NAC Proposed 1 : November 200 9 1

2

3

4



## ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 5



## FOR 6



## METHYL IODIDE 7



## (CAS Reg. No. 7 4

- 8 8

- 4 ) 8

9



## C H 3 

## I 10

11

12

13

14



## PROPOSED 15

16

17METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 2 of 49

PREFACE 1

2

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

- 463 of 3

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

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

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

chemicals. 7

8

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

emergency exposure periods ranging from 10 minutes to 8 hours. Three levels

– AEGL

- 1, 10

AEGL

- 2 and AEGL

- 3

– are developed for each of five exposure periods (10 and 30 minu tes, 1 11

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

The three AEGLs are defined as follows: 13

14

AEGL

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

cubic meter [ppm or m g/m 3 ]) of a substance above which it is predicted that the general 16

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

certain asymptomatic, non

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

transient and reversible upon cessation of exposure. 19

20

AEGL

- 2 is the airborne concentration (expressed as ppm or mg/m 3 ) of a substance above 21

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

experience irreversibl e or other serious, long

- lasting adverse health effects or an impaired ability 23

to escape. 24

25

AEGL

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

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

experience life

- threatening health effects or death. 28

29

Airborne concentrations below the AEGL

- 1 represent exposure levels that could produce 30

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

irritation or certain asymptomatic, non

- sensory effects. With increasing airborne concentrations 32

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

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

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

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

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

at concentrations below the corresponding AEGL. 38

39

40METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 3 of 49

TABLE OF CONTENTS 1

PREFACE

................................ ................................ ................................ ................................ ..................... 2 2

LIST O F TABLES

................................ ................................ ................................ ................................ ........ 5 3

SUMMARY

................................ ................................ ................................ ................................ .................. 6 4

1. INTRODUCTION

................................ ................................ ................................ ................................ 8 5

2. HUMAN TOXICITY DATA

................................ ................................ ................................ ............... 9 6

2.1

. Clinical Studies

................................ ................................ ................................ ............................ 9 7

2.2

. Case Studies

................................ ................................ ................................ ................................ . 9 8

3. ANIMAL TOXICITY D ATA

................................ ................................ ................................ ............ 10 9

3.1. Acute Toxicity

................................ ................................ ................................ ........................... 10 10

3.1.1. Rats

................................ ................................ ................................ ................................ ........ 10 11

3.1.2. Mice

................................ ................................ ................................ ................................ ....... 11 12

3.2. Repeat

- Dose Studies

................................ ................................ ................................ .................. 12 13

3.3. Neurotoxicity

................................ ................................ ................................ ............................. 14 14

3.4. Developmental /Reproductive Toxicity

................................ ................................ ...................... 14 15

3.5. Genotoxicity

................................ ................................ ................................ ............................... 15 16

3.6. Chronic Toxicity/Carcinogenicity

................................ ................................ .............................. 15 17

3.7. Summary

................................ ................................ ................................ ................................ .... 16 18

4. SPECIAL CONSIDERATIONS

................................ ................................ ................................ ........ 16 19

4.1. Metabolism and Disposition

................................ ................................ ................................ ...... 16 20

4.1.1. Clinical and Laboratory Animal Studies

................................ ................................ ................ 16 21

4.1.2. Physiologically

- Based Pharmacokinetic (PBPK) Modeling

................................ .................. 17 22

4.2. Mechanism of Toxicity

................................ ................................ ................................ .............. 18 23

4.3. Structure

- Activity Relationships

................................ ................................ ................................ 21 24

4.4. Other Relevant Information

................................ ................................ ................................ ....... 21 25

4.4.1. Species Variability

................................ ................................ ................................ ................. 21 26

4.4.2. Susceptible Populations

................................ ................................ ................................ ......... 23 27

4.4.3. Concentration

- Exposure Duration Relationship

................................ ................................ .... 23 28

4.4.4. Concurrent Exposure Issues

................................ ................................ ................................ .. 24 29

5. DATA ANALYSIS FOR AEGL

- 1

................................ ................................ ................................ ..... 24 30

5.1. Summary of Human Data Relevant to AEGL

- 1

................................ ................................ ......... 24 31

5.2. Summary of Animal Data Relevant to AEGL

- 1

................................ ................................ ........ 24 32

5.3. Derivation of AEGL

- 1

................................ ................................ ................................ ............... 24 33

6. DATA ANALYSIS FOR AEGL

- 2

................................ ................................ ................................ ..... 25 34

6.1. Summary of Human Data Relevant to AEGL

- 2

................................ ................................ ......... 25 35

6.2. Summary of Animal Data Relevant to AEGL

- 2

................................ ................................ ........ 25 36

6.3. Derivation of AEGL

- 2

................................ ................................ ................................ ............... 25 37

7. DATA ANALYSIS FOR AEGL

- 3

................................ ................................ ................................ ..... 27 38

7.1. Summary of Human Data Relevant to AEGL

- 3

................................ ................................ ......... 27 39

7.2. Summary of Ani mal Data Relevant to AEGL

- 3

................................ ................................ ........ 27 40

7.3. Derivation of AEGL

- 3

................................ ................................ ................................ ............... 27 41METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 4 of 49

8. SUMMARY OF AEGLs

................................ ................................ ................................ .................... 2 8 1

8.1. AEGL Values and Toxicity Endpoints

................................ ................................ ...................... 28 2

8.2. Comparison with Other Standards and Guidelines

................................ ................................ .... 28 3

8.3. Data A dequacy and Research Needs

................................ ................................ .......................... 30 4

9. REFERENCES

................................ ................................ ................................ ................................ ... 30 5

APPENDIX A: DERIVAT ION OF METHYL IODIDE AEGLS

................................ .............................. 39 6

APPENDIX B: CATEGOR Y GRAPH OF AEGL VALU ES AND TOXICITY DATA

.......................... 50 7

APPENDIX C: DERIVAT ION SUMMARY FOR METH YL IODIDE AEGLS

................................ ...... 47 8

9

10

11METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 5 of 49

LIST OF TABLES 1

2

S 1. S ummary of AEGL V alues for M ethyl I odide

................................ ................................ ................................ ....... 8 3

4

T able 1. C hemical and P hysical P roperties

................................ ................................ ................................ ... 9 5

T able 2. S ummary of A cute I nhalation D ata in L aboratory A nimals

................................ ......................... 12 6

T able 3. S ummary of R epeat

- D ose S tudies

................................ ................................ ................................ 13 7

Table 4. Comparison of T oxicity V alues among the M onohalomethanes

................................ .................. 21 8

T able 5. AEGL

- 1 V alues for M ethyl I odide

................................ ................................ ............................... 25 9

T able 6. AEGL

- 2 V alues for M ethyl I odide

................................ ................................ ............................... 25 10

T able 7. AEGL

- 3 V alues for M ethyl I odide

................................ ................................ ............................... 27 11

T able 8. S ummary of AEGL V alues

................................ ................................ ................................ .......... 28 12

T able 9. S tandards and G uidelines for M ethyl I odide

................................ ................................ ................ 29 13

T able 10. AEGL V alues for H alomethanes

................................ ................................ ................................ 30 14

15

16METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 6 of 49

SUMMARY 1

2

Methyl iodide (CH 3 I, CAS No. 74

- 88

- 4) is a colorless liquid that turns brown with 3

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

provides poor warning properties. Methyl iodide is a pre

- plant biocide used to control insects, 5

plant parasitic nematodes, soil

- born pathogens, and weed seeds. It is also used as a methylatin g 6

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

and in testing for pyridine. P roduction data were not located. 8

9

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

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

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

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

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

appears linked to metabolism. Halomethanes are usually conjugated via glutathione

- S

15

transferase (GST) with glutathione (GSH), but the conjugation of methyl iodide with glutathione 16

may be non

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

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

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

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

neurotoxicity is attributed to the presence of the parent chemical in n erve cell membranes

. 21

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

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

fetal hypothalamic

- pituitary

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

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

includes repeat

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

27

The AEGL

- 1 values are based on a weight

- of evidence approach. A 6

- hour exposure to 28

27 ppm was a NOAEL for clinical signs that indicated neurotoxic ity (U.S. EPA 2006). A 1

- hour 29

exposure to 100 ppm was a no

- effect concentration for lesions of the nasal passage in rats, and a 30

2

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

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

reversible. In a 4

- week repeat

- exposure study, 25 ppm was a no

- effect level for irritation, 33

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

- week 34

study

, 2 1 ppm was a NOAEL for nasal degeneration in rats (U.S. EPA 2006). 35

36

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

the repeat

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

- of 38

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

60 minutes are NOAELs for both neurotoxicity and nasal lesions. The 6

- hour 27 ppm 40

concentration was used as the point of departure for the AEGL

- 1. Based on a higher blood:a ir 41

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

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

not expected to vary greatly among humans (Nolan et al. 19 85). In addition, conjugation of 44

methyl iodide with glutathione, the primary route of metabolism, may be non

- enzymatic, further 45

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

estimated that GSH conjugation w ith methyl iodide in a GSTT

- 1 null person would be a factor of 47METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 7 of 49

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

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

3

Development of nasal lesions and n eu rotoxicity are systemic effect s; methyl iodide is not 4

an irritant at these concentrations. Therefore the AEGL

- 1 values were time

- scaled. T he 6

- hour 5

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

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

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

time scaling value was 2 (C 2 x t = k). The 6

- hour value was time scaled t o 10 minutes because 9

one of the key studies (Reed et al. 1995) utilized a 0.5

- hour exposure. Because the 8

- hour time

10

scaled value of less than 10 ppm appears unrealistic in light of no

- effect concentrations of 10 11

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

(2006), respectively, the 8

- hour value was set equal to the 4

- hour value of 11 ppm. 13

14

The AEGL

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

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

- hour 16

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

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

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

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

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

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

primary route of metabolism, may be non

- enzymatic, further minimizing individual differences. 23

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

methyl iodide in a GSTT

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

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

lowe red to 3. Values were time

- scaled using C 2 x t = k. The fetotoxic effects of iodine liberated 27

from methyl iodide were considered in the derivation of AEGL

- 2 values. Based on historical 28

evidence of medical prescription of iodine to pregnant women, the in haled dose at the 8

- hour 29

AEGL

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

31

The following data sets were considered in derivation of AEGL

- 3 values. Mortality rates 32

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

respectively (Eastman Kodak Co. 1987) . N o mortality was observed in rats inhaling 100 ppm for 34

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

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

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

all data sets, the threshold for lethality was calculated at each AEGL

- 3 exposure duration using 38

the probi t

- analysis based dose

- response program of ten Berge (2006). The threshold for lethality 39

was set at the lower limit of the 9 5% confidence limit . The data indicated a time

- scaling value of 40

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

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

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

difference is not expected to be greater than thr ee

- fold (Nolan et al. 1985). Furthermore, the 44

conjugation of methyl iodide with glutathione may be non

- enzymatic, further minimizing 45

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

estimated that GSH conjugatio n with methyl iodide in a GSTT

- 1 null person would be a factor of 47

1.4 lower than that of a person with full GST activity. Therefore, the intraspecies uncertainty 48METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 8 of 49

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

time

- scaled values of the ten Berge program. 2

3

The calculated values are listed in the table below. 4

5

S 1

. Summary of AEGL Values for Methyl Iodide

Classification 10

- min 30

- min 1

- h 4

- h 8

- h Endpoint

(Reference)

AEGL

B 1

(Nondisabl ing) 54 ppm

( 3 10 mg/m 3 ) 3 1 ppm

( 18 0 mg/m 3 ) 2 2 ppm

(1 3 0 mg/m 3 ) 11 ppm

( 64 mg/m 3 ) 11 ppm

( 64 mg/m 3 ) Weight of evidence

NOAEL for clinical

signs/effects

- rat (U.S.

EPA 2006; Reed et al.

1995)

AEGL

B 2

(Disabling) 2 0 0 ppm

( 1 2 00 mg/m 3 ) 1 2 0 ppm

( 70 0 mg/m 3 ) 82 ppm

( 480 mg/m 3 ) 4 1 ppm

( 240 mg/m 3 ) 2 9 ppm

( 1 7 0 mg/m 3 ) Reversible lesions of

the nasal passages

– rat (Reed et al. 1995)

AEGL

B 3

(Lethal) 670 ppm

( 3900 mg/m 3 ) 400 ppm

( 2300 mg/m 3 ) 2 9 0 ppm

(1 7 00 mg/m 3 ) 1 5 0 ppm

( 870 mg/m 3 ) 98 ppm

( 5 70 mg/m 3 ) Lower limit of the

9 5% CL based on the

rat toxicity data of

Eastman Kodak Co.

(1987) , Reed et al.

(1995), and U.S. EPA

(2006)

, calculated

using the probit

analysis, dose

response program of

ten Berge (2006)

6

7

1. INTRODUCTION 8

9

Methyl iodide (CH 3 I, CAS No. 74

- 88

- 4) is a col orless liquid that turns brown with 10

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

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

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

Methyl iodide is an alternative to methyl bromide, an ozone

- depleting fumigant. The vapor 14

pressure is 375 mm Hg at 20  C. Solubility is 1 part in 50 parts of water (O’Neil et al. 2 001; 15

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

Table 1. 17

18

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

regions characterized by high biomass productivity, atmospheric levels range from 40

- 128 ng/m 3 20

(IARC 1986). 21

22

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

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

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

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

methanol, iodine, and diborane (NIOSH 1984 ; Lauterbach and Ober 2001 )

. Recent productio n 27

data were not found

. In the past, t he major use s of methyl iodide were as a methylation agent in 28METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 9 of 49

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

material for examining diatoms, and in testing for pyridine (Laut erbach and Ober 2001)

. Methyl 2

iodide is a pre

- plant biocide used to control insects, plant parasitic nematodes, soil born 3

pathogens, and weed seeds (U

. S

. EPA 2006). Although stored as a liquid under pressure, it 4

volatilizes rapidly following soil injecti on as a pesticide. 5

6

TABLE 1 . Chemical and Physical Properties

Parameter Value Reference

Synonyms Iodomethane O’Neil et al. 2001

Chemical formula CH 3 I O’Neil et al. 2001

Molecular weight 141.95 O’Neil et al. 2001

CAS Reg. No. 74

- 88

- 4 ACGIH 1992

Physical state L iquid 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/m 3

1 mg/m 3

= 0.17 2 ppm Calculated

7

8

2. HUMAN TOXICITY DATA 9

2. 1

. Clinical Studies 10

11

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

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

1986) , but the source of the data was not provided

. Tw o metabolism studies were conducted 14

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

. 15

16

2.2

. Case Studies 17

18

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

patients experienc ed a chronic neurological syndrome characterized by delayed psychiatric, 20

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

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

drowsiness, and coma (Garland and Camps 1945) . In a non

- fatal case (Appel et al. 1975), 23

symptoms were delayed, but included systemic, motor

, and psychotic changes. Recovery of 24

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

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

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

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

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

provided)

. 30

31METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 10 of 49

3. ANIMAL TOXICITY DATA 1

2

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

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

(0.1 mL instilled undiluted)

. Data on methyl iodide toxicity were reviewed by Bolt and 5

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

sponsor

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

characterized studies with laboratory rodents are summarized in Table 2. Ol d er studies that 8

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

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

11

3.1. Acute Toxicity 12

3.1.1. Rats 13

14

Deichmann and Gerarde (1969) report ed a 4

- hour LC 50 in rats of 216 ppm, but details of 15

the exposure were not pr ovided. 16

17

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

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

stream at a constant rate. Rats were tested one at a time for 15 minutes

. At 14 days 20

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

exposed to 3790 ppm for 15 minutes died after 11 days. This concentration

- exposure duration 22

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

concentration

- dependent manner. The two rats that survived for 14 days post

- exposure (15

- 24

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

examined grossly and microscopically (MacNamee 1950). Foll owing a 15

- minute lethal 26

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

edema and hemorrhage. 28

29

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

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

post

- exposure. Concentration

- related mortality was observed post

- exposure (days 1 and 2) in all 32

groups: males, 0/5, 2/5, and 4/5; and females, 2/5, 4/5, and 5/5. The 1

- hour LC 10 was 1347 ppm 33

for males and 976 ppm for females. The 1

- hour LC 10 for males and females combined was 1074 34

ppm with 95% confidence limits of 565

- 1266 ppm. Concentration

- related clinical signs 35

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

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

livers with focal necrosis w ere observed

. 38

39

In a recent study, g roups o f Sprague

- Dawley rats (4 to 5/sex) inhaled 581, 710, 797, or 40

1198 ppm for 4 hours (U.S. EPA 200 6 ) . Animals were observed for 14 days post

- exposure and 41

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

at all concentrations include d gasping, ataxia, hypoactivity, nasal discharge, labore d respiration, 43

rales and red material around the nose. Deaths occurred within two days at the hig h est 44

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

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

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

red adrenal glands, and distended intestines. 48METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 11 of 49

1

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

three male Alpk:APfsD (Wistar

- derived) rats, nose

- only, to a measured concentration of 100 3

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

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

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

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

of the r ats administered 100 ppm for 0.5 or 1 hour . With increasing exposure duration

, 8

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

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

lesions were characterized as minimal at 1 00 ppm for two hours, slight at 1 00 ppm for 3 hours

, 11

moderate at 1 00 ppm for 4

∙ hour s and marked at 1 00 ppm for 6 hours

. Following the 6

- hour 12

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

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

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

- 15

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

complete regeneration of the nasal epithelium. 17

18

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

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

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

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

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

of air inhaled

. According to the authors, n either species demonstrated a sensory irritant effect or 24

decreased inhalation uptake of test atmosphere. 25

26

3.1.2. Mice 27

28

Buckell (1950) determin ed the LC 50 in an unreported strain of male white mice. 29

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

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

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

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

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

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

20

- minute exposure and 100% after an 80

- minute exposure. The LC 50 time was estimated at 57 36

minutes, i.e. 57

- minute LC 50 of 860 ppm. 37METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 12 of 49

1

TABLE 2 . Summary of Acute Inhalation Data in Laboratory Animals

Species Concentration

(ppm) Exposure

Time Effect a Reference

Rat 1190

1554

1973

1074

14 58 1 hour

1 hour

1 hour

1 hour

1 hour 20% mortality

60% mortality

90% mortality

Calculat ed LC 10

Calculated LC 50 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 LC 50 Clinical signs of gasping, ataxia,

hypoactivity, nasal discharge, labo red

respiration, rales and red material

around the nose at all concentrations U

. S

. EPA 200 6

Rat 27

93

401 6 hours

6 hours

6 hours NOAEL for neurotoxicity

Clonic convulsions ; d ecreased body

temperature, decreased motor activity

Additional neurotoxicity

, gasping,

one death (4% mortality) U

. S

. EPA 200 6

Rat 100 0.5 hour

1 hour

2 hours

3 hours

4 hours

6 hours No observable change, nasal passage s

No observable change, nasal passage s

Minimal lesions, olfactory epithelium

Slight lesion, olfactory epithelium

Mod erate 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 DeL orme et al. 2005

Mouse 860

860

860 20 minutes

80 mi nutes

57 minutes 0/10 dead

10/10 dead

LC 50 Buckell 1950

2

3

3.2. Repeat

- Exposure Studies 4

5

Repeat

- dose studies are summarized in Table 3

. 6

7

Groups of 5 male and 5 female Sprague

- Dawley rats inhaled 150 ppm methyl iodide for 6 8

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

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

11

Groups of 10 male and 10 female Sprague

- Dawley rats inhaled 0, 25, 74, or 14 0 ppm for 12

6 hours/d ay, 5 days/week for 4 weeks ( Monsanto Company 1983; Blank et al. 1984). Exposure

13

related signs in the 74

- and 143

- ppm groups included irritation of the eyes, nasal discharge, 14

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

compared with controls. Five animals , 2 males and 3 females in the 14 0

- ppm group died or were 16

sacrificed moribund during the last week of exposure . No gross lesions were observed. The “no

17

effect” level was 25 ppm. 18METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 13 of 49

1

Additional groups of 1 0 male and 10 female Sprague

- Dawley rats inhaled 0, 10, 30, or 60 2

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

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

- ppm 4

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

further details were reported in the published abstract. 6

7

In a subchronic inhalation toxicity study, described in U

. S

. EPA (2006), methyl iodide 8

(99.7% pure) was administered whole

- body to groups of 20 male and 20 female Crl:CD (SD)IGS 9

BR rats for 6 hours/day, 5 days/week for 13 weeks. Analytically

- determined concentrations were 10

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

, and the 11

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

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

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

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

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

17

In a range

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

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

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

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

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

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

24

TABLE 3

. Summary of Repeat

- Dose Studi es

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

1982 b

Rat 0, 25, 74, 14 0 6 hours/day,

5 days/week

, 4 weeks Exposure

– rel ated 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 decr ease 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 7 0 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

25METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 14 of 49

1

3. 3

. Neurotoxicity 2

3

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

, 4

whole

- body, for 6 hours (U

. S

. EPA 200 6 ) . Analytically

- determined concentrations were 0, 27, 5

93, and 401 ppm. Neurobehavioral assess ment took place pre

- exposure, at the predicted time of 6

peak effect on the day of exposure (3 hours post

- exposure), and on days 7 and 14 post

- exposure. 7

On day 7, there was a slight weight loss, 2

- 10%, in the groups exposed to 93 and 401 ppm. 8

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

, the 9

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

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

activity relative to controls ( decreases of 75 % in males and 8 1 % in females ) . More animals were 12

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

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

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

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

clinical signs in the survivi ng animals were decreased defecation and dried red mater ial around 17

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

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

neurotoxicit y in both sexes. 20

21

3. 4

. Developmental/Reproductive Toxicity 22

23

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

- Dawley 24

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

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

Glutathione may protect against chemical

- induced germ cell mutations. Substantial recovery of 27

glutathione took place by 16 hours post

- exposure. 28

29

A two

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

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

Offspring were exposed beginning on post

- natal day 28. For the parental generation, both the 32

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

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

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

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

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

delayed vaginal patency. 38

39

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

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

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

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

44

In a developmental toxicity study, groups of six timed

- pregnant New Zealand rabbits 45

inhaled 0, 10, 26, or 74 ppm methyl iodide during GD 6

- 28 (U.S. EPA 2006) . Due to maternal 46

toxicity, the 74 ppm exposure was reduced to 50 ppm beginnin g on GD 18. There was a dose

47

dependent increase in the litter proportions of late fetal deaths and post

- implantation loss and/or 48METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 15 of 49

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

At 25 ppm, there were increased fetal losses (late) and increased post

- implantation loss; fetal 2

body weight was non

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

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

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

24 timed

- pregnant rabbits inhaled 0, 2, 10, or 20 ppm on GD 6

- 28. Effects in the 20 ppm group 6

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

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

9

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

resulted in fetal loss in the above study with rabbits ( Nemec et a l. 200 9 ). Groups of 24 pregnant 11

New Zealand white rabbits inhaled 0 or 20 ppm for 6 hours/day during GD 6

- 28, 6

- 14, 15

- 22, 23

- 12

24, 25

- 26, or 27

- 28 for 6 hours/day. At 20 ppm, increased fetal losses were 21% (GD 6

- 28), 9% 13

(GD 23

- 24), and 11% (GD 25

- 26). T he most susceptible window of exposure for eliciting 14

developmental toxicity in rabbits exposed to methyl iodide vapors was GD 23

- 26. 15

16

3. 5

. Genotoxicity 17

18

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

capabilities (Bolt a nd Gansewendt 1993). Methyl iodide methylates hemoglobin at the free SH

20

group of cysteine in experimental animals as well as in hu man s

. Methyl iodide was mutagenic in 21

Salmonella typhimurium bacterial strains TA1535 and TA10 0 ( Andrews et al. 1976; McCann et 22

al. 1975). Methyl iodide was a direct

- acting mutagen for mouse lymphoma L5178Y/TK+/

- cells 23

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

(concentrations of 0 to 3 μg/mL) (Amacher and Zelljadt 1984 )

. Methyl iodide fail ed to transform 25

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

27

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

authors stated that methyl iodide induced DNA damage and is mutagenic to bacteria ( Salm o nella 29

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

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

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

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

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

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

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

. 36

37

I n a series of recent unpublished studies submitted to the U.S. EPA (2006)

, the only 38

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

in C H O. Methyl iodide was non

- mutagenic in Salmonella typhimurium strains TA98, TA100, 40

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

assay in mice. Tested concentrations were not provided. The c onflict with earlier stud y results 42

was not addressed. 43

44

3. 6

. Chronic Toxicity/Carcinogenicity 45

46

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

dosage of 10 mg/kg for an unstated period of time ( Druckrey et al. 1970 ) . It also produced lung 48METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 16 of 49

tumors in a cancer

- susceptible strain of mice (Strain A) injected intraperitoneally

, weekly for 24 1

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

mg/kg/week. Half this dose, 22 mg/kg/ day which equates to 20

- 25 ppm in a human inhaling 3

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

and a non

- significant increase in lung tumors. 5

6

In a n inhalation chronic toxicity/carcinogenicity study, grou p s of 60

- 70 male and 60

- 70 7

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

days/week ( U.S. EPA 2006)

. Animals were examined daily for clinical signs and activity. At 20 9

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

degeneration of the olfactory epithelium as well as perturbations of the thyroid

- pituitary axis, 11

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

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

14

3. 7

. Summary 15

16

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

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

ra bbits

. Six

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

(U.S. EPA 200 6 ). Exposure to 100 ppm for 6 hours induced reversib le lesions in the olfactory 20

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

lesions. The highest non

- lethal value for rats i n a well

- conducted study was a 4

- hour exposure to 22

581 ppm (U.S. EPA 200 6 ). Calcula ted 1

- hour and 4

- hour LC 50 values were 1458 (Eastman 23

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

were conflicting. Methyl iodide was not carcinogenic in a well

- conducted chronic study. In 25

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

iodide. 27

28

4. SPECIAL CONSIDERATIONS 29

4.1. Metabolism and Disposition 30

4.1.1. Clinical and Laboratory Animal Studies 31

32

Inhaled monohalomethanes such as methyl chloride and methyl brom ide are rapidly 33

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

form S

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

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

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

moieties of GSH yields S

- methylcysteine; transa m ination and decarboxylation yields the 38

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

injection of rats with methyl iodide, small amounts of S

- methylcysteine, methylthioacetylglycine, 40

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

Young 1965). The initial conjugation of monohalomethanes with GSH may be either non

42

enzymatic or enzymatically catalyzed. Although methyl chloride and methyl bromide are 43

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

tha t the major conjugation process of glutathione with methyl iodide is non

- enzymatic (Hallier et 45

al. 1990). 46

47METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 17 of 49

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

methyl iodide labeled with I

- 132 for 5 minutes (Morgan and Mor gan 1967). Subjects inhaled 2

and exhaled through a two

- way mouthpiece. Respiratory rate, duration of breath, tidal volume, 3

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

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

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

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

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

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

tidal volume

. The concentration of methyl iodide in the inspired air was not provide d

. The 10

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

Radiological Protection occupational standard was 30 rem/year. 12

13

In a second study, four of the above male subjects inhaled methyl iodide labeled with I

14

132 in order to address metabolism (Morgan et al. 1967). The subjects inhaled methyl iodide for 15

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

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

into the blood was rapid (within minutes). Half

- time for buildup of iodine in the thyroid was 200 18

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

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

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

in the inhaled air was calculated as equivalent to less than one

- quarter of the average daily intake

. 22

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

further data were provided. 24

25

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

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

(range, 51

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

(range, 57

- 92%), regardless of exposure concentration. 29

30

Sprague

- Dawley rats inhaled 14 C

- labeled methyl iodide (U. S. EPA 2006). The only 31

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

within 0

- 2 hours and were proportional t o the air concentration s

. The initial half

- life was 5.1

- 7.2 33

hours, and the terminal half

- life was 116

- 13 6 hours. Recovered radioactivity was primarily as 34

CO 2 (39

- 61%) and in the urine (27

- 33%). Feces accounted for <2% of the dose. At 0

- 1 hour 35

post

- treatment

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

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

major metabolites were expired CO 2 , and N

- (methylthioacetyl) glycine and S

- methyl glutathione 38

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

mercapturic acid, and S

- methyl cysteine. 40

41

4.1. 2

. Physiologically

- Based Pharmacokinetic (PBPK) Modeling 42

43

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

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

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

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

rabbit kidney. Maximal metabolic rates were similar in liver from rat and human donors, but a 48METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 18 of 49

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

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

was essentially first

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

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

but higher capacity

. 5

6

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

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

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

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

concentrations to the animal no

- observed levels using chemical

- specific parameters to determine 11

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

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

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

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

event. Glutathione d epletion of 50% or greater from normal leve l s may be associated with 16

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

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

to fetal losses. No

- observed adverse effect levels for these endpoints were developed for a 1

- day, 19

24

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

models support application of uncertainty factors of approximately 2 for intra

- human 21

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

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

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

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

exposure concentration of 110 ppm. 26

27

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

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

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

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

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

33

4.2. Mechanism of Toxicity 34

35

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

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

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

studies on metabolism an d toxicity, Kirma n et al. (2009) evaluated the possible mode(s) of action 39

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

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

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

following hypotheses: 43

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

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

Rabbit fetal resorptions: modulation of the thyroid hormones by iodine. 46METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 19 of 49

1

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

below critical levels due to methyl iodide metabolism ( U.S. EPA 200 6; Gargas and K inzell 2007 ; 3

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

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

respiratory epithelium, but the rate is 4

- fold higher in the olfactory epithelium. C onjugat ion with 6

glutathione, result s in S

- methyl

- glutathione. This pathway is considered a detoxifying 7

mechanism. Cytochrome P

- 450 metabolism does not appear to play a role in methyl iodide 8

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

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

11

Male Sprague

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

days (Him melstein et al. 2005; 2009). A time

- dependent reduction in GSH levels in blood, 13

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

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

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

tissue levels of GSH. E rythrocyte S

- methylcysteine hemoglobin adducts also increased

. 17

Evidence of the protection of GSH against toxicity was ob tained by pre

- treating animals with 18

substances that deplete or replenish GSH. 19

20

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

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

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

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

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

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

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

of nerve cells due to high c oncentrations of the circulating parent chemical. These factors

, which 28

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

occur

, suggest that the peak concentration of methyl iodide in the brain is the appr opriate internal 30

dose measure. 31

32

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

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

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

(GD 23

- 26) is when the fetal rabbit thyroid is undergoing maturation (Sloter et al. 2009). Two

36

or four

- day exposures of pregnant rabbits to 25 ppm for 6 hours/day during gestation days 23

- 24 37

or 23

- 2 6, respectively, diminished triiodothyronine ( T 3 ) and thyroxine ( T 4 ) in fetal serum and 38

increased TSH. Time

- course exposures at 20 ppm methyl iodide revealed highly concentrated 39

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

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

Administration of sodium iodide by intravenous infusion during GD 23

- 26 induced similar 42

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

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

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

prefere ntial accumulation of iodide in the fetal compartment causing disruption of the fetal 46

hypothalamic

- pituitary

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

thyroid. Increased serum iodide is also observed in adult rats following in halation exposure to 48METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 20 of 49

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

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

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

4

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

an increase in TSH. This “Wolff

- Chaikoff effect

, ” even with chronic exposure is transient in 6

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

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

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

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

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

12

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

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

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

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

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

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

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

hypothalamus

- pituitary

- thyroid

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

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

doses of iodine were evaluated. In humans, o rally

- administered iodine and iodide at s imilar 22

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

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

normal thyr o id function as m ea sured by blood T 3 , T 4 , and TSH were administered either iodine 25

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

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

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

days (Robinson et al. 1998), 72 or 360 mg/day for 12

- 19 days (Vagenakis et al. 1973), 50 or 250 29

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

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

32

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

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

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

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

decreases in T 4 and T 3 during administration were transient as indicated by a 1 month post

37

treatment follow

- up

. None of the healthy subjects developed signs or symptoms of 38

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

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

41

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

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

iodide th roughout pregnancy (Senior and Chernoff 1971), 900

- 1500 mg/day (Martin and Rento 44

1962), and 2

- 1650 mg/day (Carswell et al. 1970)

. Pregnant women with mild Graves’ disease 45

ingesting 6

- 40 mg of iodide or iodide daily beginning at 11

- 37 weeks of pregnancy de livered 46

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

reflected maternal thyroxine levels. 48METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 21 of 49

1

4.3. Structure

- Activity Relationships 2

3

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

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

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

, 6

although inhalation of methyl iodide at up to 100 ppm did no t change the breathing rate of rats 7

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

same for all three halomethanes

– depletion of cellular glutathione which result s in an inability of 9

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

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

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

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

1990). 14

15

16

TABLE 4

. C omparison of Toxicity Values Among the Monohalomethanes

Chemical Toxicity Value * Reference

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

Methyl bromide 1880 ppm (1

- hour LC 50 )

780 ppm (4

- hour LC 50 )

300 ppm (8

- hour LC 50 ) Zwart 1988

Kato et al. 1986

Honma et al. 1985

Methyl iodide 1347 ppm (1

- hour LC 50 )

691 ppm (4

- hour LC 50 ) Eastman Kodak Co. 1987

U.S. EP A 200 6

* All data are for the rat. 17

18

4.4. Other Relevant Information 19

4.4.1. Species Variability 20

21

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

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

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

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

Human GST T1

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

amino acid arginine for the tryptophan found in the human GST resulted in a 13

- fold increase in 27

the specific activity of the enzyme and a 2.7

- fold increase in the catalytic efficiency (Shokeer et 28

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

sheep does not metabolize monohalomethanes whereas the erythrocyte cytoplasm of 30

approximately 60% of humans does (Redford

- Ellis and Gowenlock 1971; Peter et al. 1989). 31

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

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

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

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

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

hypothesis that the rate of activation of m ono

- and dihalomethanes to toxic metabolites by the 37

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

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

40METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 22 of 49

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

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

1983; Nolan et al. 1985). Blood concentrations at steady state during a 3

- hour exposure to 50 3

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

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

6

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

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

to plasma proteins than in rats. The half

- life of thyroxine in humans varies between 5 and 9 9

days; whereas, it is 12

- 24 hours in the rat. Poet et al. (2005) compared t he metabolism of methyl 10

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

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

maximum rates of reaction ( V

max ) were s imilar in liver and kidney cytosols from rats and humans 13

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

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

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

transport. 17

18

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

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

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

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

- to 5

- 22

fold for guinea pigs and up to six

- fold in rabbits. Crone and Waago (1961) found a similar two

23

to six

- fold difference in fetal and maternal blood iodide measurements of rabbits

. Following 24

injection of Na 131

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

three

- fo ld greater blood radioiodide level in fetuses compared with dams. Levels of radioiodide 26

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

evidence of clearance over a 24

- hour sampling period. In contrast, human fe tal to maternal blood 28

iodide ratios, measured following term (37

- 41 weeks) and preterm (29

- 36 weeks) deliveries were 29

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

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

level during late gestation. 32

33

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

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

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

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

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

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

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

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

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

combination of computational fluid dynamics and physiologically

- based ph armacokinetics 43

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

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

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

to two

- to three

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

likely that higher concentrations of methyl bromide would be required to induce this lesion in 48METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 23 of 49

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

glutathione) than human tissue. 2

3

4.4.2. Susceptible Populations 4

5

Inter

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

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

chemical, methyl chloride

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

1998; Lof et al. 2000; WHO 200 0 ). The differences in metabolism rate are attribu ted to the 9

genetic polymorphism of glutathione transferase theta 1 (GST T

- 1 ). Depending on the presence 10

or absence of GST and the number of alleles , humans may be fast , slow, or non

- metabolizers

. 11

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

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

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

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

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

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

difference , toxicologically, is considered to be less than three

- fold (Nolan et al. 1985). The 18

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

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

Because methyl iodide is thought to be non

- enzymatically conjugated, the significance of the 21

variation in human genotype is unknown. 22

23

Although individuals who are lacking the GSTT

- 1 enzyme would have lower 24

susceptibility to the potenti al nasal toxicity of methyl iodide, these individuals c ould be at greater 25

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

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

Chamberlain et al. (1998a) in which rat nasal or liver homogenates were co

- incubated with GSH, 28

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

methyl iodide in a GSTT

- 1 null person would be a factor of 1.4 lower than derived for a person 30

with full GST activity. 31

32

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

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

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

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

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

in alterations in thyroid function in subjects having adequate preformed stores of T 4 and T 3 38

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

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

2004). 41

42

4.4.3. Concentration

- Exposure Duration Relationship 43

44

The concentration

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

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

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

data. Concentration, exposure duration, and response, including the number of animals 48METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 24 of 49

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

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

each parameter. The probit

- analysis dose

- response program of ten Berge was applied to the 3

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

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

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

. 6

7

4.4.4. Concurrent Exposure Issues 8

9

No information relevant to concurrent exposure issues was located. 10

11

5. DATA ANALYSIS FOR AEGL

- 1 12

5.1. Summary of Human Data Relevant to AEGL

- 1 13

14

No clinical studies were available for de rivation of AEGL

- 1 values. 15

16

5.2. Summary of Animal Data Relev ant to AEGL

- 1 17

18

A 1

- hour exposure to 100 ppm was a no

- effect concentration for lesions of the nasal 19

passage in rats, and a 2

- hour exposure to 100 ppm resulted in minimal lesions to the olfactory 20

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

nasal lesions are reversible. A 6

- hour exposure to 27 ppm was a NOAEL for clinical signs that 22

addressed neurotoxicity (U.S. EPA 2006). In a repeat

- exposure (4

- week) study, 25 ppm was a 23

no

- effect level for irritation , n eurotoxic signs, and gross pathologic changes in rats (Monsanto 24

Company 1983). In a 13

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

nasal degeneration in rats. 26

27

5.3. Derivation of AEGL

- 1 28

29

Based on the acute studies of Reed et al. (199 5) and U.S. EPA (200 6 ) with support from 30

the repeat

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

- of 31

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

minutes are NOAELs for both nasal l esions and neurotoxicity. The 6

- hour 27 ppm concentration 33

was used as the point of departure for the AEGL

- 1. Based on a higher blood:air partition 34

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

addition

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

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

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

iodide with glutathione, the primary route of metabolism, may be non

- enzymatic, further 39

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

applied. 41

42

Neurotoxicity and nasal lesions are syst emic effect s; therefore, the values were time 43

scaled. The 6

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

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

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

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

value was 2 (C 2 x t = k). The 6

- hour value was time scaled to 10 minutes because one of the key 48METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 25 of 49

s tudies (Reed et al. 1995) utilized a 0.5

- hour exposure. Because the 8

- hour time

- scaled value of 1

less than 10 ppm appears unrealistic in light of no

- effect concentrations of 10 ppm and 20 ppm in 2

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

respectively, the 8

- hour value was set equal to the 4

- hour value of 11 ppm. Values are listed in 4

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

the toxicity data is in Appendix B. 6

7

8

TABLE 5

. AEGL

- 1 Values for Methyl Iodide

10

- min 30

- min 1

- h 4

- h 8

- hour

54 ppm

( 310 mg/m 3 ) 3 1 ppm

(180 mg/m 3 ) 2 2 ppm

( 130 mg/m 3 ) 1 1 ppm

( 64 mg/m 3 ) 1 1 ppm

( 64 mg/m 3 )

9

10

6. DATA ANALYSIS FOR AEGL

- 2 11

6.1. Summary of Human Data Relevant to AEGL

- 2 12

13

No clinical studies w ere available for development of AEGL

- 2 values. 14

15

6.2. Summary of Animal Data Relevant to AEGL

- 2 16

17

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

of Wistar

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

6 hours. At the highest concentration

- exposure duration, 1 00 ppm for 6 hours, lesions of the 20

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

subsequent two

- week post

- exposure period. 22

23

6.3. Derivation of AEGL

- 2 24

25

The 100 ppm, 6

- hour exposure of rats in the study of Reed et al. (1995) was used as the 26

point of departure for the AEGL

- 2. The endpoint of r eversible lesions of the nasal olfactory 27

epithelium , a NO AEL for irreversible lesions, meets the definition of an AEGL

- 2. Based on a 28

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

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

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

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

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

may be non

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

uncertainty factor of 3 was applied. Values were time

- scaled using C 2 x t = k. Calculations are 35

in Appendix A and value s are summarized in Table 6

. A category graph of the AEGL values in 36

relation to the toxicity data is in Appendix B. 37

38

TABLE 6

. AEGL

- 2 Values for Methyl Iodide

10

- min 30

- min 1

- h 4

- h 8

- h

2 0 0 ppm

( 1200 mg/m 3 ) 1 2 0 ppm

( 700 mg/m 3 ) 82 ppm

( 480 mg/m 3 ) 4 1 ppm

( 240 mg/m 3 ) 2 9 ppm

( 170 mg/m 3 )

39METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 26 of 49

Support for the AEG L

- 2 values consists of data from acute and subchronic studies. The 1

8

- hour AEGL

- 2 value of 2 9 ppm is close to the 6

- hour NOAEL for neurotoxicity of 27 ppm in an 2

acute 6

- hour study w ith the rat and only slightly higher than the 6 hour/day 13

- week NOAEL for 3

olfactory lesions of 21 ppm in rats ( U.S. EPA 200 6 ). 4

5

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

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

the hypothalamus

- pituitary

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

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

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

(Rayburn et al. 200 8 ), the intake of iodine at the 8

- hour AEGL

- 2 was calculated. The intake of 11

iodine from methyl iodide by a pregnant woman at the 8

- hour AEGL

- 2 is 1 7 0 mg/m 3 . The 12

breathing rate of an adult human is 20 m 3 /day. Methyl iodide is 89% iodide. Assuming 13

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

pregnant female is: 15

16

1 7 0 mg/m 3 x 20 m 3 /24 hours x 8 hours x 0 .89 = 1009 mg

. 17

18

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

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

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

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

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

stores of T 4 and T 3 (Saber i and Utiger 1975). Chronic administration of similar or slightly higher 24

doses, 900

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

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

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

1500 mg/day orally

, improved spontaneously in the months following birth , and later studies 28

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

30

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

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

iodide ( I

- 132 at tracer concentrations) is absorbed in healthy adult s (Morgan and Morgan 196 7)

. 33

The half

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

absorption at the alveolar

- blood interface. Water soluble iodide salts such as potassium or 35

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

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

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

excretion rates (Morgan et al. 1 967). Thus, the effect of total dose to the primary target tissue, 39

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

41

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

iodine and is not a good model for human iodine

- induced fetotoxicity (See Section 4.4.1)

. 43

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

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

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

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

48METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 27 of 49

7. DATA ANALYSIS FOR AEGL

- 3 1

7.1. Summary of Human Data Relevant to AEGL

- 3 2

3

No clinical studies were available for development of AEGL

- 3 values

. 4

5

7.2. Summary of Animal Data Relevant to AEGL

- 3 6

7

Several studies addressed the threshold for lethality. A recent, well

- conducted study 8

reported by U.S. EPA (200 6 ) showed mortality values for male and female r ats of 0, 80, 80, and 9

100% following 4

- hour e xposures to 581, 710, 797, and 1198 ppm, respectively; the calculated 10

4

- hour LC 50 was 691 ppm , and the calculated benchmark concentration (4

- hour BMCL 05 ) was 11

489 ppm (Appendix B) . The calculated 1

- hour LC 50 was 1347 ppm in a similar study with rats

, 12

and th e calculated 1

- hour BMCL 05 was 61 2 ppm ( Eastman Kodak Co. 1987). One of 24 rats died 13

following a 6

- hour exposure to 401 ppm (U.S. EPA 200 6 )

. The 57

- minute LC 50 in mice was 860 14

ppm (Buckell 1950). No mortality was observed in rats inhaling 100 ppm for 0. 5 to 6 hours 15

(Reed et al. 1995). 16

17

7.3. Derivation of AEGL

- 3 18

19

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

and U.S. EPA 2006) were combined to estimate the threshold for lethality at each AEGL

- 3 21

exposure dura tion using the probit

- analysis based dose

- response program of ten Berge (2006). 22

The threshold s for lethality at each exposure duration w ere set at the lower limit of the 5% 23

response for lethality (the lower limit of the 95% confidence limit). Th ese value s are similar to 24

the benchmark dose BMCL 05 . The data ind icated a time

- scaling value of 2 (C 2 x t = k). Val u es 25

for the 10

- minute through 8

- hour exposure duration were: 670, 400, 290, 150, and 98 ppm, 26

respectively. Based on a higher blood:air partition co efficient for rats than humans (Sweeney et 27

al. 2009), uptake is greater in rats than humans. In addition, higher inhalation rate and cardiac 28

output in rodents indicate faster uptake. Thus, an interspecies uncertainty factor of 1 was 29

applied. Although hu mans vary in the rate at which they metabolize halomethanes, the 30

difference is not expected to be greater than three

- fold (Nolan et al. 1985). Furthermore, the 31

conjugation of methyl iodide with glutathione may be non

- enzymatic, further minimizing 32

differen ces in metabolism rates. P ersons lacking the GSTT

- 1 enzyme would be more sensitive to 33

the neurotoxic effects of the circulating unconjugated methyl iodide by a factor of 1.4 compared 34

to persons with full GSTT

- 1 activity (Sweeney et al. 2009). Therefore, the default intraspecies 35

uncertainty factor of 10 was reduced to 3. Calculations are in Appendix A and AE G L

- 3 values 36

are summarized in Table 7

. A category graph of the AEGL values in relation to the toxicity data 37

is in Appendix B. 38

39

TABLE 7

. AEGL

- 3 Values for Methyl Iodide

10

- min 30

- min 1

- h 4

- h 8

- h

6 70 ppm

( 39 00 mg/m 3 ) 400 ppm

( 23 00 mg/m 3 ) 2 9 0 ppm

( 1 7 00 mg/m 3 ) 1 5 0 ppm

( 870 mg/m 3 ) 98 ppm

( 570 mg/m 3 )

40

41METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 28 of 49

8. SUMMARY OF AEGLs 1

8.1. AEGL Values and Toxicity Endpoints 2

3

AEGL values are s ummarized in Table 8

. Derivations are summarized in Appendix C

. 4

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

( 3 1 0 mg/m 3 ) 3 1 ppm

( 18 0 mg/m 3 ) 2 2 ppm

( 1 3 0 mg/m 3 ) 1 1 ppm

( 64 mg/m 3 ) 1 1 ppm

( 64 mg/m 3 )

AEGL

- 2

(Disabling) 2 0 0 ppm

( 1 2 00 mg/m 3 ) 1 2 0 ppm

( 7 0 0 mg/m 3 ) 82 ppm

( 480 mg/m 3 ) 4 1 ppm

( 2 4 0 mg/m 3 ) 2 9 ppm

( 1 7 0 mg/m 3 )

AEGL

- 3

(Lethal) 6 70 ppm

( 39 00 mg/m 3 ) 400 ppm

( 23 00 mg/m 3 ) 2 9 0 ppm

( 1 7 00 mg/m 3 ) 1 5 0 ppm

( 870 mg/m 3 ) 98 ppm

( 5 7 0 mg/m 3 )

6

7

8.2. Comparison with Other Standards and Guidelines 8

9

Standards and guidelines for methyl iodide are summarized in Table 9

. The Emergency 10

Response Planning Guideline (ERPG) values are for 1 hour and are based primarily on 11

unpu blished studies (AIHA 2004). The ERPG

- 1 of 25 ppm was based on eye irritation noted in 12

some rats exposed to 72 ppm, 6 hr/day, after 17 exposures but not in rats exposed to 24 ppm, 6 13

hours/day for 20 exposures. The ERPG

- 2 of 50 ppm was based on a weight

- o f

- evidence 14

approach with repeat exposures of rats to concentrations ranging from 72 to 85 ppm. The ERPG

15

3 of 125 ppm was based on no deaths of rats exposed to 150 ppm, 6 hr/day, for 3 days and 16

following a 1

- hour exposure of rats to 960 ppm or of mice to 8 60 ppm for 20 minutes. The 17

NIOSH Immediately Dangerous to Life or Health (IDLH) value of 100 ppm is based on the 18

lethality studies of Bakhishev (1975), Buckell (1950), and Monsanto Company (1982a; 1982b; 19

1983 ). 20

21

The ACGIH TLV is 2 ppm and carries skin and suspected human carcinogen notations. 22

The Occupational Safety and Health Administration 8

- hr permissible exposure limit (PEL) is 2 23

ppm (skin) (NIOSH 200 5 ) as is The Netherlands MAC

. The Swedish LLV is 1 ppm with a 15

- 24

minute short

- term limit of 5 ppm. I t also bears skin and carcinogen notations. The German 25

MAK places methyl iodide in carcinogen category 2, human or animal carcinogen. 26

27

28METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 29 of 49

TABLE 9 . Standards and Guidelines for Methyl Iodide

Guideline Exposure Duration

10 min 30 m in 1 h 4 h 8 h

AEGL

- 1 54 p pm 3 1 ppm 2 2 ppm 1 1 ppm 1 1 p pm

AEGL

- 2 2 0 0 p pm 1 2 0 ppm 82 ppm 4 1 ppm 2 9 p pm

AEGL

- 3 6 70 p pm 40 0 ppm 2 9 0 ppm 1 5 0 ppm 98 p pm

ERPG

- 1 (AIHA) a 25 ppm

ERPG

- 2 (AIHA) 50 ppm

ERPG

- 3 (AIHA) 125 ppm

PEL

- TWA

( NIOSH ) b 5 pp m (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)

* The skin notation indicates the potential for dermal absorption. 1

2

a ERPG (Emergency Response Planning Guidelines, American Industrial Hygiene Association (AIHA 200 4 ) 3

The ERPG

- 1 is the maximum airborne concent ration below which it is believed nearly all individuals could be 4

exposed for up to one hour without experiencing other than mild, transient adverse health effects or without 5

perceiving a clearly defined objectionable odor. 6

The ERPG

- 2 is the maximum airb orne concentration below which it is believed nearly all individuals could be 7

exposed for up to one hour without experiencing or developing irreversible or other serious health effects or 8

symptoms that could impair an individual = s ability to take protecti v e action. 9

The ERPG

- 3 is the maximum airborne concentration below which it is believed nearly all individuals could be 10

exposed for up to one hour without experiencing or developing life

- threatening health effects. 11

12

b OSHA PEL

- TWA (Occupational Safety and H ealth Administration, Permissible Exposure Limits

- Time 13

Weighted Average) ( NIOSH 2005 ) is defined analogous to the ACGIH

- TLV

- TWA, but is for exposures of no more 14

than 10 hours/day, 40 hours/week. 15

16

c IDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health) 17

(NIOSH 2005 ) represents the maximum concentration from which one could escape within 30 minutes without any 18

escape

- impairing symptoms, or any irreversible health effects. 19

20

d NIOSH REL

- TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits

- 21

Time Weighted Average) (NIOSH 2005 ) is defined analogous to the ACGIH

- TLV

- TWA. 22

23

e ACGIH TLV

- TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value

- 24

Time Weighted Average) (ACGIH 1992 ) is the time

- weighted average concentration for a normal 8

- hour workday 25

and a 40

- hour workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse 26

effect. 27

28

f MAK (Maximale Arbeitsplatzkonzentration [Ma ximum Workplace Concentration]) (Deutsche 29

Forschungsgemeinschaft [German Research Association] 200 7 ) is defined analogous to the ACGIH

- TLV

- TWA. 30

31

g LLV (level Limit Value) Occupational Exposure Limit Values and Measures against Air Contaminants. 2000. 32

Swe dish National Board of Occupational Safety and Health. 33METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 30 of 49

1

h MAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration]) (SDU Uitgevers [under the 2

auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands 2000) is define d similar to 3

the ACGIH TLV. 4

5

8.3. Data Adequacy and Research Needs 6

7

Although no quantitative human data were located, studies with animal models were 8

adequate for derivation of AEGL values for methyl iodide. The relative toxicities of the 9

halomethanes a re: methyl iodide > methyl bromide > methyl chloride (see Section 4.3. Structure

10

Activity Relationships) . The derived AEGL values for the three chemicals reflect the relative 11

toxicities. The Interim AEGL values for methyl bromide and methyl chloride alon g with the 12

draft values for methyl iodide are summarized in Table 10

. 13

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 3 1 ppm 2 2 ppm 1 1 ppm 1 1 ppm

AEGL

- 2 2 0 0 ppm 1 2 0 ppm 82 ppm 4 1 ppm 2 9 ppm

AEGL

- 3 670 ppm 400 ppm 2 9 0 ppm 1 5 0 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

NR = Not Recommended; values are not recommended because there are no odor or warning properties and toxic 15

effects may occur below the odor threshold. 16

17

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Poet, T., H. Wu, J. Soelberg, J. Kinzell, and M . Gargas. 2005. Species and tissue comparison of the 8

glutathione conjugation of methyl iodide in rat, rabbit, and h uman cytosol. Toxicol. Sci. 84 ( S

- 1) :48

- 9

49 (abstract). 10

11

Poet, T., H. Wu, R.A. Corley, and K.D . Thrall.

. 200 9

. In vitro glutathione conjugation of methyl iodide in 12

the rat, rabbit, and human blood and tissues

. Inhal. Toxicol. 21:524

- 530. 13

14

Poirier, L.A., G.D. Stoner, and M.B. Shimkin. 1975. Bioassay of alkyl halides and nucleotide base 15

analogs by pulmonary tumor response in strain A mice. Cancer Res. 35:1411

- 1415. 16

17

Price, D.J. and J.R. Sherwin. 1986. Autoregulation of iodide transport in the rabbit: absence of 18

autoregulation in fetal tissue and comparison of maternal and fetal thyroid iodination products. 19

Endocrinology 119:2547

- 2552. 20

21

Rayburn, W.F., A. Robinson, L.E. Braverman, X.M. He, S. Pino, M.L. Gargas, and J.H. Kinzell. 200 8

. 22

Iodide concentra tions in matched maternal serum, cord serum, and amniotic fluid from preterm and 23

term human pregnancies. Reprod. Toxicol. 25:129

- 132. 24

25

Redford

- Ellis, M. and A.H. Gowenlock. 1971. Studies on the reaction of chloromethane with human 26

blood. Acta. Pharmaco l. Toxicol. 30:36

- 48. 27

28

Reed, C.J., B.A. Gaskell, K.K. Banger, and E.A. Lock. 1995. Olfactory toxicity of methyl iodide in the 29

rat. Arch. Toxicol. 70:51

- 56. 30

31

Reitz, R.H., A.L. Mendrala, and F.P. Guengerich. 1989. In vitro metabolism of methylene chlori de in 32

human and animal tissues: Use in physiologicall y based pharmacokinetic model s Toxicol. Appl. 33

Pharamcol. 97:230

- 246. 34

35

Robinson, L.M., P.W. Sylvester, P. Birkenfeld, J.P. Lang, and R.J. Bull. 1998. Comparison of the effects 36

of iodine and iodide on t hyroid function in humans. J. Toxicol. Environ. Health, Part A, 55:93

- 106. 37

38

Ruth, J.H. 1986. Odor threshold and irritation levels of several chemical substances: A review. Am. Ind. 39

Hyg. Assoc. J. 47:A124

- A151. 40

41

Saberi, M. and R.D. Utiger. 1975. Augme ntation of thyrotropin responses to thyrotropin

- releasing 42

horm o ne following small decreases in serum thyroid hormone concentrations. J. Clin. Endocrinol. 43

Metab. 40:435

- 441. 44

45

Schwartz, M.D., A.O. O bamwonyi, J.D. Thomas, J.F. Moorhead, and B.W. Morgan. 200 5. Acute methyl 46

iodide exposure with delayed neuropsychiatric sequelae: Report of a case. Am. J. Industr. Med. 47

47:550

- 556. 48

49

SDU Uitgevers. 2000. Nationale MAC List. Under the auspices of the Ministry of Social Affairs and 50

Employment. The Netherlands: The Hague. 51

52

Senior, B. and H.L. Chernoff. 1971. Iodide goiter in the newborn. Pediatrics 47:510

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1

Shokeer, A., A

- K. Larsson, and B. Mannervik. 2005. Residue 234 in glutathione transferase T1

- 1 plays a 2

pivotal role in the catalytic activity and th e selectivity against alternative substrates. Biochem. J. 3

388:387

- 392. 4

5

Sloter, E.D., M.D. Nemec, R. Baumgartner, J.F. Holson, M. Gargas, and J. Kinzell. 2005. Methyl iodide

6

induced hypothyroidism in fetal rabbits. Toxicol. Sci. 84 (S

- 1) :50 (abstract). 7

8

Sloter

, E., M. Nemec

, D. Stump

, J. Holson

, D. Kirkpatrick

, M. Gargas

, J. Kinzell . 2009. Methyl iodide

9

induced fetal hypothyroidism implicated in late

- stage fetal death in rabbits

. Inhal

. Toxicol

. 21 : 462

- 10

479. 11

12

Swedish National Board of Occupational Saf ety and Health. 2000. Occupational Exposure Limit Values 13

and Measures against Air Contaminants. Swedish Work Environment Authority, Solna, Sweden. 14

15

Sweeney, L.M., J.H. Kinzell, and M.L. Gargas. 2005. Derivation of human toxicity reference values for 16

m ethyl iodide using PBPK modeling. The Toxicologist 84:49 (abstract)

. 17

18

Sweeney, L.M., C.R. Kirman, S.A

. Gannon, K.D. Thrall, M.L. Gargas, and J.H. Kinzell. 200 9

. 19

D evelopment of a physiologically based pharmacokinetic ( PBPK ) model for methyl iodide in rat s, 20

rabbits, and humans. Inhal. Toxicol. 21:552

- 582. 21

22

ten Berge. 2006. Online Excel Program: http://home.wxs.nl/~wtberge/doseresp.html

. 23

24

Thrall, K.D., A.D. Woodstock, J.J. Soelberg, J.H. Kinzell, and M.L. Gargas. 2005. Uptake of methyl 25

iodide in the nasal cavity of rats and rabbits. Toxicol. Sci. 84 ( S

- 1) :48 (abstract). 26

27

Thrall, K.D., A.D. Woodstock, J.J. Soelberg, J.H. Kinzell, and M.L. Gargas. 2009a. A real

- time 28

methodology to evaluate the n asal absorption of volatile compounds in anesthetized animals. Inhal. 29

Toxicol. 21:531

- 536. 30

31

Thrall, K.D., L.B. Sasser, J.A. Creim, M.L. Gargas, J.H. Kinzell, and R.A. Corley. 2009 b . Studies 32

supporting the development of a physiologically based pharmacok inetics (PBPK) model of methyl 33

iodide: pharmacokinetics of sodium iodide (NaI) in pregnant rabbits. Inhal. Toxicol. 21:519

- 523. 34

35

U.S. EPA (U.S. Environmental Protection Agency). 200 5

. Guidelines for Carcinogen Risk Assessment. 36

EPA/630/P

- 03/001F. Washi ngton DC: U.S. Environmental Protection Agency. 37

38

U.S. EPA (U.S. Environmental Protection Agency). 2006. Human Health Risk Assessment: 39

Iodomethane. Washington, DC: Health Effects Division, Office of Pesticide Programs. 40

41

U.S. EPA ( U.S. Environmental Prote ction Agency). 2007a. Interim Acute Exposure Guidelines for 42

Methyl Chloride. EPA, Washington, DC. 43

44

U.S. EPA ( U.S. Environmental Protection Agency). 2007b. Interim Acute Exposure Guidelines for 45

Methyl Bromide. EPA, Washington, DC. 46

47

Vagenakis, A.G. P. Downs, L.E. Braverman, A. Burger, and S.H. Ingbar. 1973. Control of thyroid 48

hormone secretion in normal subjects receiving iodides. J. Clin. Investig. 52:528

- 532. 49

50

Warholm, M., A

- K. Alexandrie, J. Hogsberg, K. Sigvardsson, and K. Rannug. 1994. Polymor phic 51

distribution of glutathione transferase activity with methyl chloride in human blood. 52

Pharmacogenetics 4:307

- 311. 53METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 38 of 49

1

WHO (World Health Organization). 2000. Concise International Chemical Assessment Document 28: 2

Methyl Chloride. Geneva, Switzerland. 3

4

Xu, D., H. Peter, E. Hallier, and H.M. Bolt. 1990. Hemoglobin adducts of monohalomethanes. Industr. 5

Health 28:121

- 123. 6

7

Zwart, A. 1988. Acute inhalation study of methyl bromide in rats. CIVO Report No. V88. 127/27 CIVO 8

Institutes, TNO, Zeist, The N etherlands, 17pp. 9METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 39 of 49



### APPENDIX A: Derivation of Methyl Iodide AEGLs 1

2

Derivation of AEGL

- 1 Values 3

4

Key Stud ies : (1) Reed et al. 1995. Olfactory toxicity of methyl iodide in the rat. Arch. 5

Toxicol. 70:51

- 56 ; (2) U.S. EPA. 2006. Human Health Risk Assessme nt: 6

Iodomethane. Washington, DC: Health Effects Division, Office of Pesticide 7

Programs. 8

9

Toxicity endpoint: Weight of Evidence: NOAEL for clinical signs and neurotoxicity in rats (27 10

ppm for 6 hours (U.S. EPA 2006). Supported by acute no

- effect study ( 100 11

ppm for 1 hour) and repeat

- exposure and subchronic studies). 12

13

Time scaling: C n x t = k where n = 2.0 based on the rat toxicity/ lethality data sets of Eastman 14

Kodak Co. (1987) , Reed et al. (1995), and U.S. EPA (2006). 15

16

Uncertainty factors: Total uncert ainty factor: 3 17

Interspecies: 1

– Chemical uptake is higher in rodents than humans based on 18

a higher blood:air partition coefficient. In addition, the respiratory rate and 19

cardiac output of rodents is higher than in humans. 20

Intraspecies: 3

– Humans do not differ greatly in their ability to metabolize 21

monohalomethanes (Nolan et al. 1985). 22

23

Modifying factor: None applied 24

25

Calculations: C 2 x t = k 26

(27 ppm/3) 2 x 360 minutes 29160 ppm 2

 minutes 27

28

10

- minute AEGL

- 1: C = ( 29160 ppm 2

 minutes/10) 1/ 2 29

C = 54 ppm 30

31

30

- minute AEGL

- 1: C = ( 29160 ppm 2

 minutes/10) 1/ 2 32

C = 31 ppm 33

34

1

- hour AEGL

- 1: C = ( 29160 ppm 2

 minutes/10) 1/ 2 35

C = 2 2 ppm 36

37

4

- hour AEGL

- 1: C = ( 29160 ppm 2

 minutes/10) 1/ 2 38

C = 1 1 ppm 39

40

8

- hour AEGL

- 1: Because the time

- scaled value of 7. 8 ppm appears low in c omparison with 41

subchronic and chronic NOAELs for effects on the olfactory epithelium of 20 42

ppm (U.S. EPA 2006), the 8

- hour value was set equal to the 4

- hour value. 43

C = 1 1 ppm 44

45METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 40 of 49

1

Derivation of AEGL

- 2 Values 2

3

Key Study: Reed, C.J., B.A. Gaskell, K.K. Banger , and E.A. Lock. 1995. Olfactory 4

toxicity of methyl iodide in the rat. Arch. Toxicol. 70:51

- 56. 5

6

Toxicity endpoint: Reversible lesions of the olfactory epithelium following a 6

- hour exposure of 7

rats to 100 ppm 8

9

Time scaling C n x t = k where n = 2 based on the rat lethality data sets of Eastman Kodak 10

Co. (1987) and U.S. EPA (2006). 11

12

Uncertainty factors: Total uncertainty factor: 3 13

Interspecies: 1

– Chemical uptake is higher in rodents than humans based on 14

a higher blood:air partition coefficient. In addition, rodents have a higher 15

respiratory rate and cardiac output than humans. 16

Intraspecies: 3

– Humans do not differ greatly in their ability to metabolize 17

monohalomethanes (Nolan et al. 1985). 18

19

Calculations: C 2 x t = k 20

(100 ppm/3) 2 x 360 minutes = 400,000 ppm 2

- minutes 21

22

10

- minute AEGL

- 2: C = 400,000 ppm 2

- minutes/10 ) 1 / 2 23

C = 2 0 0 ppm 24

25

3 0

- minute AEGL

- 2: C = ( 400,000 ppm 2

- minutes /30) 1/ 2 26

C = 1 2 0 ppm 27

28

1

- hour AEGL

- 2: C = ( 400,000 ppm 2

- minutes/60) 1/ 2 29

C = 82 ppm 30

31

4

- hour AEGL

- 2: C = ( 400,000 ppm 2

- minute s/24 0) 1/ 2 32

C = 41 ppm 33

34

8

- hour AEGL

- 2: C = ( 400,000 ppm 2

- minutes/480) 1/ 2 35

C

= 2 9 ppm 36

37

38METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 41 of 49

1

Derivation of AEGL

- 3 Values 2

3

Key Stud ies : (1) Eastman Kodak Co . 1987. Initial Submission: Acute Inhalation Toxicity 4

of Methyl Iodide in the Rat with Cover Letter Dated 0 8/26/92. Na tional 5

Technical Information Service, Springfield, VA ; (2) Reed, C.J., B.A. 6

Gaskell, K.K. Banger, and E.A. Lock. 1995. Olfactory toxicity of methyl 7

iodide in the rat. Arch. Toxicol. 70:51

- 56 ; ( 3 ) U.S. EPA (U.S. 8

Environmental Protection Age ncy). 200 6

. Human Health Risk Assessment: 9

Iodomethane. Washington, DC: Health Effects Division, Office of Pesticide 10

Programs. 11

12

To xicity endpoint : Threshold for lethality in rats at the lower limit of the 95% confidence limit, 13

calculated using probit

- an alysis dose

- response program of ten Berge (2006). 14

15

Time scaling C n x t = k where n = 2.0 based on the rat toxicity/ lethality data sets of Eastman 16

Kodak Co. (1987) , Reed et al. (1995), and U.S. EPA (2006). 17

18

Uncertainty factors: Total uncertainty factor: 3 19

Interspecies: 1

– Chemical uptake is higher in r ats than humans based on a 20

higher blood:air partition coefficient (Sweeney et al. 2009); in addition, the 21

respiratory rate and cardiac o utput is higher in rats than humans resulting in 22

faster uptake

. 23

Intra species: 3

– Humans do not differ greatly in their ability to metabolize 24

monohalomethanes (Nolan et al. 1985). 25

26

Modifying factor: None applied 27

28

Data for c alculations: 29

Exposure Duration

(minutes) Concentration

(ppm) Mortality

(percent) Reference

60 119 0

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

Program output (with intraspecies uncertainty fac tor of 3 applied) : 31

Exposure Duration AEGL

- 3 Value

10 minutes 670 ppm

30 minutes 400 ppm

60 minutes 2 9 0 ppm

4 hours 1 5 0 ppm

8 hours 9 8 ppm

n = 2.0 32METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 42 of 49



### Calculations: Methyl Iodide

– Log Probit Model (te n Berge 2006) 1

2

Filename: methyl iodide for Log Prob it Model 3

Date: 20 June 2008 Time: 11:51:12 4

Data of Eastman Kodak Co. (1987), Reed et al. (1995), and U.S. EPA (2006) 5

Lower limit of the 5% response 6

7

Seq.Nr conc ppm min exposed responded 8

1 1190 60 10 2 9

2 1554 60 10 6 10

3 1973 60 10 9 11

4 581 240 10 0 12

5 710 240 10 8 13

6 797 240 10 8 14

7 1198 240 10 10 15

8 27 360 24 0 16

9 93 360 24 0 17

10 401 360 24 1 18

11 100 30 3 0 19

12 100 60 3 0 20

13 100 120 3 0 21

14 100 180 3 0 22

15 100 240 3 0 23

16 100 360 3 0 24

25

Observations 1 through 16 considered! 26

27

Seq.nr conc ppm min exposed responded 28

29

1 1190 60 10 2 30

2 1554 60 10 6 31

3 1973 60 10 9 32

4 581 240 10 0 33

5 710 240 10 8 34

6 797 240 10 8 35

7 1198 240 10 10 36

8 27 360 24 0 37

9 93 360 24 0 38

10 401 360 24 1 39

11 100 30 3 0 40

12 100 60 3 0 41

13 100 120 3 0 42

14 100 180 3 0 43

15 100 240 3 0 44

16 100 360 3 0 45

46

Used Probit Equat ion Y = B0 + B1*X1 + B2*X2 47

X1 = conc ppm, ln

- transformed 48

X2 = min, ln

- transformed 49

50

ChiSquare = 5.32 51

Degrees of freedom = 13 52METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 43 of 49

Probability Model = 9.68E

- 01 1

2

Ln(Likelihood) =

- 10.45 3

4

B 0 =

- 4.8449E+01 Student t =

- 4.8126 5

B 1 = 5.5950E+00 Student t = 5.5485 6

B 2 = 3.0903E+00 Student t = 4.5552 7

8

variance B 0 0 = 1.0135E+02 9

covariance B 0 1 =

- 1.0077E+01 10

covariance B 0 2 =

- 6.6311E+00 11

variance B 1 1 = 1.0168E+00 12

covariance B 1 2 = 6.3995E

- 0 1 13

variance B 2 2 = 4.6026E

- 01 14

15

Estimation of conc ppm at response of 5 % 16

min = 10 17

Point estimate conc ppm = 2.943E+03 for response of 5 % 18

Lower limit (95% CL) conc ppm = 2.002E+03 for response of 5 % 19

Upper limit (95% CL) con c ppm = 3.778E+03 for response of 5 % 20

21

Estimation of conc ppm at response of 5 % 22

min = 30 23

Point estimate conc ppm = 1.604E+03 for response of 5 % 24

Lower limit (95% CL) conc ppm = 1.213E+03 for response of 5 % 25

Upper limit (95% C L) conc ppm = 1.899E+03 for response of 5 % 26

27

Estimation of conc ppm at response of 5 % 28

min = 60 29

Point estimate conc ppm = 1.094E+03 for response of 5 % 30

Lower limit (95% CL) conc ppm = 8.777E+02 for response of 5 % 31

Upper limit (95% CL) conc ppm = 1.239E+03 for response of 5 % 32

33

Estimation of conc ppm at response of 5 % 34

min = 240 35

Point estimate conc ppm = 5.086E+02 for response of 5 % 36

Lower limit (95% CL) conc ppm = 4.365E+02 for response of 5 % 37

Upper limit (95% CL) conc ppm = 5.552E+02 for response of 5 % 38

39

Estimation of conc ppm at response of 5 % 40

min = 480 41

Point estimate conc ppm = 3.468E+02 for response of 5 % 42

Lower limit (95% CL) conc ppm = 2.938E+02 for response of 5 % 43

Upper limit (95% CL) conc ppm = 3.895E+02 for response of 5 % 44

45

AEGL concentrations at 5% lethality response (The point estimate is similar to the BMC 05 . The 46

BMCL 05 would be similar to the lower limit) 47

48

49METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 44 of 49

1

1% response 2

3

Estimation of conc ppm at respons e of 1 % 4

min = 10 5

Point estimate conc ppm = 2.605E+03 for response of 1 % 6

Lower limit (95% CL) conc ppm = 1.688E+03 for response of 1 % 7

Upper limit (95% CL) conc ppm = 3.393E+03 for response of 1 % 8

9

Estimation of conc ppm at r esponse of 1 % 10

min = 30 11

Point estimate conc ppm = 1.420E+03 for response of 1 % 12

Lower limit (95% CL) conc ppm = 1.017E+03 for response of 1 % 13

Upper limit (95% CL) conc ppm = 1.714E+03 for response of 1 % 14

15

Estimation of conc pp m at response of 1 % 16

min = 60 17

Point estimate conc ppm = 9.684E+02 for response of 1 % 18

Lower limit (95% CL) conc ppm = 7.331E+02 for response of 1 % 19

Upper limit (95% CL) conc ppm = 1.123E+03 for response of 1 % 20

21

Estimation of c onc ppm at response of 1 % 22

min = 240 23

Point estimate conc ppm = 4.503E+02 for response of 1 % 24

Lower limit (95% CL) conc ppm = 3.646E+02 for response of 1 % 25

Upper limit (95% CL) conc ppm = 5.032E+02 for response of 1 % 26

27

Estimati on of conc ppm at response of 1 % 28

min = 480 29

Point estimate conc ppm = 3.071E+02 for response of 1 % 30

Lower limit (95% CL) conc ppm = 2.480E+02 for response of 1 % 31

Upper limit (95% CL) conc ppm = 3.492E+02 for response of 1 % 32

33

34

35

36METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 45 of 49



### APPENDIX B: Category Graph of AEGL Values and Toxicity Data 1

2

1 10 100 1000 10000ppm

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

Data: 5

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 2 0 0 10 AEGL

NAC/AEGL

- 2 1 2 0 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 2 9 0 60 AEGL

NAC/AEGL

- 3 1 5 0 240 AEGL

NAC/AEGL

- 3 98 480 AEGLMETHYL IODIDE NAC Proposed 1 : November 200 9/ Page 46 of 49

Eastman Kodak Co.

1987 rat 1190 60 SL 20% mortali ty

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 2 7 360 0 NOAEL for neurotoxicity

rat 93 360 2 Clonic convulsions

rat 401 360 SL Neurotoxic ity , 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

2METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 47 of 49



### APPENDIX C: Derivation Summary for Methyl Iodide AEGLs 1

2

ACUTE EXPOSURE GUIDELINE LEVELS FOR METHYL IODIDE 3

(CAS Reg. No. 79

- 38

- 9) 4

5

AEGL

- 1 VALUES

10

- min 30

- min 1

- h 4

- h 8

- hour

54 p pm 3 1 p pm 2 2 ppm 1 1 ppm 1 1 ppm

Key Reference s : (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

io dide 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

I ntraspecies: 3, considered sufficient to account for metabolism

- mediated variability

Modifying Factor: None applied

Animal to Human Dosimetric Adjustment: Not applicable

Time Scaling: C n x t = k, where n = 2 based on toxicity studies with the rat (Eas tman 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 NOAEL s 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 o f AEGLs.

6

7METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 48 of 49

AEGL

- 2 VALUES

10

- minute 30

- minute 1

- hour 4

- h 8

- h

2 0 0 ppm 1 2 0 ppm 82 ppm 4 1 ppm 2 9 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 /Num ber: 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: mi nimal lesions, olfactory epithelium

3 hour: slight lesions, olfactory epithelium

4 hours: moderate lesion s , olfactory epithelium

6 hours: marked lesion s , olfactory epithelium; regeneration after 2 weeks

Endpoint/Concentration/Rationale: 6 hour expo sure 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, considere d sufficient to account for metabolism

- mediated variability

Modifying Factor: None applied

Animal to Human Dosimetric Adjustment: Not applicable

Time Scaling: C n 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 epitheliu m was a target organ for methyl iodide. The data base of acute, repeat

exposure , genotoxicity, developmental, subchronic, and chronic animal studies was sufficient for derivation of

AEGL values.

1

2

3METHYL IODIDE NAC Proposed 1 : November 200 9/ Page 49 of 49

AEGL

- 3 VALUES

10

- min 30

- min 1

- h 4

- h 8

- h

670 ppm 400 p pm 2 9 0 ppm 1 5 0 ppm 98 ppm

Key Reference s : (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. Washingto n, 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, 15 54, 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

. Modifyin g Factor: None applied

Animal to Human Dosimetric Adjustment: Not applicable

Time Scaling: Calculated using the ten Berge program (n in C n 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