppm No clinical signs at 25 ppm.

Monsanto Company 

1983; Blank et al. 1984

Rat 0, 10, 30, 60 6 hours/day,

5 days/week,

14 weeks

Ocular irritation and decrease in 

mean body weight in 30 and 60 

ppm groups; no lesions 

observable microscopically; 10 

ppm – no effect concentration

Blank et al. 1984

Rat 0, 5, 21, 70 6 hours/day,

5 days/week, 

13 weeks

No systemic effects. 

Degeneration of olfactory 

epithelium at 70 ppm in both 

sexes; initial body weight 

decrease in males at 70 ppm. 

NOAEL for olfactory lesions was 

21 ppm

U.S. EPA 2006

Rabbit 0, 30, 100, 300 6 hours/day, 

5 days

30 ppm: no signs reported

100 ppm: reduced body weight

300 ppm: death of all 3 rabbits

Nemec et al. 2009

25
METHYL IODIDE NAC Proposed 1: November 2009/ Page 14 of 49

1

2 3.3. Neurotoxicity

3

4 Groups of 12 male and 12 female Crl:CD rats inhaled methyl iodide (100% purity), 

5 whole-body, for 6 hours (U.S. EPA 2006). Analytically-determined concentrations were 0, 27, 

6 93, and 401 ppm. Neurobehavioral assessment took place pre-exposure, at the predicted time of 

7 peak effect on the day of exposure (3 hours post-exposure), and on days 7 and 14 post-exposure. 

8 On day 7, there was a slight weight loss, 2-10%, in the groups exposed to 93 and 401 ppm. 

9 Neurotoxicity signs were limited to the day of exposure. At 93 ppm on the day of exposure, the 

10 following neurotoxicity signs were observed: clonic convulsions in one female (slight repetitive 

11 movements of the jaw), decreased body temperature (both sexes), and decreased total motor 

12 activity relative to controls (decreases of 75% in males and 81% in females). More animals were 

13 affected at the 401 ppm concentration and signs were more severe, e.g., gasping. In addition, one 

14 female in the 401 ppm group was found dead on day 6. This animal experienced clonic 

15 convulsions, yellow material around the urogenital area, dried red material around the nose, 

16 mouth, and eye, shallow respiration, and decreased defecation prior to death. The most common 

17 clinical signs in the surviving animals were decreased defecation and dried red material around 

18 the nose, mouth, and/or eyes in both sexes. Slightly decreased motor activity in females on the 

19 day of exposure was considered equivocal, and 27 ppm was considered a NOAEL for 

20 neurotoxicity in both sexes. 

21

22 3.4. Developmental/Reproductive Toxicity

23

24 An intraperitoneal injection of 100 mg/kg methyl iodide to adult male Sprague-Dawley 

25 rats reduced hepatic and epididymal glutathione levels to 2 and 37% of control values, 

26 respectively, at 1 hour, but had little effect on testicular glutathione (Gandy et al. 1990). 

27 Glutathione may protect against chemical-induced germ cell mutations. Substantial recovery of 

28 glutathione took place by 16 hours post-exposure.

29

30 A two-generation reproductive toxicity study with rats was reported by U.S. EPA (2006). 

31 Tested concentrations were 0, 5, 20, and 50 ppm, and exposure duration was 6 hours/day. 

32 Offspring were exposed beginning on post-natal day 28. For the parental generation, both the 

33 systemic and portal of entry NOAELs were 20 ppm. The parental LOAELs for portal of entry 

34 and systemic effects, both 50 ppm, were based on body weight changes and histopathology 

35 including degeneration of the olfactory epithelium. The offspring NOAEL was 5 ppm. The 

36 offspring LOAEL of 20 ppm was based on decreases in body weight, body weight gain, and 

37 thymus weight. The reproductive NOAEL was 5 ppm; the LOAEL of 20 ppm was based on 

38 delayed vaginal patency.

39

40 In a developmental toxicity study, female rats (strain unidentified) inhaled 0, 5, 20, or 60 

41 ppm for 6 hours/day on gestation days (GD) 6 through 19 (U.S. EPA 2006). The maternal 

42 NOAEL was 20 ppm. The maternal LOAEL was 60 ppm and was based on a decreased body 

43 weight gain of 19%. The developmental NOAEL was 60 ppm; a LOAEL was not attained.

44

45 In a developmental toxicity study, groups of six timed-pregnant New Zealand rabbits 

46 inhaled 0, 10, 26, or 74 ppm methyl iodide during GD 6-28 (U.S. EPA 2006). Due to maternal 

47 toxicity, the 74 ppm exposure was reduced to 50 ppm beginning on GD 18. There was a dose48 dependent increase in the litter proportions of late fetal deaths and post-implantation loss and/or 
METHYL IODIDE NAC Proposed 1: November 2009/ Page 15 of 49

1 decreased fetal body weight. Three females were euthanized in extremis between GD 24 and 27. 

2 At 25 ppm, there were increased fetal losses (late) and increased post-implantation loss; fetal 

3 body weight was non-significantly reduced. At 74/50 ppm, late fetal losses were increased and 

4 fetal body weight was reduced. The NOAEL for developmental effects was 10 ppm. No 

5 maternal toxicity was observed in the females exposed to 10 ppm. In a second study, groups of 

6 24 timed-pregnant rabbits inhaled 0, 2, 10, or 20 ppm on GD 6-28. Effects in the 20 ppm group 

7 were similar to those described for the 25 ppm group in the earlier study. There were no evident 

8 effects on fetal morphology. The NOAEL for developmental effects was 10 ppm. 

9

10 A study was conducted to establish the critical period of exposure during gestation that 

11 resulted in fetal loss in the above study with rabbits (Nemec et al. 2009). Groups of 24 pregnant 

12 New Zealand white rabbits inhaled 0 or 20 ppm for 6 hours/day during GD 6-28, 6-14, 15-22, 23-

13 24, 25-26, or 27-28 for 6 hours/day. At 20 ppm, increased fetal losses were 21% (GD 6-28), 9% 

14 (GD 23-24), and 11% (GD 25-26). The most susceptible window of exposure for eliciting 

15 developmental toxicity in rabbits exposed to methyl iodide vapors was GD 23-26. 

16

17 3.5. Genotoxicity

18

19 Numerous studies indicate that methyl iodide is genotoxic due to its methylating 

20 capabilities (Bolt and Gansewendt 1993). Methyl iodide methylates hemoglobin at the free SH21 group of cysteine in experimental animals as well as in humans. Methyl iodide was mutagenic in

22 Salmonella typhimurium bacterial strains TA1535 and TA100 (Andrews et al. 1976; McCann et 

23 al. 1975). Methyl iodide was a direct-acting mutagen for mouse lymphoma L5178Y/TK+/- cells 

24 (Clive et al. 1979) and at the HGPRT locus in Chinese hamster ovary (CHO) cells 

25 (concentrations of 0 to 3 μg/mL) (Amacher and Zelljadt 1984). Methyl iodide failed to transform 

26 C3H/10T1⁄2 CL8 cells (Oshiro et al. 1981).

27

28 Results were conflicting in other studies. In a summary provided by IARC (1986), the 

29 authors stated that methyl iodide induced DNA damage and is mutagenic to bacteria (Salmonella 

30 typhimurium TA100 (assayed in desiccators in the absence of S9) but not TA1535, TA1536, 

31 TA1537, TA1538, TA98, or TA100 in plate incorporation assays. Methyl iodide gave a positive 

32 result in the Escherichia coli pol A and WP2 uvrA assays in the presence or absence of an 

33 exogenous metabolic system. It induced mitotic recombination in yeast and mutations in 

34 cultured mammalian cells. It induced transformation in Syrian hamster embryo cells, but not in 

35 C3H 10T1⁄2 cells. Methyl iodide tested positive in the Syrian hamster embryo micronucleus test 

36 in vitro (concentrations not provided) (Fritzenschaf et al. 1993).

37

38 In a series of recent unpublished studies submitted to the U.S. EPA (2006), the only 

39 evidence of genotoxicity was the induction of structural chromosome aberrations (clastogenesis) 

40 in CHO. Methyl iodide was non-mutagenic in Salmonella typhimurium strains TA98, TA100, 

41 TA1535, and TA1537 and in Escherichia coli. It was also negative in an in vivo micronucleus 

42 assay in mice. Tested concentrations were not provided. The conflict with earlier study results

43 was not addressed. 

44

45 3.6. Chronic Toxicity/Carcinogenicity

46

47 Methyl iodide induced local sarcomas in rats injected subcutaneously with a weekly 

48 dosage of 10 mg/kg for an unstated period of time (Druckrey et al. 1970). It also produced lung 
METHYL IODIDE NAC Proposed 1: November 2009/ Page 16 of 49

1 tumors in a cancer-susceptible strain of mice (Strain A) injected intraperitoneally, weekly for 24 

2 weeks (Poirier et al. 1975). In the latter study, survival was adversely affected at a dose of 44 

3 mg/kg/week. Half this dose, 22 mg/kg/day which equates to 20-25 ppm in a human inhaling 

4 methyl iodide for 8 hours (calculated by ACGIH 1992) allowed survival of all 20 treated mice, 

5 and a non-significant increase in lung tumors.

6

7 In an inhalation chronic toxicity/carcinogenicity study, groups of 60-70 male and 60-70

8 female Crl:CD (SD)IGS BR rats inhaled 0, 5, 10, 20, or 60 ppm, whole body, for 6 hours/day, 5 

9 days/week (U.S. EPA 2006). Animals were examined daily for clinical signs and activity. At 20 

10 ppm there was an increased incidence of salivary gland squamous cell metaplasia. At 60 ppm, 

11 degeneration of the olfactory epithelium as well as perturbations of the thyroid-pituitary axis, 

12 accompanied by thyroid histopathology, were observed. No other histopathological lesions were 

13 observed. The NOAEL for effects on the olfactory epithelium was 20 ppm.

14

15 3.7. Summary

16

17 Acute exposures to methyl iodide produce a number of effects in laboratory animals 

18 including degeneration of the nasal epithelium and neurotoxicity in rats and fetal toxicity in 

19 rabbits. Six-hour exposures to 27 and 93 ppm were a NOAEL and LOAEL for neurotoxicity 

20 (U.S. EPA 2006). Exposure to 100 ppm for 6 hours induced reversible lesions in the olfactory 

21 epithelium of rats (Reed et al. 1995). Exposures of ≤1 hour to 100 ppm did not result in nasal 

22 lesions. The highest non-lethal value for rats in a well-conducted study was a 4-hour exposure to 

23 581 ppm (U.S. EPA 2006). Calculated 1-hour and 4-hour LC50 values were 1458 (Eastman 

24 Kodak Co. 1987) and 691 ppm (U.S. EPA 2006), respectively. Results of genotoxicity studies 

25 were conflicting. Methyl iodide was not carcinogenic in a well-conducted chronic study. In 

26 developmental studies, rabbits, but not rats, were sensitive to the fetotoxic effects of methyl 

27 iodide.

28

29 4. SPECIAL CONSIDERATIONS

30 4.1. Metabolism and Disposition

31 4.1.1. Clinical and Laboratory Animal Studies

32

33 Inhaled monohalomethanes such as methyl chloride and methyl bromide are rapidly 

34 absorbed by the lungs and metabolized in the liver by conjugation with glutathione (GSH) to 

35 form S-methylglutathione (Kornbrust and Bus 1983; U.S. EPA 2007a). Metabolism of methyl 

36 iodide following oral or subcutaneous injection follows the same pathway (Barnsley and Young 

37 1965; Johnson 1966; Bolt and Gansewendt 1993). Cleavage of the glutamic acid and glycine 

38 moieties of GSH yields S-methylcysteine; transamination and decarboxylation yields the 

39 mercapturic acid, methylthioacetic acid, which is excreted in the urine. Following subcutaneous 

40 injection of rats with methyl iodide, small amounts of S-methylcysteine, methylthioacetylglycine, 

41 methylmercapturic acid, and methylthioacetic acid were identified in the urine (Barnsley and 

42 Young 1965). The initial conjugation of monohalomethanes with GSH may be either non43 enzymatic or enzymatically catalyzed. Although methyl chloride and methyl bromide are 

44 conjugated primarily enzymatically, an in vitro study with human erythrocyte cytoplasm showed

45 that the major conjugation process of glutathione with methyl iodide is non-enzymatic (Hallier et 

46 al. 1990).

47
METHYL IODIDE NAC Proposed 1: November 2009/ Page 17 of 49

1 In a clinical study, eighteen healthy adult volunteers (17 males and 1 female) inhaled 

2 methyl iodide labeled with I-132 for 5 minutes (Morgan and Morgan 1967). Subjects inhaled 

3 and exhaled through a two-way mouthpiece. Respiratory rate, duration of breath, tidal volume, 

4 minute volume and vital capacity were measured or calculated. Absorption was measured as the 

5 amount inhaled minus the amount exhaled. Volunteers varied their breathing rates in order to 

6 observe the effect of respiratory rate on absorption. Under these conditions, absorption by the 

7 lungs ranged from 53% at 19.5 breaths/minute to 92% at 2.3 breaths/minute; the average 

8 retention was 72%. There was no excretion of methyl iodide from the lungs at the end of the 

9 exposure period. Absorption was correlated with breathing rate to a greater degree than with 

10 tidal volume. The concentration of methyl iodide in the inspired air was not provided. The 

11 radiation dose to the thyroid averaged 3 mrem; the then current International Commission on 

12 Radiological Protection occupational standard was 30 rem/year.

13

14 In a second study, four of the above male subjects inhaled methyl iodide labeled with I15 132 in order to address metabolism (Morgan et al. 1967). The subjects inhaled methyl iodide for 

16 5 minutes. Iodine uptake by the thyroid was measured externally with a radiation detector over a 

17 period of approximately 12 hours. Radioactivity in blood and urine were also sampled. Uptake 

18 into the blood was rapid (within minutes). Half-time for buildup of iodine in the thyroid was 200 

19 minutes; uptake was 42% of the inhaled dose. About 30% of the radioactive iodine was excreted 

20 in the urine in 5 hours. The authors concluded that inhaled methyl iodide is broken down into 

21 iodide ion which is subsequently involved in normal iodine metabolism. The amount of iodine 

22 in the inhaled air was calculated as equivalent to less than one-quarter of the average daily intake. 

23 The radiation dose to the thyroid of the subjects averaged less than 20 mrem/experiment. No 

24 further data were provided.

25

26 Thrall et al. (2005; 2009a) described the extent of nasal absorption of methyl iodide in 

27 anesthetized rats and rabbits. Nasal absorption in six rats exposed to 1 ppm averaged 63% 

28 (range, 51-71%). Nasal absorption in nine rabbits exposed at 2, 10, or 50 ppm averaged 72% 

29 (range, 57-92%), regardless of exposure concentration. 

30

Sprague-Dawley rats inhaled 14 31 C-labeled methyl iodide (U.S. EPA 2006). The only 

32 stated concentrations were 25 and 233 ppm. Maximum blood concentrations were achieved 

33 within 0-2 hours and were proportional to the air concentrations. The initial half-life was 5.1-7.2 

34 hours, and the terminal half-life was 116-136 hours. Recovered radioactivity was primarily as 

35 CO2 (39-61%) and in the urine (27-33%). Feces accounted for <2% of the dose. At 0-1 hour 

36 post-treatment, radioactivity was relatively high in the kidney, lung, and nasal turbinates of the 

37 rats exposed to 25 ppm, and in the kidney, thyroid, and lung of rats exposed to 233 ppm. The 

38 major metabolites were expired CO2, and N-(methylthioacetyl) glycine and S-methyl glutathione 

39 which were excreted in the urine. Minor metabolites were methylthioacetic acid, methyl 

40 mercapturic acid, and S-methyl cysteine.

41

42 4.1.2. Physiologically-Based Pharmacokinetic (PBPK) Modeling

43

44 Rate constants for the GSH metabolism of methyl iodide were determined in cytosols 

45 prepared from the liver and kidneys of rats, human donors, female rabbits and rabbit fetuses; 

46 from rabbit olfactory and respiratory epithelium; and from rabbit and rat blood (Poet et al. 2009). 

47 Methyl iodide was metabolized in the kidney tissue of adults of all three species, but not in fetal 

48 rabbit kidney. Maximal metabolic rates were similar in liver from rat and human donors, but a 
METHYL IODIDE NAC Proposed 1: November 2009/ Page 18 of 49

1 factor of 4 less in the liver of adult rabbits. A similar pattern was observed in kidney cytosols 

2 from the adults of the three species. Metabolism of methyl iodide in nasal tissues of the rabbit 

3 was essentially first-order. The metabolism of methyl iodide in human liver cytosol from five 

4 donors indicated two populations, one high affinity/low capacity and one with a lower affinity 

5 but higher capacity.

6

7 A PBPK model developed by Sweeney et al. (2005; 2009) reduces uncertainties in risk 

8 assessment extrapolations for methyl iodide. The model describes (1) nasal tract dosimetry and 

9 glutathione depletion in the rat to evaluate nasal toxicity and (2) iodide kinetics in the pregnant 

10 rabbit to address developmental toxicity. The model enables calculation of human equivalent 

11 concentrations to the animal no-observed levels using chemical-specific parameters to determine 

12 the internal dose instead of default assumptions. The proposed mechanism for nasal 

13 histopathology involves GSH depletion as a key event leading to damage of the nasal olfactory 

14 epithelium. Nasal toxicity may also involve methylation of cell macromolecules, formation of 

15 reactive metabolites, or oxidative stress. A sustained decrease in GSH is considered the critical 

16 event. Glutathione depletion of 50% or greater from normal levels may be associated with 

17 toxicity. Excess serum iodide is implicated as the critical element in the mechanism proposed for

18 fetal losses. Excess iodine has been shown to lead to fetal thyroid hormone disruptions leading 

19 to fetal losses. No-observed adverse effect levels for these endpoints were developed for a 1-day, 

20 24-hour exposure of bystanders or 8 hour/day exposure of workers. Variability of the PBPK 

21 models support application of uncertainty factors of approximately 2 for intra-human 

22 pharmacokinetic variability for the nasal effects and acute neurotoxicity. The adult human model 

23 indicated that depletion of GSH in the dorsal olfactory epithelium to 50% of control for 

24 bystanders would be achieved after 24 hours of exposure to 72 ppm methyl iodide. For workers 

25 exposed for 8 hours, 50% GSH depletion would be achieved by the end of the shift at an 

26 exposure concentration of 110 ppm. 

27

28 Data showing that humans are less sensitive to the effect that causes developmental 

29 toxicity in rabbits was incorporated into the PBPK model developed by Sweeney et al. (2009). 

30 The result shows that the concentration causing the developmental endpoint in rabbits is higher 

31 than that for the nasal endpoint (Mileson et al. 2009). Thus, nasal olfactory degeneration is the 

32 primary endpoint for risk assessment of acute exposure to methyl iodide.

33

34 4.2. Mechanism of Toxicity

35

36 In studies performed as part of the registration process for methyl iodide, three effects 

37 were identified that warrant consideration for human risk assessment: nasal lesions in the rat, 

38 acute neurotoxicity in the rat, and fetal loss in the rabbit. Following a review of recent key 

39 studies on metabolism and toxicity, Kirman et al. (2009) evaluated the possible mode(s) of action 

40 through which methyl iodide produces toxicity in animals. Key studies were summarized and 

41 several possible modes of action were compared to the modified Hill criteria (described in U.S. 

42 EPA’s 2005 Guidelines for Carcinogen Risk Assessment). The available data support the 

43 following hypotheses:

44 Nasal lesions in rats: glutathione depletion in the rat nasal epithelium;

45 Transient neurotoxicity in rats: modification of ion currents in nerve cells;

46 Rabbit fetal resorptions: modulation of the thyroid hormones by iodine.
METHYL IODIDE NAC Proposed 1: November 2009/ Page 19 of 49

1

2 The olfactory toxicity of methyl iodide is attributed to the sustained depletion of GSH 

3 below critical levels due to methyl iodide metabolism (U.S. EPA 2006; Gargas and Kinzell 2007; 

4 Kirman et al. 2009). In the nasal cavity of the rat, the olfactory epithelium is the target tissue of 

5 methyl iodide. Cytosolic GST catalyzes conjugation with GSH in both the olfactory and 

6 respiratory epithelium, but the rate is 4-fold higher in the olfactory epithelium. Conjugation with 

7 glutathione, results in S-methyl-glutathione. This pathway is considered a detoxifying 

8 mechanism. Cytochrome P-450 metabolism does not appear to play a role in methyl iodide 

9 toxicity. Depletion of glutathione leads to olfactory tissue lesions and cell death (Chamberlain et 

10 al. 1998a; 1998b). Methyl iodide is also an alkylating agent (Bolt and Gansewendt 1993).

11

12 Male Sprague-Dawley rats inhaled 0, 25, or 100 ppm methyl iodide for 6 hours/day for 2 

13 days (Himmelstein et al. 2005; 2009). A time-dependent reduction in GSH levels in blood, 

14 kidney, liver, and nasal tissue was observed, with the greatest reduction in nasal and olfactory 

15 tissue. In the group exposed to 100 ppm, GSH levels were 24 and 14% of control in olfactory 

16 and respiratory epithelia, respectively. Control animals showed normal diurnal fluctuations in 

17 tissue levels of GSH. Erythrocyte S-methylcysteine hemoglobin adducts also increased. 

18 Evidence of the protection of GSH against toxicity was obtained by pre-treating animals with 

19 substances that deplete or replenish GSH. 

20

21 The same mechanism of toxicity, mediated via glutathione depletion, was originally 

22 considered responsible for neurotoxicity (Bonnefoi et al. 1991; Bonnefoi 1992; Davenport et al. 

23 1992). In in vitro studies with rat cerebellar granular cells, methyl iodide depleted GSH, likely 

24 rendering the tissue susceptible to methylation and/or oxidative stress; in addition DNA repair 

25 processes may be inhibited (Chamberlain et al. 1999; Fonnum and Lock 2004). However, based 

26 on several factors, Gargas and Kinzell (2007; Kirman et al. 2009) suggest that neurotoxicity 

27 observed in rats is most likely the result of a general inhibition of ion currents in the membranes 

28 of nerve cells due to high concentrations of the circulating parent chemical. These factors, which 

29 include the reversibility of the neurological effects and the speed with which neurological effects 

30 occur, suggest that the peak concentration of methyl iodide in the brain is the appropriate internal 

31 dose measure. 

32

33 The mechanism of toxicity leading to developmental effects in rabbits is considered 

34 excess iodide which leads to fetal thyroid hormone disruptions, resulting in fetal loss (U.S. EPA 

35 2006; Gargas and Kinzell 2007; Kirman et al. 2009). The sensitive period during late gestation 

36 (GD 23-26) is when the fetal rabbit thyroid is undergoing maturation (Sloter et al. 2009). Two37 or four-day exposures of pregnant rabbits to 25 ppm for 6 hours/day during gestation days 23-24 

38 or 23-26, respectively, diminished triiodothyronine (T3) and thyroxine (T4)in fetal serum and 

39 increased TSH. Time-course exposures at 20 ppm methyl iodide revealed highly concentrated 

40 levels of iodide in fetal versus maternal serum. Changes in the fetal thyroid included reduced 

41 colloid formation, epithelial follicular hypertrophy, and epithelial cytoplasmic vacuolation. 

42 Administration of sodium iodide by intravenous infusion during GD 23-26 induced similar 

43 effects on fetal thyroid structure and function. Dietary administration of iodine, 250 to 1000 ppm 

44 for 2 to 5 days prior to parturition, also induced fetal deaths in pregnant rabbits but not in rats or 

45 hamsters (Arrington et al. 1965). These developmental effects in the rabbit fetus are the result of 

46 preferential accumulation of iodide in the fetal compartment causing disruption of the fetal 

47 hypothalamic-pituitary-thyroid axis at a critical time in the development of the rabbit fetal 

48 thyroid. Increased serum iodide is also observed in adult rats following inhalation exposure to 
METHYL IODIDE NAC Proposed 1: November 2009/ Page 20 of 49

1 methyl iodide (Himmelstein et al. 2009), but methyl iodide exposure did not cause 

2 developmental effects in rats (U.S. EPA 2006). See Section 4.4.1 for species differences in 

3 transfer of iodide from the dam/mother to the fetus.

4

5 In humans, an acute iodine load can cause a decrease in thyroid hormone production and 

6 an increase in TSH. This “Wolff-Chaikoff effect,” even with chronic exposure is transient in 

7 most individuals, i.e., hypothyroidism and goiter are not common in individuals ingesting large 

8 amounts of iodine for asthma (Abraham 2003). Both chronic iodine deficiency and chronic 

9 iodine ingestion at therapeutic doses may induce effects on the thyroid in adults as well as in the 

10 developing fetus (NSF International 2002; ATSDR 2004). Endemic cretinism is a syndrome 

11 associated with iodine deficiency in certain geographic areas of the world. 

12

13 During pregnancy and lactation, iodine requirements are higher than normal (Beckers and 

14 Reinwein 1991), and sufficient iodine for synthesis of thyroid hormone is important for normal 

15 brain development in the developing embryo and fetus (Hetzel and Mano 1989). Chronic 

16 ingestion of excessive amounts of iodide during pregnancy, usually as a constituent of 

17 medication for the treatment of asthma or Graves’ disease (hypothyroidism), may induce iodide 

18 goiter in the fetus with or without hypothyroidism. Because there is concern that excess iodine 

19 may have an effect on the developing embryo/fetus in humans via its effects on the 

20 hypothalamus-pituitary-thyroid-feedback loop, the available data on oral administration of iodine 

21 or iodide to individuals with normal thyroid function and on pregnant women taking therapeutic 

22 doses of iodine were evaluated. In humans, orally-administered iodine and iodide at similar 

23 doses have a similar effect on thyroid function, reflecting similar absorption of iodine and iodide 

24 from the gastrointestinal tract (Robinson et al. 1998). In the following studies, volunteers with 

25 normal thyroid function as measured by blood T3, T4, and TSH were administered either iodine 

26 or iodide (iodide is the form taken up by cells; in the thyroid, conversion to reactive iodine and 

27 hormone synthesis takes place within cell follicular lumen). Iodine or iodide was administered to 

28 healthy adults at doses of 32 mg/day for 7 days (Georgitis et al. 1993), 25 or 70 mg/day for 14 

29 days (Robinson et al. 1998), 72 or 360 mg/day for 12-19 days (Vagenakis et al. 1973), 50 or 250 

30 mg/day for 13 days (Saberi and Utiger 1975), or 1080 mg iodide/day for 11 weeks (Jubiz et al. 

31 1977). In studies in which recovery was addressed, the effects on thyroid function were transient.

32

33 In the Jubiz et al. (1977) study, the thyroid response of four healthy young males and a 

34 female subject, ages 27 to 36 years, to potassium iodide was compared to that of 13 hypothyroid 

35 patients, ages 40 to 79 years. The hypothyroid patients had been treated with 1080 or 2160 mg 

36 potassium iodide/day for 1 month to 8 years. In the healthy subjects, an increase in TSH and 

37 decreases in T4 and T3 during administration were transient as indicated by a 1 month post38 treatment follow-up. None of the healthy subjects developed signs or symptoms of 

39 hypothyroidism, and the thyroid gland was not enlarged. Recovery of thyroid function was 

40 observed in seven of the 13 patients in whom the iodide was discontinued.

41

42 Congenital goiter is the result of chronic administration of iodine to the pregnant mother. 

43 Congenital iodide goiter was observed following maternal oral intakes of 1000 mg/day iodine or 

44 iodide throughout pregnancy (Senior and Chernoff 1971), 900-1500 mg/day (Martin and Rento 

45 1962), and 2-1650 mg/day (Carswell et al. 1970). Pregnant women with mild Graves’ disease 

46 ingesting 6-40 mg of iodide or iodide daily beginning at 11-37 weeks of pregnancy delivered 

47 normal fetuses (Momotani et al. 1992). In the latter study, fetal serum thyroxine generally 

48 reflected maternal thyroxine levels. 
METHYL IODIDE NAC Proposed 1: November 2009/ Page 21 of 49

1

2 4.3. Structure-Activity Relationships

3

4 For halogenated methanes, toxicity increases according to atomic weight, in the order 

5 methyl chloride, methyl bromide, and methyl iodide (Table 4). All produce similar toxic 

6 syndromes in man (Gosselin et al. 1984). The halomethanes are considered respiratory irritants, 

7 although inhalation of methyl iodide at up to 100 ppm did not change the breathing rate of rats 

8 (DeLorme et al. 2009). The systemic mechanism of toxicity for nasal lesions appears to be the 

9 same for all three halomethanes– depletion of cellular glutathione which results in an inability of 

10 tissues to suppress lipid peroxidation (Kornbrust and Bus, 1983; see also U.S. EPA 2007a; 

11 2007b). The halomethanes also bind to macromolecules (Gansewendt et al. 1990). Following 

12 oral exposure of male and female F344 rats to the three compounds, the amount of methyl halide 

13 bound to hemoglobin was in the order methyl bromide>methyl iodide> methyl chloride (Xu et al. 

14 1990).

15

16

TABLE 4. Comparison of Toxicity Values Among the Monohalomethanes

Chemical Toxicity Value* Reference

Methyl chloride 5000 ppm (6 hours, no deaths) Chellman et al. 1986

Methyl bromide 1880 ppm (1-hour LC50)

780 ppm (4-hour LC50)

300 ppm (8-hour LC50)

Zwart 1988

Kato et al. 1986

Honma et al. 1985

Methyl iodide 1347 ppm (1-hour LC50)

691 ppm (4-hour LC50)

Eastman Kodak Co. 1987

U.S. EPA 2006

17 *All data are for the rat.

18

19 4.4. Other Relevant Information

20 4.4.1. Species Variability

21

22 Results of several studies indicate that there are species differences in the uptake and rate 

23 of metabolism of monohalomethanes. In in vitro studies, methyl iodide blood:air partition 

24 coefficients for rat, rabbit, and human blood were 39, 16, and 18, respectively (Gannon et al. 

25 2005; Sweeney et al. 2009). Rodents may metabolize methyl iodide more rapidly than humans. 

26 Human GST T1-1 differs from rodent GST by a single amino acid. Substitution of the rodent 

27 amino acid arginine for the tryptophan found in the human GST resulted in a 13-fold increase in 

28 the specific activity of the enzyme and a 2.7-fold increase in the catalytic efficiency (Shokeer et 

29 al. 2005). Furthermore, erythrocyte cytoplasm of rats, mice Rhesus monkeys, cows, pigs, and 

30 sheep does not metabolize monohalomethanes whereas the erythrocyte cytoplasm of 

31 approximately 60% of humans does (Redford-Ellis and Gowenlock 1971; Peter et al. 1989). 

32 Lack of erythrocytic metabolism may explain the rapid equilibrium between the gas phase of the 

33 related halomethanes (methyl chloride and methyl bromide) and whole blood of rats observed in 

34 pharmacokinetic studies. In addition, both in vitro and in vivo comparisons of different species 

35 indicate that levels of GST enzymes are much lower in human liver and lung than in mice and rat 

36 liver and lung (Andersen et al. 1987; Reitz et al. 1989). The data are consistent with the 

37 hypothesis that the rate of activation of mono- and dihalomethanes to toxic metabolites by the 

38 GST pathway occurs much more slowly in humans than in rodents. Ratios of rat/human and 

39 mouse/human GST activity in liver are 3.95 and 7.64, respectively (Griem et al. 2002).

40
METHYL IODIDE NAC Proposed 1: November 2009/ Page 22 of 49

1 When inhaling the same concentration, uptake for the related chemical, methyl chloride, 

2 was greater in the rat and dog than in humans, regardless of human metabolic rate (Landry et al. 

3 1983; Nolan et al. 1985). Blood concentrations at steady state during a 3-hour exposure to 50 

4 ppm for the rat and dog were 194 and 160 ng/g, respectively; whereas, blood concentrations in 

5 rapid and slow human metabolizers were 100 and 35 ng/g, respectively. 

6

7 The relative rate of thyroid hormone metabolism in humans and rats is significantly 

8 different (Robinson et al. 1998; Capen 2008). In humans thyroxine is bound to a greater degree 

9 to plasma proteins than in rats. The half-life of thyroxine in humans varies between 5 and 9 

10 days; whereas, it is 12-24 hours in the rat. Poet et al. (2005) compared the metabolism of methyl 

11 iodide in the kidney and liver cytosols of the rat, rabbit, and humans. Methyl iodide was well 

12 metabolized in most of the tissue cytosol samples, but not in blood or fetal rabbit kidney. The 

13 maximum rates of reaction (Vmax) were similar in liver and kidney cytosols from rats and humans 

14 donors, but were lower in rabbit tissues. In an in vitro study, thyroid tissue from fetal rabbits 

15 failed to exhibit autoregulation of iodide uptake compared to maternal thyroid tissue (Price and 

16 Sherwin 1986). Fetal iodide transport into thyroid cells was 10 times higher than maternal 

17 transport.

18

19 The placentas of certain species possess an active transport mechanism for transporting 

20 iodide from mother to fetus. Logothetopoulos and Scott (1956) observed active transport of 

21 iodide across the placentas of guinea pigs, rabbits, and to a lesser extent, the rat. Using 

22 radiotracer techniques, measurement of fetal to maternal blood iodide ratios ranged up to 4- to 5-

23 fold for guinea pigs and up to six-fold in rabbits. Crone and Waago (1961) found a similar two24 to six-fold difference in fetal and maternal blood iodide measurements of rabbits. Following 

injection of Na131 25 -radiolabeled sodium iodide to pregnant rabbits, Thrall et al. (2009b) found a 

26 three-fold greater blood radioiodide level in fetuses compared with dams. Levels of radioiodide 

27 were higher in fetal than maternal tissues, and in contrast to maternal animals, showed no 

28 evidence of clearance over a 24-hour sampling period. In contrast, human fetal to maternal blood 

29 iodide ratios, measured following term (37-41 weeks) and preterm (29-36 weeks) deliveries were 

30 approximately 1:1 (Rayburn et al. 2008). The authors concluded that the human fetus, unlike the 

31 rabbit and other species, does not highly concentrate iodide relative to the maternal plasma iodide 

32 level during late gestation. 

33

34 The related chemical, methyl bromide, was specifically toxic to the olfactory epithelium 

35 of the rat, whereas, the other nasal epithelia were unaffected (Hurtt et al. 1988). Histochemical 

36 techniques revealed degeneration of the sensory and sustentacular cells but not the basal cells 

37 from which the former cells are regenerated. This was a reversible effect as the basal cells were 

38 not affected. The olfactory region (dorsal meatus) of rats is highly exposed to chemicals due to 

39 air flow characteristics in the nasal turbinates. In rodents, an inhaled vapor traverses a few 

40 millimeters of resistant respiratory epithelium before reaching sensitive olfactory tissue; whereas, 

41 in humans an inhaled vapor has to traverse several centimeters and a much larger surface area of 

42 respiratory epithelium to reach the olfactory tissue. A mathematical model based on a 

43 combination of computational fluid dynamics and physiologically-based pharmacokinetics 

44 showed that the dorsal meatus region of the rat nose receives 12 to 20% of the inhaled air (Bush 

45 et al. 1998; Frederick et al. 1998). A comparison with airflow patterns in the human nose shows 

46 that the olfactory epithelium in the dorsal meatus region of the nasal cavity of the rat is exposed 

47 to two- to three-fold greater concentrations of chemicals. Therefore, compared with the rat, it is 

48 likely that higher concentrations of methyl bromide would be required to induce this lesion in 
METHYL IODIDE NAC Proposed 1: November 2009/ Page 23 of 49

1 humans. In addition, rat nasal tissue is higher in nonprotein sulfhydral content (primarily 

2 glutathione) than human tissue.

3

4 4.4.2. Susceptible Populations

5

6 Inter-individual variation in the rate of metabolism of methyl halides has been observed 

7 in humans. Three distinct populations with differences in the rate of metabolism of the related 

8 chemical, methyl chloride, have been identified (Nolan et al. 1985; Warholm et al. 1994; ATSDR 

9 1998; Lof et al. 2000; WHO 2000). The differences in metabolism rate are attributed to the 

10 genetic polymorphism of glutathione transferase theta 1 (GSTT-1). Depending on the presence 

11 or absence of GST and the number of alleles, humans may be fast, slow, or non-metabolizers. 

12 Fast metabolism may lead to the formation of toxic metabolites that can exert their action before 

13 they can be eliminated. Slow metabolizers would be expected to be less susceptible to the toxic 

14 effects of the metabolites. Because the elimination of methyl chloride is rapid in both 

15 populations, the difference is of questionable toxicological significant. Exposure of humans to 

16 50 ppm methyl chloride did not affect the blood GST levels of either population. Although 

17 humans differ in their capacity to metabolize the related chemical, methyl chloride, the 

18 difference, toxicologically, is considered to be less than three-fold (Nolan et al. 1985). The 

19 metabolism of methyl iodide in human liver cytosols prepared from 5 human donors indicated a 

20 single outlier, with much less metabolism than the other human liver samples (Poet et al. 2005). 

21 Because methyl iodide is thought to be non-enzymatically conjugated, the significance of the 

22 variation in human genotype is unknown.

23

24 Although individuals who are lacking the GSTT-1 enzyme would have lower 

25 susceptibility to the potential nasal toxicity of methyl iodide, these individuals could be at greater 

26 risk for acute neurotoxicity because reduced metabolism of methyl iodide results in higher 

27 concentrations reaching the brain (Sweeney et al. 2009). Based on the in vitro studies of 

28 Chamberlain et al. (1998a) in which rat nasal or liver homogenates were co-incubated with GSH, 

29 GSH inhibitors, and methyl iodide, Sweeney et al. (2009) estimated that GSH conjugation with 

30 methyl iodide in a GSTT-1 null person would be a factor of 1.4 lower than derived for a person 

31 with full GST activity.

32

33 Maternal ingestion of iodide has been implicated in the causation of congenital goiter in 

34 the newborn (Carswell et al. 1970). Chronic ingestion of excessive amounts of iodine, ten times 

35 or more the normal daily requirement, may cause iodide goiter, with or without hypothyroidism 

36 in both the mother and fetus (Senior and Chernoff 1971). Following an acute exposure, iodine 

37 inhibition of thyroid hormone synthesis is transient in normal subjects and is not likely to result 

38 in alterations in thyroid function in subjects having adequate preformed stores of T4 and T3

39 (Saberi and Utiger 1975). Individuals with thyroid diseases may be more susceptible to the 

40 increased iodine load from methyl iodide than individuals with normal thyroid function (ATSDR 

41 2004).

42

43 4.4.3. Concentration-Exposure Duration Relationship

44

45 The concentration-time relationship for many irritant and systemically acting vapors and 

gases may be described by Cn 46 x t = k. A computer program developed by ten Berge (2006) and 

47 based on probit analysis integrates all concentration and time information for a range of lethality 

48 data. Concentration, exposure duration, and response, including the number of animals 
METHYL IODIDE NAC Proposed 1: November 2009/ Page 24 of 49

1 responding, are considered simultaneously in a linear regression equation, with the Maximum 

2 Likelihood statistical method used to find the closest estimates of the regression coefficients for 

3 each parameter. The probit-analysis dose-response program of ten Berge was applied to the 

4 Eastman Kodak Co. (1987), Reed et al. (1995), and U.S. EPA (2006) lethality data (see Table 2) 

5 to estimate the threshold for lethality at each AEGL exposure duration (with confidence limits of 

95%). The calculated value of n in Cn 6 x t = k is 2. 

7

8 4.4.4. Concurrent Exposure Issues

9

10 No information relevant to concurrent exposure issues was located. 

11

12 5. DATA ANALYSIS FOR AEGL-1

13 5.1. Summary of Human Data Relevant to AEGL-1

14

15 No clinical studies were available for derivation of AEGL-1 values.

16

17 5.2. Summary of Animal Data Relevant to AEGL-1

18

19 A 1-hour exposure to 100 ppm was a no-effect concentration for lesions of the nasal 

20 passage in rats, and a 2-hour exposure to 100 ppm resulted in minimal lesions to the olfactory 

21 epithelium (Reed et al. 1995). Results of studies with longer exposure durations showed that the 

22 nasal lesions are reversible. A 6-hour exposure to 27 ppm was a NOAEL for clinical signs that 

23 addressed neurotoxicity (U.S. EPA 2006). In a repeat-exposure (4-week) study, 25 ppm was a 

24 no-effect level for irritation, neurotoxic signs, and gross pathologic changes in rats (Monsanto 

25 Company 1983). In a 13-week study described in U.S. EPA (2006), 21 ppm was a NOAEL for 

26 nasal degeneration in rats. 

27

28 5.3. Derivation of AEGL-1

29

30 Based on the acute studies of Reed et al. (1995) and U.S. EPA (2006) with support from 

31 the repeat-exposure studies of Monsanto Company (1983) and U.S. EPA (2006), a weight-of 

32 evidence approach shows that exposures up to 27 ppm for 6 hours and to 100 ppm for 30 or 60 

33 minutes are NOAELs for both nasal lesions and neurotoxicity. The 6-hour 27 ppm concentration 

34 was used as the point of departure for the AEGL-1. Based on a higher blood:air partition 

35 coefficient for rats than humans (Sweeney et al. 2009), uptake is greater in rats than humans. In 

36 addition, higher inhalation rate and cardiac output in rodents indicate faster uptake. Thus, an 

37 interspecies uncertainty factor of 1 was applied. Metabolism via glutathione conjugation is not 

38 expected to vary greatly among humans (Nolan et al. 1985). In addition, conjugation of methyl 

39 iodide with glutathione, the primary route of metabolism, may be non-enzymatic, further 

40 minimizing individual differences. Therefore, an intraspecies uncertainty factor of 3 was 

41 applied. 

42

43 Neurotoxicity and nasal lesions are systemic effects; therefore, the values were time 

44 scaled. The 6-hour NOAEL for nasal lesions and neurotoxicity of 9 ppm (27 ppm/3) was time 

scaled using Cn 45 x t = k. Because glutathione depletion resulting in nasal lesions and 

46 neurotoxicity is on a continuum with lethality, time scaling was based on the rat lethality data 

47 sets of Eastman Kodak Co. (1987), Reed et al. (1995), and U.S. EPA (2006). The time scaling 

value was 2 (C2 48 x t = k). The 6-hour value was time scaled to 10 minutes because one of the key 
METHYL IODIDE NAC Proposed 1: November 2009/ Page 25 of 49

1 studies (Reed et al. 1995) utilized a 0.5-hour exposure. Because the 8-hour time-scaled value of 

2 less than 10 ppm appears unrealistic in light of no-effect concentrations of 10 ppm and 20 ppm in 

3 subchronic and chronic studies reported by Blank et al. (1984) and U.S. EPA (2006), 

4 respectively, the 8-hour value was set equal to the 4-hour value of 11 ppm. Values are listed in 

5 Table 5, and calculations are in Appendix A. A category graph of the AEGL values in relation to 

6 the toxicity data is in Appendix B.

7

8

TABLE 5. AEGL-1 Values for Methyl Iodide

10-min 30-min 1-h 4-h 8-hour

54 ppm

(310 mg/m3)

31 ppm

(180 mg/m3)

22 ppm

(130 mg/m3)

11 ppm

(64 mg/m3)

11 ppm

(64 mg/m3)

9

10

11 6. DATA ANALYSIS FOR AEGL-2

12 6.1. Summary of Human Data Relevant to AEGL-2

13

14 No clinical studies were available for development of AEGL-2 values. 

15

16 6.2. Summary of Animal Data Relevant to AEGL-2

17

18 Reed et al. (1995) addressed the effect of methyl iodide on the nasal olfactory epithelium 

19 of Wistar-derived rats. A concentration of 100 ppm was tested over exposure durations of 0.5 to 

20 6 hours. At the highest concentration-exposure duration, 100 ppm for 6 hours, lesions of the 

21 olfactory epithelium were marked, but almost complete regeneration took place over a 

22 subsequent two-week post-exposure period. 

23

24 6.3. Derivation of AEGL-2

25

26 The 100 ppm, 6-hour exposure of rats in the study of Reed et al. (1995) was used as the 

27 point of departure for the AEGL-2. The endpoint of reversible lesions of the nasal olfactory 

28 epithelium, a NOAEL for irreversible lesions, meets the definition of an AEGL-2. Based on a 

29 higher blood:air partition coefficient for rats than humans (Sweeney et al. 2009), uptake is greater 

30 in rats than humans. In addition, higher inhalation rate and cardiac output in rodents indicate 

31 faster uptake. Thus, an interspecies uncertainty factor of 1 was applied. Metabolism via 

32 glutathione conjugation is not expected to vary greatly among humans (Nolan et al. 1985). In 

33 addition, the conjugation of methyl iodide with glutathione, the primary route of metabolism, 

34 may be non-enzymatic, further minimizing individual differences. Therefore, an intraspecies 

uncertainty factor of 3 was applied. Values were time-scaled using C2 35 x t = k. Calculations are 

36 in Appendix A and values are summarized in Table 6. A category graph of the AEGL values in 

37 relation to the toxicity data is in Appendix B.

38

TABLE 6. AEGL-2 Values for Methyl Iodide

10-min 30-min 1-h 4-h 8-h

200 ppm

(1200 mg/m3)

120 ppm

(700 mg/m3)

82 ppm

(480 mg/m3)

41 ppm

(240 mg/m3)

29 ppm

(170 mg/m3)

39
METHYL IODIDE NAC Proposed 1: November 2009/ Page 26 of 49

1 Support for the AEGL-2 values consists of data from acute and subchronic studies. The 

2 8-hour AEGL-2 value of 29 ppm is close to the 6-hour NOAEL for neurotoxicity of 27 ppm in an 

3 acute 6-hour study with the rat and only slightly higher than the 6 hour/day 13-week NOAEL for 

4 olfactory lesions of 21 ppm in rats (U.S. EPA 2006).

5

6 There is concern that inhalation of methyl iodide may have an effect on the developing 

7 fetus. Iodine released from methyl iodide may decrease thyroid hormones and increase TSH via 

8 the hypothalamus-pituitary-thyroid negative feedback loop. The developing fetuses of rabbits 

9 were susceptible to methyl iodide toxicity (Nemec et al. 2005; 2009; U.S. EPA 2006). Although 

10 it is unlikely that iodide would concentrate in the human fetus as it does in the rabbit fetus 

11 (Rayburn et al. 2008), the intake of iodine at the 8-hour AEGL-2 was calculated. The intake of 

iodine from methyl iodide by a pregnant woman at the 8-hour AEGL-2 is 170 mg/m3 12 . The 

breathing rate of an adult human is 20 m3 13 /day. Methyl iodide is 89% iodide. Assuming 

14 complete uptake of methyl iodide from the respiratory tract, the resulting uptake of iodine for the 

15 pregnant female is:

16

170 mg/m3 x 20 m3 17 /24 hours x 8 hours x 0.89 = 1009 mg.

18

19 Assuming 100% absorption from the gastrointestinal tract of both iodine and iodide 

20 (Robinson et al. 1998; ATSDR 2004), this value is close to the 1080 mg/day that produced only 

21 transient changes in hormone status in healthy adults following ingestion for 11 weeks (Jubiz et 

22 al. 1977). Thus, iodine inhibition of thyroid hormone synthesis is transient in normal subjects 

23 and is not likely to result in alterations in thyroid function in subjects with adequate preformed 

24 stores of T4 and T3 (Saberi and Utiger 1975). Chronic administration of similar or slightly higher 

25 doses, 900-1650 mg/day, to pregnant women may induce congenital goiter of the newborn 

26 (Martin and Rento 1962; Carswell et al. 1970; Senior and Chernoff 1971). Two newborns

27 diagnosed with goitrous cretinism secondary to transplacental transfer of maternal iodide, 900 or 

28 1500 mg/day orally, improved spontaneously in the months following birth, and later studies 

29 showed normal thyroid indices (Martin and Rento 1962). 

30

31 The above studies involve oral administration of iodine or iodide. The absorption of 

32 iodide via the inhalation and oral route can be compared. Approximately 72% of inhaled methyl 

33 iodide (I-132 at tracer concentrations) is absorbed in healthy adults (Morgan and Morgan 1967). 

34 The half-life in the respiratory tract is approximately 5 seconds, suggesting extremely rapid 

35 absorption at the alveolar-blood interface. Water soluble iodide salts such as potassium or 

36 sodium iodide are approximately 100% absorbed after oral ingestion (ATSDR 2004). The fate of 

37 iodine following inhalation of radiolabeled methyl iodide in tracer amounts was similar to that of 

38 iodine following ingestion of sodium iodide. This was confirmed by thyroid uptake and urinary 

39 excretion rates (Morgan et al. 1967). Thus, the effect of total dose to the primary target tissue, 

40 the thyroid, would not likely vary with exposure route. 

41

42 In summary, the rabbit is unique in that the rabbit fetus does not regulate the uptake of 

43 iodine and is not a good model for human iodine-induced fetotoxicity (See Section 4.4.1). 

44 Rabbit fetal blood contains up to 6 times the iodine of maternal blood (Crone and Waago 1961). 

45 The high iodine uptake in the rabbit fetus results in thyroid dysfunction and early death. In 

46 humans, iodine uptake by the fetus is regulated, and the maternal to fetal ratio of blood iodine is 

47 1:1 (Rayburn et al. 2008).

48
METHYL IODIDE NAC Proposed 1: November 2009/ Page 27 of 49

1 7. DATA ANALYSIS FOR AEGL-3

2 7.1. Summary of Human Data Relevant to AEGL-3

3

4 No clinical studies were available for development of AEGL-3 values.

5

6 7.2. Summary of Animal Data Relevant to AEGL-3

7

8 Several studies addressed the threshold for lethality. A recent, well-conducted study 

9 reported by U.S. EPA (2006) showed mortality values for male and female rats of 0, 80, 80, and 

10 100% following 4-hour exposures to 581, 710, 797, and 1198 ppm, respectively; the calculated 

11 4-hour LC50 was 691 ppm, and the calculated benchmark concentration (4-hour BMCL05) was 

12 489 ppm (Appendix B). The calculated 1-hour LC50 was1347 ppm in a similar study with rats, 

13 and the calculated 1-hour BMCL05 was 612 ppm (Eastman Kodak Co. 1987). One of 24 rats died 

14 following a 6-hour exposure to 401 ppm (U.S. EPA 2006). The 57-minute LC50 in mice was 860 

15 ppm (Buckell 1950). No mortality was observed in rats inhaling 100 ppm for 0.5 to 6 hours 

16 (Reed et al. 1995). 

17

18 7.3. Derivation of AEGL-3

19

20 The lethality and toxicity data sets for the rat (Eastman Kodak Co. 1987, Reed et al. 1995, 

21 and U.S. EPA 2006) were combined to estimate the threshold for lethality at each AEGL-3 

22 exposure duration using the probit-analysis based dose-response program of ten Berge (2006). 

23 The thresholds for lethality at each exposure duration were set at the lower limit of the 5% 

24 response for lethality (the lower limit of the 95% confidence limit). These values are similar to 

the benchmark dose BMCL05. The data indicated a time-scaling value of 2 (C2 25 x t = k). Values 

26 for the 10-minute through 8-hour exposure duration were: 670, 400, 290, 150, and 98 ppm, 

27 respectively. Based on a higher blood:air partition coefficient for rats than humans (Sweeney et 

28 al. 2009), uptake is greater in rats than humans. In addition, higher inhalation rate and cardiac 

29 output in rodents indicate faster uptake. Thus, an interspecies uncertainty factor of 1 was 

30 applied. Although humans vary in the rate at which they metabolize halomethanes, the 

31 difference is not expected to be greater than three-fold (Nolan et al. 1985). Furthermore, the 

32 conjugation of methyl iodide with glutathione may be non-enzymatic, further minimizing 

33 differences in metabolism rates. Persons lacking the GSTT-1 enzyme would be more sensitive to 

34 the neurotoxic effects of the circulating unconjugated methyl iodide by a factor of 1.4 compared 

35 to persons with full GSTT-1 activity (Sweeney et al. 2009). Therefore, the default intraspecies 

36 uncertainty factor of 10 was reduced to 3. Calculations are in Appendix A and AEGL-3 values 

37 are summarized in Table 7. A category graph of the AEGL values in relation to the toxicity data 

38 is in Appendix B.

39

TABLE 7. AEGL-3 Values for Methyl Iodide

10-min 30-min 1-h 4-h 8-h

670 ppm

(3900 mg/m3

)

400 ppm

(2300 mg/m3)

290 ppm

(1700 mg/m3)

150 ppm

(870 mg/m3)

98 ppm

(570 mg/m3)

40

41
METHYL IODIDE NAC Proposed 1: November 2009/ Page 28 of 49

1 8. SUMMARY OF AEGLs

2 8.1. AEGL Values and Toxicity Endpoints 

3

4 AEGL values are summarized in Table 8. Derivations are summarized in Appendix C.

5

TABLE 8. Summary of AEGL Values

Classification

Exposure Duration

10-min 30-min 1-h 4-h 8-h

AEGL-1

(Nondisabling)

54 ppm

(310 mg/m3

)

31 ppm

(180 mg/m3)

22 ppm

(130 mg/m3)

11 ppm

(64 mg/m3)

11 ppm

(64 mg/m3)

AEGL-2

(Disabling)

200 ppm

(1200 mg/m3)

120 ppm

(700 mg/m3)

82 ppm

(480 mg/m3)

41 ppm

(240 mg/m3)

29 ppm

(170 mg/m3)

AEGL-3

(Lethal)

670 ppm

(3900 mg/m3)

400 ppm

(2300 mg/m3)

290 ppm

(1700 mg/m3)

150 ppm

(870 mg/m3)

98 ppm

(570 mg/m3)

6

7

8 8.2. Comparison with Other Standards and Guidelines

9

10 Standards and guidelines for methyl iodide are summarized in Table 9. The Emergency 

11 Response Planning Guideline (ERPG) values are for 1 hour and are based primarily on 

12 unpublished studies (AIHA 2004). The ERPG-1 of 25 ppm was based on eye irritation noted in 

13 some rats exposed to 72 ppm, 6 hr/day, after 17 exposures but not in rats exposed to 24 ppm, 6 

14 hours/day for 20 exposures. The ERPG-2 of 50 ppm was based on a weight-of-evidence 

15 approach with repeat exposures of rats to concentrations ranging from 72 to 85 ppm. The ERPG16 3 of 125 ppm was based on no deaths of rats exposed to 150 ppm, 6 hr/day, for 3 days and 

17 following a 1-hour exposure of rats to 960 ppm or of mice to 860 ppm for 20 minutes. The 

18 NIOSH Immediately Dangerous to Life or Health (IDLH) value of 100 ppm is based on the 

19 lethality studies of Bakhishev (1975), Buckell (1950), and Monsanto Company (1982a; 1982b; 

20 1983).

21

22 The ACGIH TLV is 2 ppm and carries skin and suspected human carcinogen notations. 

23 The Occupational Safety and Health Administration 8-hr permissible exposure limit (PEL) is 2 

24 ppm (skin) (NIOSH 2005) as is The Netherlands MAC. The Swedish LLV is 1 ppm with a 15-

25 minute short-term limit of 5 ppm. It also bears skin and carcinogen notations. The German 

26 MAK places methyl iodide in carcinogen category 2, human or animal carcinogen.

27

28
METHYL IODIDE NAC Proposed 1: November 2009/ Page 29 of 49

TABLE 9. Standards and Guidelines for Methyl Iodide

Guideline

Exposure Duration

10 min 30 min 1 h 4 h 8 h

AEGL-1 54 ppm 31 ppm 22 ppm 11 ppm 11 ppm

AEGL-2 200 ppm 120 ppm 82 ppm 41 ppm 29 ppm

AEGL-3 670 ppm 400 ppm 290 ppm 150 ppm 98 ppm

ERPG-1 (AIHA)a 25 ppm

ERPG-2 (AIHA) 50 ppm

ERPG-3 (AIHA) 125 ppm

PEL-TWA

(NIOSH)

b

5 ppm (skin)*

IDLH

(NIOSH)c

100 ppm

REL-TWA

(NIOSH)d

2 ppm (skin)

TLV-TWA

(ACGIH)e

2 ppm (skin)

MAK (Germany)f No values; skin notation; carcinogen category 2 (human or animal carcinogen)

LLV (Sweden)g 1 ppm (skin, 

carcinogen);

5 ppm (15 min)

MAC (The 

Netherlands)h

2 ppm (skin)

1 * The skin notation indicates the potential for dermal absorption.

2 a 3 ERPG (Emergency Response Planning Guidelines, American Industrial Hygiene Association (AIHA 2004)

4 The ERPG-1 is the maximum airborne concentration below which it is believed nearly all individuals could be 

5 exposed for up to one hour without experiencing other than mild, transient adverse health effects or without 

6 perceiving a clearly defined objectionable odor. 

7 The ERPG-2 is the maximum airborne concentration below which it is believed nearly all individuals could be 

8 exposed for up to one hour without experiencing or developing irreversible or other serious health effects or 

9 symptoms that could impair an individual=s ability to take protective action. 

10 The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be 

11 exposed for up to one hour without experiencing or developing life-threatening health effects. 

12 b 13 OSHA PEL-TWA (Occupational Safety and Health Administration, Permissible Exposure Limits - Time 

14 Weighted Average) (NIOSH 2005) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of no more 

15 than 10 hours/day, 40 hours/week.

16 c 17 IDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health)

18 (NIOSH 2005) represents the maximum concentration from which one could escape within 30 minutes without any 

19 escape-impairing symptoms, or any irreversible health effects. 

20 d 21 NIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits -

22 Time Weighted Average) (NIOSH 2005) is defined analogous to the ACGIH-TLV-TWA.

23 e 24 ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value -

25 Time Weighted Average) (ACGIH 1992) is the time-weighted average concentration for a normal 8-hour workday 

26 and a 40-hour workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse 

27 effect.

28

29 fMAK (Maximale Arbeitsplatzkonzentration [Maximum Workplace Concentration]) (Deutsche 

30 Forschungsgemeinschaft [German Research Association] 2007) is defined analogous to the ACGIH-TLV-TWA.

31 g 32 LLV (level Limit Value) Occupational Exposure Limit Values and Measures against Air Contaminants. 2000. 

33 Swedish National Board of Occupational Safety and Health.
METHYL IODIDE NAC Proposed 1: November 2009/ Page 30 of 49

1

2 hMAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration]) (SDU Uitgevers [under the 

3 auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands 2000) is defined similar to 

4 the ACGIH TLV. 

5

6 8.3. Data Adequacy and Research Needs

7

8 Although no quantitative human data were located, studies with animal models were 

9 adequate for derivation of AEGL values for methyl iodide. The relative toxicities of the 

10 halomethanes are: methyl iodide > methyl bromide > methyl chloride (see Section 4.3. Structure11 Activity Relationships). The derived AEGL values for the three chemicals reflect the relative 

12 toxicities. The Interim AEGL values for methyl bromide and methyl chloride along with the 

13 draft values for methyl iodide are summarized in Table 10. 

14

TABLE 10. AEGL Values for Halomethanes

Classification

Exposure Duration

10-min 30-min 1-h 4-h 8-h

Methyl Iodide

AEGL-1 54 ppm 31 ppm 22 ppm 11 ppm 11 ppm

AEGL-2 200 ppm 120 ppm 82 ppm 41 ppm 29 ppm

AEGL-3 670 ppm 400 ppm 290 ppm 150 ppm 98 ppm

Methyl Bromide

AEGL-1 NR NR NR NR NR

AEGL-2 940 ppm 380 ppm 210 ppm 67 ppm 67 ppm

AEGL-3 3300 ppm 1300 ppm 740 ppm 230 ppm 130 ppm

Methyl Chloride

AEGL-1 NR NR NR NR NR

AEGL-2 1100 ppm 1100 ppm 910 ppm 570 ppm 380 ppm

AEGL-3 3800 ppm 3800 ppm 3000 ppm 1900 ppm 1300 ppm

15 NR = Not Recommended; values are not recommended because there are no odor or warning properties and toxic 

16 effects may occur below the odor threshold.

17

18 9. REFERENCES

19

20 Abraham, G.E. 2003. The Wolff-Chaikoff effect of increasing iodide intake on the thyroid – Letters to the 

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1 APPENDIX A: Derivation of Methyl Iodide AEGLs

2

3 Derivation of AEGL-1 Values

4

5 Key Studies: (1) Reed et al. 1995. Olfactory toxicity of methyl iodide in the rat. Arch. 

6 Toxicol. 70:51-56; (2) U.S. EPA. 2006. Human Health Risk Assessment: 

7 Iodomethane. Washington, DC: Health Effects Division, Office of Pesticide 

8 Programs.

9

10 Toxicity endpoint: Weight of Evidence: NOAEL for clinical signs and neurotoxicity in rats (27 

11 ppm for 6 hours (U.S. EPA 2006). Supported by acute no-effect study (100 

12 ppm for 1 hour) and repeat-exposure and subchronic studies).

13

Time scaling: Cn 14 x t = k where n = 2.0 based on the rat toxicity/lethality data sets of Eastman 

15 Kodak Co. (1987), Reed et al. (1995), and U.S. EPA (2006). 

16

17 Uncertainty factors: Total uncertainty factor: 3

18 Interspecies: 1 – Chemical uptake is higher in rodents than humans based on 

19 a higher blood:air partition coefficient. In addition, the respiratory rate and 

20 cardiac output of rodents is higher than in humans. 

21 Intraspecies: 3 – Humans do not differ greatly in their ability to metabolize 

22 monohalomethanes (Nolan et al. 1985).

23

24 Modifying factor: None applied

25

Calculations: C2 26 x t = k

(27 ppm/3)2 x 360 minutes 29160 ppm

2 27 minutes 

28

10-minute AEGL-1: C = (29160 ppm

2

minutes/10)1/2 29

30 C = 54 ppm

31

30-minute AEGL-1: C = (29160 ppm

2

minutes/10)1/2 32

33 C = 31 ppm

34

1-hour AEGL-1: C = (29160 ppm

2

minutes/10)1/2 35

36 C = 22 ppm

37

4-hour AEGL-1: C = (29160 ppm

2

minutes/10)1/2 38

39 C = 11 ppm

40

41 8-hour AEGL-1: Because the time-scaled value of 7.8 ppm appears low in comparison with 

42 subchronic and chronic NOAELs for effects on the olfactory epithelium of 20 

43 ppm (U.S. EPA 2006), the 8-hour value was set equal to the 4-hour value.

44 C = 11 ppm

45
METHYL IODIDE NAC Proposed 1: November 2009/ Page 40 of 49

1

2 Derivation of AEGL-2 Values

3

4 Key Study: Reed, C.J., B.A. Gaskell, K.K. Banger, and E.A. Lock. 1995. Olfactory 

5 toxicity of methyl iodide in the rat. Arch. Toxicol. 70:51-56.

6

7 Toxicity endpoint: Reversible lesions of the olfactory epithelium following a 6-hour exposure of 

8 rats to 100 ppm

9

Time scaling Cn 10 x t = k where n = 2 based on the rat lethality data sets of Eastman Kodak 

11 Co. (1987) and U.S. EPA (2006). 

12

13 Uncertainty factors: Total uncertainty factor: 3

14 Interspecies: 1 – Chemical uptake is higher in rodents than humans based on 

15 a higher blood:air partition coefficient. In addition, rodents have a higher 

16 respiratory rate and cardiac output than humans. 

17 Intraspecies: 3 – Humans do not differ greatly in their ability to metabolize 

18 monohalomethanes (Nolan et al. 1985).

19

Calculations: C2 20 x t = k

(100 ppm/3)2 x 360 minutes = 400,000 ppm

2 21 -minutes

22

10-minute AEGL-2: C = 400,000 ppm

2

-minutes/10)

1/2 23

24 C = 200 ppm

25

30-minute AEGL-2: C = (400,000 ppm

2

-minutes/30)1/2 26

27 C = 120 ppm

28

1-hour AEGL-2: C = (400,000 ppm

2

-minutes/60)1/2 29

30 C = 82 ppm

31

4-hour AEGL-2: C = (400,000 ppm

2

-minutes/240)1/2 32

33 C = 41 ppm

34

8-hour AEGL-2: C = (400,000 ppm

2

-minutes/480)1/2 35

36 C = 29 ppm

37

38
METHYL IODIDE NAC Proposed 1: November 2009/ Page 41 of 49

1

2 Derivation of AEGL-3 Values

3

4 Key Studies: (1) Eastman Kodak Co. 1987. Initial Submission: Acute Inhalation Toxicity 

5 of Methyl Iodide in the Rat with Cover Letter Dated 08/26/92. National 

6 Technical Information Service, Springfield, VA; (2) Reed, C.J., B.A. 

7 Gaskell, K.K. Banger, and E.A. Lock. 1995. Olfactory toxicity of methyl 

8 iodide in the rat. Arch. Toxicol. 70:51-56; (3) U.S. EPA (U.S. 

9 Environmental Protection Agency). 2006. Human Health Risk Assessment: 

10 Iodomethane. Washington, DC: Health Effects Division, Office of Pesticide 

11 Programs. 

12

13 Toxicity endpoint: Threshold for lethality in rats at the lower limit of the 95% confidence limit, 

14 calculated using probit-analysis dose-response program of ten Berge (2006). 

15

Time scaling Cn 16 x t = k where n = 2.0 based on the rat toxicity/lethality data sets of Eastman 

17 Kodak Co. (1987), Reed et al. (1995), and U.S. EPA (2006). 

18

19 Uncertainty factors: Total uncertainty factor: 3

20 Interspecies: 1 – Chemical uptake is higher in rats than humans based on a 

21 higher blood:air partition coefficient (Sweeney et al. 2009); in addition, the 

22 respiratory rate and cardiac output is higher in rats than humans resulting in 

23 faster uptake.

24 Intraspecies: 3 – Humans do not differ greatly in their ability to metabolize 

25 monohalomethanes (Nolan et al. 1985).

26

27 Modifying factor: None applied

28

29 Data for calculations: 

Exposure Duration

(minutes)

Concentration

(ppm)

Mortality

(percent) Reference

60 1190

1554

1973

20

60

90

Eastman Kodak Co. (1987)

30, 60, 120, 180, 240, 

360

100 0 at all time points Reed et al. (1995)

240 581

710

797

1198

0

80

80

100

U.S. EPA (2006)

360 27

93

401

0

0

4

U.S. EPA (2006)

30

31 Program output (with intraspecies uncertainty factor of 3 applied):

Exposure Duration AEGL-3 Value

10 minutes 670 ppm

30 minutes 400 ppm

60 minutes 290 ppm

4 hours 150 ppm

8 hours 98 ppm

32 n = 2.0
METHYL IODIDE NAC Proposed 1: November 2009/ Page 42 of 49

1 Calculations: Methyl Iodide – Log Probit Model (ten Berge 2006)

2

3 Filename: methyl iodide for Log Probit Model

4 Date: 20 June 2008 Time: 11:51:12

5 Data of Eastman Kodak Co. (1987), Reed et al. (1995), and U.S. EPA (2006)

6 Lower limit of the 5% response

7

8 Seq.Nr conc ppm min exposed responded 

9 1 1190 60 10 2

10 2 1554 60 10 6

11 3 1973 60 10 9

12 4 581 240 10 0

13 5 710 240 10 8

14 6 797 240 10 8

15 7 1198 240 10 10

16 8 27 360 24 0

17 9 93 360 24 0

18 10 401 360 24 1

19 11 100 30 3 0

20 12 100 60 3 0

21 13 100 120 3 0

22 14 100 180 3 0

23 15 100 240 3 0

24 16 100 360 3 0

25

26 Observations 1 through 16 considered!

27

28 Seq.nr conc ppm min exposed responded

29

30 1 1190 60 10 2

31 2 1554 60 10 6

32 3 1973 60 10 9

33 4 581 240 10 0

34 5 710 240 10 8

35 6 797 240 10 8

36 7 1198 240 10 10

37 8 27 360 24 0

38 9 93 360 24 0

39 10 401 360 24 1

40 11 100 30 3 0

41 12 100 60 3 0

42 13 100 120 3 0

43 14 100 180 3 0

44 15 100 240 3 0

45 16 100 360 3 0

46

47 Used Probit Equation Y = B0 + B1*X1 + B2*X2

48 X1 = conc ppm, ln-transformed

49 X2 = min, ln-transformed

50

51 ChiSquare = 5.32

52 Degrees of freedom = 13
METHYL IODIDE NAC Proposed 1: November 2009/ Page 43 of 49

1 Probability Model = 9.68E-01

2

3 Ln(Likelihood) = -10.45

4

5 B 0 = -4.8449E+01 Student t = -4.8126

6 B 1 = 5.5950E+00 Student t = 5.5485

7 B 2 = 3.0903E+00 Student t = 4.5552

8

9 variance B 0 0 = 1.0135E+02

10 covariance B 0 1 = -1.0077E+01

11 covariance B 0 2 = -6.6311E+00

12 variance B 1 1 = 1.0168E+00

13 covariance B 1 2 = 6.3995E-01

14 variance B 2 2 = 4.6026E-01

15

16 Estimation of conc ppm at response of 5 %

17 min = 10 

18 Point estimate conc ppm = 2.943E+03 for response of 5 %

19 Lower limit (95% CL) conc ppm = 2.002E+03 for response of 5 %

20 Upper limit (95% CL) conc ppm = 3.778E+03 for response of 5 %

21

22 Estimation of conc ppm at response of 5 %

23 min = 30 

24 Point estimate conc ppm = 1.604E+03 for response of 5 %

25 Lower limit (95% CL) conc ppm = 1.213E+03 for response of 5 %

26 Upper limit (95% CL) conc ppm = 1.899E+03 for response of 5 %

27

28 Estimation of conc ppm at response of 5 %

29 min = 60 

30 Point estimate conc ppm = 1.094E+03 for response of 5 %

31 Lower limit (95% CL) conc ppm = 8.777E+02 for response of 5 %

32 Upper limit (95% CL) conc ppm = 1.239E+03 for response of 5 %

33

34 Estimation of conc ppm at response of 5 %

35 min = 240 

36 Point estimate conc ppm = 5.086E+02 for response of 5 %

37 Lower limit (95% CL) conc ppm = 4.365E+02 for response of 5 %

38 Upper limit (95% CL) conc ppm = 5.552E+02 for response of 5 %

39

40 Estimation of conc ppm at response of 5 %

41 min = 480 

42 Point estimate conc ppm = 3.468E+02 for response of 5 %

43 Lower limit (95% CL) conc ppm = 2.938E+02 for response of 5 %

44 Upper limit (95% CL) conc ppm = 3.895E+02 for response of 5 %

45

46 AEGL concentrations at 5% lethality response (The point estimate is similar to the BMC05. The 

47 BMCL05 would be similar to the lower limit)

48

49
METHYL IODIDE NAC Proposed 1: November 2009/ Page 44 of 49

1

2 1% response

3

4 Estimation of conc ppm at response of 1 %

5 min = 10 

6 Point estimate conc ppm = 2.605E+03 for response of 1 %

7 Lower limit (95% CL) conc ppm = 1.688E+03 for response of 1 %

8 Upper limit (95% CL) conc ppm = 3.393E+03 for response of 1 %

9

10 Estimation of conc ppm at response of 1 %

11 min = 30 

12 Point estimate conc ppm = 1.420E+03 for response of 1 %

13 Lower limit (95% CL) conc ppm = 1.017E+03 for response of 1 %

14 Upper limit (95% CL) conc ppm = 1.714E+03 for response of 1 %

15

16 Estimation of conc ppm at response of 1 %

17 min = 60 

18 Point estimate conc ppm = 9.684E+02 for response of 1 %

19 Lower limit (95% CL) conc ppm = 7.331E+02 for response of 1 %

20 Upper limit (95% CL) conc ppm = 1.123E+03 for response of 1 %

21

22 Estimation of conc ppm at response of 1 %

23 min = 240 

24 Point estimate conc ppm = 4.503E+02 for response of 1 %

25 Lower limit (95% CL) conc ppm = 3.646E+02 for response of 1 %

26 Upper limit (95% CL) conc ppm = 5.032E+02 for response of 1 %

27

28 Estimation of conc ppm at response of 1 %

29 min = 480 

30 Point estimate conc ppm = 3.071E+02 for response of 1 %

31 Lower limit (95% CL) conc ppm = 2.480E+02 for response of 1 %

32 Upper limit (95% CL) conc ppm = 3.492E+02 for response of 1 %

33

34

35

36
METHYL IODIDE NAC Proposed 1: November 2009/ Page 45 of 49

1 APPENDIX B: Category Graph of AEGL Values and Toxicity Data

2

1 

10 

100 

1000 

10000 ppm

0 60 120 180 240 300 360 420 480 

Minutes

No Effect

Discomfort

Disabling

Some Lethality

Lethal

AEGL

Chemical Toxicity - Animal Data

Methyl Iodide

AEGL-3

AEGL-2

AEGL-1

3

4

5 Data:

 Category: 0 = No effect, 1 = Discomfort, 2 = Disabling, SL = Some Lethality, 3 = Lethal

Source Species ppm Minutes Category Comments

NAC/AEGL-1 54 10 AEGL

NAC/AEGL-1 31 30 AEGL

NAC/AEGL-1 22 60 AEGL

NAC/AEGL-1 11 240 AEGL

NAC/AEGL-1 11 480 AEGL

NAC/AEGL-2 200 10 AEGL

NAC/AEGL-2 120 30 AEGL

NAC/AEGL-2 82 60 AEGL

NAC/AEGL-2 41 240 AEGL

NAC/AEGL-2 29 480 AEGL

NAC/AEGL-3 670 10 AEGL

NAC/AEGL-3 400 30 AEGL

NAC/AEGL-3 290 60 AEGL

NAC/AEGL-3 150 240 AEGL

NAC/AEGL-3 98 480 AEGL
METHYL IODIDE NAC Proposed 1: November 2009/ Page 46 of 49

Eastman Kodak Co. 

1987

rat 1190 60 SL 20% mortality

rat 1554 60 SL 60% mortality

rat 1973 60 SL 90% mortality

U.S. EPA 2006 rat 581 240 2 No mortality

rat 710 240 SL 80% mortality

rat 797 240 SL 80% mortality

rat 1198 240 3 100% mortality

U.S. EPA 2006 rat 27 360 0 NOAEL for neurotoxicity

rat 93 360 2 Clonic convulsions

rat 401 360 SL Neurotoxicity, gasping, 

4% mortality

Reed et al. 1995 rat 100 30 0 No lesions, nasal passages

rat 100 60 1 No lesions, nasal passages

rat 100 120 1 Minimal lesions, nasal passages

rat 100 180 1 Slight lesions, nasal passages

rat 100 240 1 Moderate lesions, nasal passages

rat 100 360 2 Marked lesions, nasal passages;

regeneration after 2 weeks

Delorme et al. 2005 rat 25 360 0 No effect, respiratory parameters

1

2
METHYL IODIDE NAC Proposed 1: November 2009/ Page 47 of 49

1 APPENDIX C: Derivation Summary for Methyl Iodide AEGLs

2

3 ACUTE EXPOSURE GUIDELINE LEVELS FOR METHYL IODIDE

4 (CAS Reg. No. 79-38-9)

5

AEGL-1 VALUES

10-min 30-min 1-h 4-h 8-hour

54 ppm 31 ppm 22 ppm 11 ppm 11 ppm

Key References: (1) U.S. EPA. 2006. Human Health Risk Assessment: Iodomethane. Washington, DC: Health 

Effects Division, Office of Pesticide Programs.

(2) Reed, C.J., B.A. Gaskell, K.K. Banger, and E.A. Lock. 1995. Olfactory toxicity of methyl 

iodide in the rat. Arch. Toxicol. 70:51-56.

Test Species/Strain/Number: (1) Rat/CRL/5 males and 5 females per group; (2) Rat/Wistar/3 males per group

Exposure Route/Concentration/Duration: (1) Inhalation/27, 93, or 401 ppm for 6 hours; (2) Inhalation/100 ppm 

for 0.5, 1, 2, 3, 4, or 6 hours

Effects: 

(1) 27 ppm for 6 hours was a NOAEL for neurotoxic signs

(2) No observable change, respiratory epithelium following 1 hour exposure to 100 ppm 

Endpoint/Concentration/Rationale: NOAEL for clinical signs: 27 ppm for 6 hours and 100 ppm for 1 hour 

The point of departure was the 6-hour exposure to 27 ppm.

Uncertainty Factors/Rationale: 

Total uncertainty factor: 3

Interspecies: 1, considered sufficient as chemical uptake is greater in rodents than humans

Intraspecies: 3, considered sufficient to account for metabolism-mediated variability 

Modifying Factor: None applied

Animal to Human Dosimetric Adjustment: Not applicable 

Time Scaling: Cn x t = k, where n = 2 based on toxicity studies with the rat (Eastman Kodak Co. 1987, Reed et al. 

1995, U.S. EPA 2006) and calculated using the ten Berge (2006) probit analysis dose-response program. The 8-

hour value was set equal to the 4-hour value because the time-scaled 8-hour value of 7.8 ppm appears 

inconsistent with the 20 ppm NOAELs reported in subchronic and chronic studies (U.S. EPA 2006).

Data Adequacy: There are no clinical data with clearly stated exposure concentrations. The animal data were 

adequate for derivation of three levels of AEGLs. 

6

7
METHYL IODIDE NAC Proposed 1: November 2009/ Page 48 of 49

AEGL-2 VALUES

10-minute 30-minute 1-hour 4-h 8-h

200 ppm 120 ppm 82 ppm 41 ppm 29 ppm

Key Reference: Reed, C.J., B.A. Gaskell, K.K. Banger, and E.A. Lock. 1995. Olfactory toxicity of methyl 

iodide in the rat. Arch. Toxicol. 70:51-56.

Test Species/Strain/Number: Rat/Wistar/three males per group,

Exposure Route/Concentration/Duration: Inhalation/100 ppm for 0.5, 1, 2, 3, 4, or 6 hours

Effects: 

0.5 hours: no observable change, nasal passages

1 hour: no observable change, nasal passages

2 hours: minimal lesions, olfactory epithelium

3 hour: slight lesions, olfactory epithelium

4 hours: moderate lesions, olfactory epithelium

6 hours: marked lesions, olfactory epithelium; regeneration after 2 weeks

Endpoint/Concentration/Rationale: 6 hour exposure to 100 ppm resulted in reversible lesions in the olfactory 

epithelium.

Uncertainty Factors/Rationale: 

Total uncertainty factor: 3

Interspecies: 1, considered sufficient as chemical uptake is greater in rodents than humans

Intraspecies: 3, considered sufficient to account for metabolism-mediated variability 

Modifying Factor: None applied

Animal to Human Dosimetric Adjustment: Not applicable

Time Scaling: Cn x t = k, where n = 2 based on toxicity studies with the rat (Eastman Kodak Co. 1987, Reed et 

al. 1995, U.S. EPA 2006) and calculated using the ten Berge (2006) probit analysis dose-response program. 

Data Adequacy: There are no clinical studies with clearly stated exposure concentrations. Several studies 

showed that the olfactory epithelium was a target organ for methyl iodide. The data base of acute, repeatexposure, genotoxicity, developmental, subchronic, and chronic animal studies was sufficient for derivation of 

AEGL values. 

1

2

3
METHYL IODIDE NAC Proposed 1: November 2009/ Page 49 of 49

AEGL-3 VALUES

10-min 30-min 1-h 4-h 8-h

670 ppm 400 ppm 290 ppm 150 ppm 98 ppm

Key References: (1) Eastman Kodak Co. 1987. Initial Submission: Acute Inhalation Toxicity of Methyl 

Iodide in the Rat with Cover Letter Dated 08/26/92. Available from National Technical Information 

Service, Springfield, VA. (2) Reed, C.J., B.A. Gaskell, K.K. Banger, and E.A. Lock. 1995. Olfactory 

toxicity of methyl iodide in the rat. Arch. Toxicol. 70:51-56. (3) U.S. EPA (U.S. Environmental 

Protection Agency). 2006. Human Health Risk Assessment: Iodomethane. Washington, DC: Health 

Effects Division, Office of Pesticide Programs.

Test Species/Strain/Number: (1) Rat/Crl:CD/10 per group; 

(2) Rat (male)/Wistar/3per group;

(3) Rat/Sprague-Dawley/10 per group

Exposure Route/Concentration/Duration: (1) Inhalation/1190, 1554, or 1973 ppm for 1 hour;

(2) Inhalation/100 ppm for 0.5-6 hours ;

(3) Inhalation/581, 710, 797, or 1198 ppm for 4 hours; 27, 93, 401 ppm for 6 hours

Effects: (1) Respectively mortalities of 20, 60, and 90%;

(2) No mortality

(3) Respective mortalities of 0, 80, 80, and 100% (4 hours); 0, 0, 4% (6 hours)

Endpoint/Concentration/Rationale: Lower limit of the 95% confidence limit, calculated at each AEGL exposure 

duration using the probit-analysis dose-response program of ten Berge (2006).

Uncertainty Factors/Rationale: 

Total uncertainty factor: 3

Interspecies: 1, considered sufficient as chemical uptake is greater in rodents than humans. 

Intraspecies: 3, considered sufficient to account for metabolism-mediated variability. 

Modifying Factor: None applied

Animal to Human Dosimetric Adjustment: Not applicable

Time Scaling: Calculated using the ten Berge program (n in Cn x t = 2)

Data Adequacy: Several well-conducted toxicity/lethality studies with rats were available. The data base of 

acute, repeat-exposure, genotoxicity, developmental, subchronic, and chronic animal studies was sufficient for 

derivation of AEGL values.

1