NAC Proposed 1: June 2009 1
2
3
4 

## ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 5



## FOR 6



## METHOMYL 7


## (CAS Reg. No. 16752-77-5) 8

9

10 11

12
13 

## PROPOSED 14

15
16
17METHOMYL NAC Proposed 1: June 2009/ Page 2 of 35

1
PREFACE 2
3 Under the authority of the Federal Adviso ry Committee Act (FACA) P. L. 92-463 of 4 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous 5 Substances (NAC/AEGL Committee) has been es tablished to identify, review and interpret 6 relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic 7
chemicals. 8
9 AEGLs represent threshold exposure limits for the general public and are applicable to 10 emergency exposure periods ranging from 10 minut es to 8 hours. Three levels – AEGL-1, 11 AEGL-2 and AEGL-3 – are developed for each of five exposure periods (10 and 30 minutes, 1 12 hour, 4 hours, and 8 hours) and are distinguished by va rying degrees of severity of toxic effects. 13
The three AEGLs are defined as follows: 14
15 AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per 16 cubic meter [ppm or mg/m 3 ]) of a substance above which it is predicted that the general 17 population, including susceptible individuals, could experience notable discomfort, irritation, or 18 certain asymptomatic, non-sensory effects. Ho wever, the effects are not disabling and are 19 transient and reversible upon cessation of exposure. 20

21 AEGL-2 is the airborne concentration (expressed as ppm or mg/m 3 ) of a substance above 22 which it is predicted that the general population, including susceptible individuals, could 23 experience irreversible or other serious, long-lasting adverse health effects or an impaired ability 24
to escape. 25
26 AEGL-3 is the airborne concentration (expressed as ppm or mg/m 3 ) of a substance above 27 which it is predicted that the general population, including susceptible individuals, could 28 experience life-threatening health effects or death. 29
30 Airborne concentrations below the AEGL-1 represent exposure levels that could produce 31 mild and progressively increasing but transi ent and nondisabling odor, taste, and sensory 32 irritation or certain asymptomatic, non-sensory eff ects. With increasing airborne concentrations 33 above each AEGL, there is a progressive increase in the likelihood of occurrence and the 34 severity of effects described for each corresponding AEGL. Although the AEGL values 35 represent threshold levels for the general public, including susceptible subpopulations, such as 36 infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized 37 that individuals, subject to unique or idiosyncratic responses, could experience the effects 38 described at concentrations below the corresponding AEGL. 39
40METHOMYL NAC Proposed 1: June 2009/ Page 3 of 35

TABLE OF CONTENTS 1

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

SUMMARY........................................................................................................................ ..........................6 3

1. INTRODUCTION................................................................................................................ ................7 4

2. HUMAN TOXI CITY DATA......................................................................................................... ......8 5

3. ANIMAL TOXI CITY DATA........................................................................................................ ......9 6

3.1. Acute Toxicity ............................................................................................................ .................9 7

3.2. Repeat-Exposure Studies................................................................................................... ........11 8

3.3. Neurotoxicity............................................................................................................. ................12 9

3.4. Developmental/Reproductive Toxicity......................................................................................1 2 10

3.5. Genotoxicity .............................................................................................................. ................13 11

3.6. Chronic Toxicity/Carcinogenicity .......................................................................................... ...13 12

3.7. Summary................................................................................................................... .................13 13

4. SPECIAL CONS IDERATIONS ...................................................................................................... ..14 14

4.1. Metabolism and Disposition................................................................................................ ......14 15

4.2. Mechanism of Toxicity..................................................................................................... .........14 16

4.3. Structure-Activity Relationships .......................................................................................... .....15 17

4.4. Other Relevant Information................................................................................................ .......16 18 4.4.1. Species Variability ..................................................................................................... ...........16 19 4.4.2. Susceptible Populations ................................................................................................. .......16 20 4.4.3. Concentration-Exposur e Duration Relationship ...................................................................16 21 4.4.4. Concurrent Exposure Issues.............................................................................................. ....17 22

5. DATA ANALYSIS FOR AEGL-1 .................................................................................................... 17 23

5.1. Summary of Human Data Relevant to AEGL-1........................................................................17 24

5.2. Summary of Animal Data Relevant to AEGL-1........................................................................17 25

5.3. Derivation of AEGL-1...................................................................................................... .........17 26

6. DATA ANALYSIS FOR AEGL-2 .................................................................................................... 17 27

6.1. Summary of Human Data Relevant to AEGL-2........................................................................17 28

6.2. Summary of Animal Data Relevant to AEGL-2........................................................................18 29

6.3. Derivation of AEGL-2...................................................................................................... .........18 30

7. DATA ANALYSIS FOR AEGL-3 .................................................................................................... 18 31METHOMYL NAC Proposed 1: June 2009/ Page 4 of 35

7.1. Summary of Human Data Relevant to AEGL-3........................................................................18 1

7.2. Summary of Animal Data Relevant to AEGL-3........................................................................18 2

7.3. Derivation of AEGL-3...................................................................................................... .........19 3

8. SUMMARY OF AEGLs............................................................................................................ ........19 4

8.1. AEGL Values and Toxicity Endpoints......................................................................................19 5

8.2. Comparison with Other Standards and Guidelines....................................................................20 6

8.3. Data Adequacy and Research Needs .........................................................................................2 1 7

9. REFERENCES.................................................................................................................. .................21 8

APPENDIX A: Derivation of Methomyl AEGLs...................................................................................... 25 9

APPENDIX B: Category Graph of AE GL Values and Toxicity Data.......................................................27 10

APPENDIX C: Benchmark Con centration Calculations ...........................................................................29 11

APPENDIX D: Derivation Summary for Methomyl AEGLs....................................................................33 12METHOMYL NAC Proposed 1: June 2009/ Page 5 of 35

LIST OF TABLES 1

S 1. Summary of AEGL Values fo r Metho myl...................................................................................... ...................7 2

TABLE 1. Chemical and Physical Pr operties...................................................................................... ......................8 3 TABLE 2. Acute Toxicity of Methomy l to Rats Expose d for 4 Hours ............................................................... ..11 4

TABLE 3. Adult Rat and Human BMD 10 and BMDL 10 Values for Cholinesterase Activity Inhibition with N

5 Methyl Carbamate Pestic ides (Oral Dosing)...................................................................................... ............15 6

TABLE 4. AEGL-1 Va lues for Methomyl ........................................................................................... ...................17 7

TABLE 5. AEGL-2 Va lues for Methomyl ........................................................................................... ...................18 8

TABLE 6. AEGL-3 Va lues for Methomyl ........................................................................................... ...................19 9 TABLE 7. Summary of AEGL Values fo r Metho myl.................................................................................. ..........20 10

TABLE 8. Standards and Gu idelines fo r Metho myl ................................................................................ .............20 11
12
13 14 15METHOMYL NAC Proposed 1: June 2009/ Page 6 of 35

SUMMARY 1
2 Methomyl (CAS No. 16752-77-5) is a crystalline solid N -methyl carbamate insecticide 3 with a slightly sulfurous odor. Methomyl is used as an insecticide on field crops such as 4 vegetables, soybeans, and cotton and on some fruits and ornamentals. Technical methomyl is 5 commercially available as a solid, dust or granular formulation, and as a water soluble 6 concentrate. Methomyl is manufactured commercially by the reaction of methyl thiomethyl 7 oxime with methyl isocyanate. An estimated 2.5 to 3.5 million pounds of active ingredient are 8 applied annually in the United States. 9
10 Methomyl and other carbamate pesticides are neurotoxic in that they are inhibitors of the 11 enzyme acetylcholinesterase. Inhibition of acetylcholinesterase, responsible for termination of 12 the biological activity of the neurotransmitter acetylcholine at various nerve endings, results in 13 sustained stimulation of electrical activity. Depending on concentrations administered, 14 symptoms following acute exposure of rats to methomyl may include salivation, lacrimation, 15 gasping and tremors or convulsions. Inhibition of acetylcholinesterase activity is reversible. In 16 humans, inhibition of erythrocyte acetylcholinesterase activity is used as a biomarker of methyl 17 carbamate exposure. Based on oral studies, th e half-life for methomyl-induced inhibition of 18 erythrocyte acetylcholinesterase activity in human s is 1.6 hours. No inhalation studies involving 19 human subjects were located. Given that methyl carbamate pesticides do not have a port of entry 20 effect, are expected to be rapidly absorbed, and do not require activation, relative 21 acetylcholinesterase activity inhibition levels measured in oral studies with humans and adult 22 and juvenile rodents are applicable for determination of interspecies and intraspecies uncertainty 23
factors. Four inhalation rat studies with met homyl administered in different physical forms 24 provided consistent, concentration-related effect s. All exposure durations were for 4 hours. 25
26 No studies that adequately reported details of methomyl exposure and effects consistent 27 with the definition of AEGL-1 were located. Therefore, AEGL-1 values are not recommended. 28
29 The lethality study of DuPont (1991) in which methomyl was administered to rats via the 30 inhalation route shows that methomyl has a steep concentration-response curve. In the absence 31 of other relevant data, AEGL-2 values for chemicals with a steep concentration-response curve 32 may be derived by dividing the AEGL-3 values by 3 (NRC 2001). For consistency with the 33 aerosol study used to derive AEGL-3 values, the AEGL-2 values were derived by dividing the 34 AEGL-3 values by 3. The AEGL-2 values are supported by the vapor study of DuPont (1966a) 35 in which all six rats exposed to 44 mg/m 3 of methomyl vapor for 4 hours displayed clinical signs 36 of slight salivation and lacrimation, slight to moderate hyperpnea, and mild dyspnea. 37 Application of the same uncertainty factors and time scaling relationship to the 4-hour 44 mg/m 3 38 value results in AEGL-2 values similar to those derived by dividing the AEGL-3 by 3 (10- 39 minute through 8-hour values of 5.9, 5.9, 4.7, 2.9, and 1.5 mg/m 3 ). 40

41 The exposure of rats for 4 hours to a range of aqueous aerosol concentrations that 42 resulted in lethality at the higher concentrations (DuPont 1991; Panepinto 1991) was chosen as 43 the key study for derivation of AEGL-3 values. The study used an adequate number of rats of 44
both sexes and five test concentrations. Mortality in rats inhaling 137, 181, 182, 232, or 326 45 mg/m 3 of an aqueous aerosol of methomyl for 4 hours showed mortality of 0/10, 0/10, 1/10, 46 6/10, and 7/10, respectively. The benchmark concentration program was used to estimate the 47METHOMYL NAC Proposed 1: June 2009/ Page 7 of 35

threshold for lethality. The benchmark concentration program was run with and without the 1 highest value of 326 mg/m 3 . Omitting the highest value resulted in a better fit of the data to the 2
curve. The calculated 4-hour BMCL 05 was 157.3 mg/m 3 , and the BMC 01 was 166.51 mg/m 3

. 3
The BMCL 05 was considered the threshold for lethality. The 4-hour 157.3 mg/m 3 value was 4 divided by inter- and intraspecies uncertainty factors of 5 and 3.05, respectively, for a total of 15. 5 The methomyl-specific uncertainty factors we re derived by U.S. EPA (2007). The methomyl6 specific interspecies inhalation uncertainty factor of 5 was based on differences in modeled 7 values for erythrocyte acetylcholinesterase activity inhibition between rats and humans. The 8 intraspecies uncertainty factor was based on comparative brain acetylcholinesterase activity 9 inhibition in post-natal day 11 juvenile rats and adult rats; the U.S. EPA calculated an 10 uncertainty factor of 3.05 to protect sensitive young. The resulting 4-hour 10.48 mg/m 3 value 11 was time-scaled (C n x t = k) using the default values of 3 and 1 for longer and shorter exposure 12 durations, respectively (NRC 2001). 13

14
The calculated values are listed in the table below. 15
16

S 1. Summary of AEGL Values for Methomyl

Classification 10-min 30-min 1-h 4-h 8-h Endpoint (Reference)

AEGL

B 1 (Nondisabling) Not
recommended Not
recommended Not
recommended Not
recommended Not
recommended Inadequate data

AEGL

B 2 (Disabling) 7.0 mg/m 3 7.0 mg/m 3 5.7 mg/m 3 3.3 mg/m 3 1.7 mg/m 3 AEGL-3 values divided by 3 (based on steep concentration-response curve)

AEGL

B 3 (Lethal) 21 mg/m 3 21 mg/m 3 17 mg/m 3 10 mg/m 3 5.2 mg/m 3 Calculated BMCL 05 for lethality – rat (DuPont 1991)
Not recommended: absence of AEGL-1 values does not impl y that exposure below AEGL-2 levels is without effect.
All values were derived from 4-hour studies. 17
18
1. INTRODUCTION 19
20 Technical methomyl (CAS No. 16752-77-5) is a crystalline solid N -methyl carbamate 21 insecticide with a slight sulfurous odor. Methomyl is a broad-spectrum insecticide used on 22 vegetables, soybeans, cotton and other field crops and on some fruits and ornamentals. The 23 technical material is formulated as a bait/solid, dust, or granular formulation, and as a water 24 soluble concentrate liquid. Formulated products such as LannateTM contain 90% methomyl (U.S. 25 EPA 1998; O’Neil 2001 et al.; DuPont 2007). Methom yl is available as wettable powder (25%), 26 soluble concentrate (200 g/L), and water sol uble powder (deVreede et al. 1988). Dilution 27 instructions are: soluble concentrate, 100-150 mL/100 L water and wettable powder, 80-120 28 g/100 L water. Products are intended for occupational use only and not for homeowner use. 29 Methomyl is also a degradate of the pestic ide thiodicarb (U.S. EPA 1998). Chemical and 30 physical properties are listed in Table 1. 31
32 Methomyl is manufactured commercially by the reaction of methyl thiomethyl oxime 33 with methyl isocyanate (HSDB 2009). An estimated 2.5 to 3.5 million pounds of active 34 ingredient of methomyl are applied annually in the United States (U.S. EPA 1998). 35METHOMYL NAC Proposed 1: June 2009/ Page 8 of 35

1

TABLE 1. Chemical and Physical Properties

Parameter Value Reference
Synonyms N -[[(Methylamino)carbonyl]oxy] ethanimidothioic acid methyl ester; N

- [(methylcarbamoly)oxy]thioacetimidic acid methyl ester; S-methyl N

- [(methylcarbamoyl)oxy]thioacetimidate; methyl O-(methylcarbamyl)thiol acetohydroxamate; Methyl carbamic acid,
ester with oxime function of thiolacetohydroxamic acid, S-methyl ester; DuPont 1179; Lannate; Nudrin; DPX-X1179; INX-1179 O’Neil et al. 2001;
DuPont 2007

Chemical formula C 5 H 10 N 2 O 2 S O’Neil et al. 2001 Molecular weight 162.21 O’Neil et al. 2001 CAS Reg. No. 16752-77-5 O’Neil et al. 2001 Physical state crystalline solid O’Neil et al. 2001 Solubility in water 58 g/L O’Neil et al. 2001 Vapor pressure 5 x 10 -5 torr at 25oC ACGIH 1992 Vapor density (air =1) No data Liquid density (water =1) 1.2946 at 25oC DuPont 2007 Melting point 78-79oC O’Neil et al. 2001 Boiling point 136 oC (autodecomposition) DuPont 2007 Flammability limits in air 0.096 g/L (lower explosive limit) DuPont 2007 Conversion factors 1 ppm = 6.63 mg/m 3 1 mg/m 3 = 0.15 ppm Calculated

2
3
2. HUMAN TOXICITY DATA 4

5 No inhalation studies other than accidental exposures were located. Most of these 6 accidental exposures lacked information on concentrations. A pilot who was spraying methomyl 7 and Bravo (chlorothalonil) accidently cras hed and died (Driskell et al. 1991). Gas 8 chromatography/flame ionization analysis of the pilot’s blood revealed a methomyl 9 concentration of 570 ng/mL of blood. Blood was not analyzed for Bravo. A farmer who died 10 following several days of application of me thomyl in his greenhouse had a blood methomyl 11 concentration of 1.6 mg/L and 89% blood cholinesterase activity inhibition upon admittance to 12 the hospital in an unconscious state (Tsatsakis et al. 2001). Death was attributed to inhalation 13 and dermal exposure as the farmer’s hair and clothes were wet with pesticide and no methomyl 14 was found in his stomach. An oral lethal dose for humans has been estimated at 12 to 15 mg/kg 15 (ACGIH 1992). 16
17 In a double-blind human oral dosing study, 19 healthy male volunteers, ages 18-40 years 18 ingested a single oral dose of methomyl formula tion (89% a.i.) (McFarlane et al. 1998, reviewed 19 in U.S. EPA 2005). Five subjects comprised each treated group; there were four control 20 subjects. Doses of 0, 0.1, 0.2, or 0.3 mg/kg body we ight were ingested in capsule form along 21 with a light breakfast. Clinical symptoms were recorded pre-dose and at set times post-dose. 22 Plasma and erythrocyte cholinesterase activity were assayed pre-dose and at set times post-dose 23 as were clinical chemistry and hematology parameters. One subject in the 0.3 mg/kg group 24METHOMYL NAC Proposed 1: June 2009/ Page 9 of 35

reported a headache at one hour. The only dose-related clinical sign was an increase in saliva in 1 the 0.3 mg/kg group at 1-hour post dose. Dose-re lated inhibition of plasma and erythrocyte 2 cholinesterase activity peaked at 45 minutes post dose. At that time, plasma cholinesterase 3 activity in the 0.1, 0.2, and 0.3 mg/kg dose groups were -5.6, -11.5, and -21% of baseline. 4 Respective decreases in erythrocyte cholinesterase activity were -2.5, -20, and -35%. However, 5 erythrocyte acetylcholinesterase activity in the 0.1 and 0.2 mg/kg groups was inhibited by 19% 6 (75 minutes post dose) and 28% (90 minutes post dose), respectively. The Human Studies 7 Review Board (HSRB 2006) reviewed the study and found it met ethical considerations. 8
9
3. ANIMAL TOXICITY DATA 10
11 Using standard protocols, methomyl has been tested for ocular and dermal irritation in 12 the rabbit and dermal sensitization with the guinea pig (Kaplan and Sherman 1977; U.S. EPA 13 1998). In studies summarized by U.S. EPA (1998), methomyl induced transient corneal opacity 14 of the rabbit eye following instillation of 10 mg, but failed to induce skin irritation or skin 15 sensitization. A female rabbit treated with 15 mg technical methomyl in the eye died within 20 16 minutes with typical cholinergic symptoms indicative of neurotoxicity. The oral LD 50 in male 17 and female rats was 20 mg/kg, and the dermal LD 50 in rabbits as an aqueous suspension was 18 >5000 mg/kg (Kaplan and Sherman 1977). 19
20 3.1. Acute Toxicity 21
22 All inhalation studies were conducted with rats (Table 2). Studies were conducted with 23 methomyl vapor (one study), dust/powder (one study), or mist/aerosol (three studies). Methomyl 24 has a low vapor pressure and vapor atmospheres high enough to cause clinical signs are difficult 25 to sustain. In the vapor study, two groups of six male ChR-CD rats inhaled methomyl vapor at 26 nominal concentrations of 36 or 44 mg/m 3 for 4 hours (DuPont 1966a). The vapor was 27 generated by passing dry air through a tube of the test material. Exposures were conducted in a 28 whole-body 16-L chamber. No deaths occurred. Clinical signs during exposure included face29 pawing, slight salivation and lacrimation, hyperemia, hyperpnea, and mild dyspnea in all rats in 30 the 44 mg/m 3 group and in one of six rats in the 36 mg/m 3 group. Mild hyperpnea and 31 exophthalmos lasted up to 30 minutes post-exposure. No gross effects attributed to exposure 32 were seen at necropsy. Microscopically, lung and tracheal tissue were similar to those of control 33 rats in other studies conducted by the same laboratory. The atmospheres were characterized as 34 one-tenth of the approximate lethal concentration and almost six times the saturated vapor 35 pressure of 7 x 10 -4 mm Hg at 35oC cited in this study. 36
37 Fifteen male Wistar rats inhaled 9.9 mg/m 3 methomyl dust/powder for 4 hours in a 0.43 38

m 3 exposure chamber (Ta’naka et al. 1987). The powder concentration was monitored with a 39 light scattering system. The mass median aerodynamic diameter of the particles was 4.4±2.9 40 μm. Rats were sacrificed at 0, 1, 2, 4, or 20 hours post-exposure, and erythrocyte and plasma 41 cholinesterase activities were measured by the Ellman method at each time point. Plasma 42 acetylcholinesterase activity was inhibited at 0, 1, 2, and 4 hours by approximately 50% (values 43 read from graph), but had recovered by 20 hours post-exposure. Erythrocyte 44 acetylcholinesterase activity was either not inhibited or only slightly inhibited depending on 45 erythrocyte preparation procedures. Erythrocytes were washed three times with isotonic saline 46 prior to hemolysis. Repeated washing may have removed some of the enzyme from the cell 47METHOMYL NAC Proposed 1: June 2009/ Page 10 of 35

membrane. Histologic findings in major organs we re unremarkable. Clinical signs, if present, 1
were not described. 2
3 Groups of five male and five female CrL: CD rats inhaled methomyl mist, nose-only, at 4 concentrations of 137, 181, 182, 232, or 326 mg/m 3 for 4 hours (DuPont 1991; Panepinto 1991). 5 The study adhered to U.S. EPA’s Good Laboratory Pr actice (GLP) standards. Purity of the test 6 material was 97.7%. Atmospheres were generated by suspending the milled solid material at a 7 concentration of 3% in water and maintaining suspensions with a nebulizer. Aerosol 8 atmospheres were measured with a gravimetric method. Mass median aerodynamic diameter of 9 the particles ranged from 1.3 to 3.8 μ. Surviving rats were observed for 14 days post-exposure. 10 There was a moderate weight loss in most rats during the first two days post-exposure. No rats 11 died at the two lower concentrations. In these two groups, clinical signs observed during the 12 first two days post-exposure included diarrhea a nd stained, ruffled, or wet fur, and discharge 13 from the eyes or nose, the latter in a few males on days 1, 2, or 3. Mortalities were 1/10, 6/10, 14 and 7/10 at the three highest concentrations, with mortality comparable between the sexes. 15 Clinical signs among rats that died included those seen at the lower concentrations and in 16 addition, abnormal gait, tremors, hyperactivity, hyperreactivity, muscle fasciculations, and 17 hunched posture. The calculated 4-hour LC 50 was 258 mg/m 3

. 18
19 Groups of six male ChR-CD rats inhale d an aerosol of methomyl, whole-body, for 4 20 hours (DuPont 1966b). Concentrations were 250, 300, 350, and 560 mg/m 3 . The atmospheres 21 were generated by melting 20 grams of the test material followed by aerosolization of the heated 22 compound with a nebulizer in a heated air stream. A second unheated air stream carried the 23 aerosol into a 16-L exposure chamber containing the rats. Aerosol particle size ranged from 1.1- 24 6.8 μ. Gross and histologic examinations were performed on selected rats. No rats died 25 following the 4-hour exposure to 250 mg/m 3 . The approximate LC 50 was 300 mg/m 3 . Clinical 26 signs observed in dying rats were ptosis, face-pawing, lacrimation and salivation, moderate to 27 heavy dyspnea, gasping, hyperemia with slight cyanosis, red discharge from the nostrils, and 28 tremor with mild convulsions followed by terminal convulsions. Similar, but milder signs were 29 seen at the non-lethal concentrations. Gross effects at necropsy included slight pulmonary 30 hyperinflation with irregular congestion. 31
32 Groups of six male rats (strain not identified) inhaled an aqueous spray mist of 33 methomyl, whole-body in a 16 m 3 chamber for 4 hours (DuPont 1967; Hornberger 1967; 34 summarized in Kaplan and Sherman 1977). The respirable mist of average mass median 35 diameter of 3.2-6.3 μ in the different trials was generated with a nebulizer. Atmospheres were 36 measured gravimetrically. Concentrations were 97, 130, 333, 420, 540, 600, and 950 mg/m 3

. 37 Respective mortality was 0/6, 0/6, 1/6, 2/6, 5/6. 5/ 6, and 6/6. Clinical signs during the first 38 minutes of exposure included rapid tremors, i rregular breathing, increased grooming, salivation, 39 and lacrimation. Irregular breathing was observed throughout the exposure. Deaths occurred 40 only during the first 150 minutes of the 4-hour exposure. Surviving rats were maintained for two 41 weeks during which time they displayed normal growth. A second study in the same report 42 indicated that all six rats exposed head-only to 450 mg/m 3 generated as non-respirable droplets 43 >100 μ in size died within 18 minutes. All exposed areas were wet. 44
45
46
47METHOMYL NAC Proposed 1: June 2009/ Page 11 of 35

TABLE 2. Acute Toxicity of Methomyl in Rats Exposed for 4 Hours

Concentration (mg/m 3 ) Effect or Mortality LC 50 (mg/m 3 ) Reference
Vapor

36

44 No mortality, face-pawing, slight salivation and lacrimation hyperemia, hyperpnea, mild dyspnea (1 of 6 animals) No mortality; above clinical signs in 6 of 6

rats ─ DuPont 1966a

Powder 9.9 Transient plasma acetylcholinesterase activity inhibition (50%); little or no effect on erythrocyte acetylcholinesterase activity a ─ Ta’naka et al. 1987

Mist/Liquid Aerosol

137
181
182
232

326 No mortality; diarrhea, ruffled fur No mortality; diarrhea, ruffled fur Mortality: 1 of 10 rats; stained fur Mortality: 6 of 10 rats; clinical signs including tremors in one female (day 1) Mortality: 7 of 10 rats; tremors, clinical signs including tremors in one male and one female (day 1) 258 DuPont 1991; Panepinto 1991

250
300
350
560 No mortality Mortality: 3 of 6 rats Mortality: 6 of 6 rats Mortality: 6 of 6 rats 300 DuPont 1966b

97
130
333
420
540
600
950 No mortality No mortality Mortality of 1 of 6 rats Mortality of 2 of 6 rats Mortality of 5 of 6 rats Mortality of 5 of 6 rats Mortality of 6 of 6 rats 450 DuPont 1967; Hornberger 1967

a The values for erythrocyte cholinesterase activity inhib ition are questionable due to repeated washing of the cells. 1

2
3 3.2. Repeat-Exposure Studies 4

5 Ten male Wistar rats inhaled 14.8 mg/m 3 methomyl powder for 4 hours/day, 5 days/week 6 for 3 months (Ta’naka et al. 1987). The powder concentration in the chamber was monitored 7 with a light scattering system. The mass median aerodynamic diameter of the particles was 8 4.4±2.9 μ. Rats were weighed and sacrificed 4 hour s after the last exposure, and erythrocyte and 9 plasma cholinesterase activity were measured by the Ellman method. Major organs were 10 weighed and examined microscopically and lungs were analyzed for lipid concentration. No 11 statistically significant differences were found between the control and exposed groups in body 12 or organ weights. At 4 hours post-exposure, mean plasma cholinesterase activity was inhibited 13 by 28% and erythrocyte acetylcholinesterase activity was inhibited by 8%. There were no 14 histopathologic changes in major organs and no accumulation of lipids in the lungs. The authors 15 concluded that the effects of methomyl exposure are not cumulative. 16
17METHOMYL NAC Proposed 1: June 2009/ Page 12 of 35

For comparison to the inhalation route, a repeat exposure dermal study and a repeat 1 exposure dietary toxicity study are provided. In a 21-day dermal toxicity study with New 2 Zealand rabbits, the NOAEL was 90 mg/kg/day, the highest dose tested. There were no 3 mortalities and no toxicologically significant i nhibition of plasma, erythrocyte, or brain 4 cholinesterase activity. In a 90-day feeding study with CD rats, the NOAEL was 6.25 mg/kg/day 5 (summarized in U.S. EPA 1998), based on lower body weight gain in both sexes and erythroid 6 hyperplasia in male rats at the next higher dose of 12.5 mg/kg/day. There were no mortalities 7 and no inhibition of cholinesterase activity. 8
9 3.3. Neurotoxicity 10
11 Acute toxicity studies (see Section 3.1) show ed that methomyl is neurotoxic. Although 12 no clinical signs were reported in rats inhaling methomyl dust at 9.9 mg/m 3 for 4 hours (Ta’naka 13 et al. 1987), higher concentrations including vapor concentration as low as 36 mg/m 3 and dust 14 aerosols as low as 137 mg/m 3 induced clinical signs consistent with cholinesterase activity 15 inhibition (See Section 4.1 for the mode of action of carbamate insecticides). 16
17 In a study of gavage administration of methomyl to male Long-Evans rats, motor activity 18 in the period 15 minutes to 35 minutes post-dosing was a reliable predictor of brain and 19 erythrocyte cholinesterase activity inhibition (McDaniel et al. 2007). Doses were 0.10, 0.25, 20 0.60, 1.25, or 2.50 mg/kg. Cholinesterase activity inhibition and related decreased motor activity 21 were dose dependent above 0.10 mg/kg. Brain and erythrocyte cholinesterase activity were 22 similarly inhibited at the higher doses. At 2.50 mg/kg, vertical motor activity was 20% of the 23 control value and brain and erythrocyte cholinesterase were 50-60% of the control value. 24
25 3.4. Developmental/Reproductive Toxicity 26
27 No inhalation studies were conducted that addressed the developmental/reproductive 28 toxicity of methomyl. Reproductive and developmen tal toxicity studies that used the oral route 29 of administration were reviewed by Kaplan and Sherman (1977) and U.S. EPA (1998). In 30 developmental studies, pregnant CD rats were ad ministered methomyl at concentrations of 0, 31 4.9, 9.4, or 33.9 mg/kg/day on gestation days 6- 19. The maternal LOAEL was 33.9 mg/kg/day 32 based on decreased body weight gain and food consumption; the developmental NOAEL was 33 33.9 mg/kg/day. In a recent study, pregnant New Z ealand rabbits were administered 0, 2, 6, or 34 16 mg/kg/day by stomach tube on gestation days 7-19. The maternal LOAEL was 16 mg/kg/day 35 based on mortality and clinical signs indicati ng neurotoxicity. The developmental NOAEL was 36 16 mg/kg/day, the highest dose tested. In a two-generation reproduction study, the F 0 generation 37 of Sprague-Dawley rats was fed methomyl at dose levels of 0, 3.75, 30, or 60 mg/kg/day. The F 1 38 offspring were treated at the same dosage. The parental NOAEL and LOAEL were 3.75 and 30 39 mg/kg/day, respectively; the LOAEL was based on decreased body weight and food 40 consumption and altered hematology parameters . The offspring NOAEL and LOAEL were also 41 3.75 and 30 mg/kg/day, based on a decrease in mean number of pups and decreased pup body 42 weight at 30 mg/kg/day. The U.S. EPA concl uded that the data provided no indication of 43 increased sensitivity of rats or rabbits to in utero or postnatal exposure to methomyl. There was 44 no assessment of functional development. 45
46METHOMYL NAC Proposed 1: June 2009/ Page 13 of 35

3.5. Genotoxicity 1
2 Methomyl has been tested in a range of in vitro genotoxicity assays (IPCS 1996; 2001; U.S. 3 EPA 1998; HSDB 2009). Most assays were conducted both with and without metabolic 4 activation. Methomyl did not cause mutagenicity or primary DNA damage in bacterial or 5 mammalian cells. Assay results were negative for point mutations in Salmonella typhimurium 6 (TA98, TA100, TA1535, TA1537, and TA1538) and Escherichia coli WP2 uvrA. Results were 7 negative for DNA damage in E. coli; Bacillus subtilis; Saccharomyces cerevisiae ; human lung 8 fibroblasts, lymphocytes, and skin cells; and rat hepatocytes. Methomyl assay results were 9 negative in gene mutation tests with Chinese hamster V79 and ovary cells and in a sister10 chromatid exchange assay in human lymphocytes. Methomyl showed cytogenetic potential in 11 human lymphocytes in vitro as indicated by an increase in micronuclei and chromosomal 12
aberrations. 13

14 3.6. Chronic Toxicity/Carcinogenicity 15
16 Methomyl was tested for chronic toxicity a nd carcinogenicity in two-year dietary studies 17 with male and female beagle dogs, male and female CD rats, and male and female CD-1 mice 18 (Kaplan and Sherman 1977; ACGIH 1992; U.S. EPA 1998). No increased tumor incidence 19 occurred in any study. Dogs fed ≥ 10 mg/kg/day showed microscopic changes in the kidneys, 20 spleen and liver. The NOAEL for dogs was 5 mg/kg/day. The NOAEL for rats was 5 21 mg/kg/day based on depressed body weight gain in both sexes at higher doses. No effects were 22 observed in mice at the highest dose, 120 mg/kg/da y. The U.S. EPA has classified methomyl in 23 Group E, not likely to be carcinogenic to human s via relevant routes of exposure. The 24 carcinogenicity of methomyl has not been evaluated by the International Agency for Research on 25
Cancer. 26
27 3.7. Summary 28
29 Acute inhalation lethality studies were conducted with the rat. The 4-hour LC 50 values 30 for rats ranged from 258 to 510 mg/m 3 for methomyl suspended as a mist or aerosol (DuPont 31 1966b ; Kaplan and Sherman 1977; DuPont 1991). During exposure rats showed signs 32 indicative of cholinesterase activity inhibition. In another study, clinical signs were either not 33 described or not observed in rats exposed to 9.9 mg/m 3 of dust for 4 hours (Ta’naka et al. 1987). 34 Plasma cholinesterase activity inhibition was greater (50%) following the acute exposure than 35 following exposure to 14.8 mg/m 3 for 4 hours/day, 5 days/week for 3 months (28%). A study 36 with the saturated vapor of methomyl (36 or 44 mg/m 3 ) did not attain concentrations high 37 enough to elicit mortality, although clinical signs indicative of acetylcholinesterase activity 38 inhibition were evident (DuPont 1966a). 39
40 No evidence of teratogenicity was observed in either rats or rabbits treated in the diet 41 with methomyl (rats, up to 60 mg/kg/day) even in the presence of maternal toxicity. A range of 42 genotoxicity assays provided mostly negative results. In 2-year feeding studies with the dog, rat, 43 and mouse at concentrations that approached toxic, there was no evidence of a tumorigenic 44

response. 45
46METHOMYL NAC Proposed 1: June 2009/ Page 14 of 35

4. SPECIAL CONSIDERATIONS 1 4.1. Metabolism and Disposition 2
3 Inhalation studies with methomyl that addressed metabolism were not located. Oral 4 absorption is near complete (95-98%) and most of the compound is eliminated in 24 hours 5 (ACGIH 1992). The N -methyl carbamates do not have a port of entry effect, are expected to be 6 rapidly absorbed, and do not require activation (U.S. EPA 2007). Unlike some organophosphate 7 pesticides that are metabolized by A-esterases which show great inter-individual variation, the 8 biotransformation of the carbamate pesticides does not involve these esterases. Metabolism was 9 outlined following oral dosing of male and female CD rats (Harvey et al. 1973) and male and 10 female Sprague-Dawley rats (Jaglan and Arnold 1984) with radiolabeled methomyl. Syn

11 methomyl, the form of methomyl that is produced and sold, is hydrolyzed at the ester linkage to 12 give rise to an oxime which is metabolized to CO 2 . Approximately 34-54% of the label is 13 eliminated in the urine as the oxime or conjugates of the oxime and 20-39% is eliminated as 14 expired CO 2 and acetonitrile (ratio 2:1). The major urinary metabolite was the mercapturic acid 15 derivative of methomyl (IPCS 1996). Acetonitrile is likely formed following partial conversion 16
of the syn -isomer to the anti -isomer prior to hydrolysis at the ester linkage. Two to three percent 17 of the radiolabel is eliminated in the feces, and less than 10% remains in the carcass. 18
19 Metabolism pathways in the monkey were similar to those of the rat, but with differences 20 in the percent of metabolites formed (IPCS 1996). Following administration of an oral dose of 5 21 mg/kg body weight, expired air contained 32-38% of the dose as CO 2 and 4-7% of the dose as 22 acetonitrile. Eighteen metabolites were characterized in the urine, with no metabolite 23 representing more than 4% of the dose. Most of the metabolites were eliminated in the first 24 24 hours post-exposure. 25
26 In addition to hydrolysis of the carbamate ester linkage, several oxidation and reduction 27 reactions involving cytochrome P450-related monooxygenases can form polar metabolites 28 (Costa 2008). Methyl and N -methyl side chains undergo hydroxylation, followed by conjugation 29 with glucuronide or sulfate derivatives. 30
31 4.2. Mechanism of Toxicity 32
33 Methomyl is an N -methyl carbamate insecticide. The mode of action of carbamate 34 pesticides involves cholinesterase inhibition (U.S. EPA 2007; Costa 2008). Carbamic acid esters 35 attach to the serine hydroxyl group of the reactive site of acetylcholinesterase, the enzyme 36 responsible for the destruction and termination of the biological activity of the neurotransmitter 37 acetylcholine. When unbound acetylcholine accumulates at the cholinergic nerve endings, there 38 is continual stimulation of electrical activity. The resulting signs of toxicity resulting from 39 stimulation of the muscarinic receptors of the parasympathetic autonomic nervous system are 40 manifest as increased secretions, bronchoconstriction, miosis, gastrointestinal cramps, diarrhea, 41 urination, and bradycardia. Stimulation of the parasympathetic junctions of the autonomic 42 nervous system as well as the junctions between nerves and muscles cause tachycardia, 43 hypertension, muscle fasciculation, tremors, muscle weakness, and flaccid paralysis. Signs and 44 symptoms resulting from effects on the central nervous system include restlessness, emotional 45 lability, ataxia, lethargy, mental confusion, loss of memory, generalized weakness, convulsion, 46 cyanosis, and coma. 47METHOMYL NAC Proposed 1: June 2009/ Page 15 of 35

1 Inhibition of acetylcholinesterase activity is transient and reversible because there is 2 rapid reactivation of the carbamylated enzyme in the presence of water. Maximum inhibition 3 typically occurs between 15 and 45 minutes after exposure. Carbamates also inhibit 4 butylcholinesterase, the primary form found in blood plasma. The toxicological significance of 5 butylcholinesterase activity inhibition is unknown. Acetylcholinesterase is the primary form of 6 cholinesterase found in erythrocytes and is present at neuromuscular and nerve-nerve junctions. 7 A review of studies submitted to U.S. EPA (2007) for pesticide registration shows that clinical 8 signs and behavioral effects are not evident belo w 10% cholinesterase activity inhibition, but in 9 most studies a 10% brain cholinesterase activity inhibition can be reliably detected. Due to 10 human variability, it is difficult to measure erythrocyte acetylcholinesterase activity inhibition of 11 <20% (U.S. EPA 2000). At greater than 30% eryt hrocyte or 50% plasma cholinesterase activity 12 inhibition, workers are withdrawn from pe sticide application areas (U.S. EPA 2000). 13

14 In adult Long-Evans rats dosed orally with 3 mg/kg methomyl, brain and erythrocyte 15 acetylcholinesterase activity were approximately 47 and 33% of control values, respectively, at 16 0.5 hours; activity in both compartments returned to the level of control values by 4 hours post17 dosing (Padilla et al. 2007). 18
19 4.3. Structure-Activity Relationships 20
21 Organophosphate and carbamate pesticides have a common mode of action (Costa 2008). 22 Compared to organophosphate ester pesticides, the carbamic acid esters are poor substrates for 23 cholinesterase-type enzymes. The carbamic acid esters which attach to the reactive site of acetyl 24 cholinesterase undergo fairly rapid hydrolysis; the carbamylated (inhibited) enzyme is 25 decarbamylated fairly rapidly with the generation of the free, active enzyme. 26
27 Information is available on the relative oral toxicity of three N -methyl carbamate 28 pesticides (HSRB 2006; U.S. EPA 2007). Th e endpoints were brain and erythrocyte 29 cholinesterase activity inhibition in the rat and erythrocyte cholinesterase activity inhibition in 30 humans. Raw data consisting of erythrocyte cho linesterase activity inhibition were not provided 31 for all three chemicals, but relative toxicity can be derived from the benchmark doses (BMD 10 32
and BMDL 10 ) calculated by U.S. EPA (2007) from a range of oral doses (Table 3). For 33 methomyl and oxamyl, rat data on brain and erythrocyte cholinesterase activity are presented by 34 McDaniel et al. (2007). If oxamyl is assigned a re lative oral potency factor of 1, then the oral 35 potencies of aldicarb and methomyl are 4 and 0.67, respectively (U.S. EPA 2007). 36
37

TABLE 3. Adult Rat and Human BMD 10 and BMDL 10 Values for Cholinesterase Activity Inhibition with N

Methyl Carbamate Pesticides (Oral Dosing)

Rat Human
Brain Erythrocyte Erythrocyte Chemical Benchmark Dose (mg/kg) Half-life (h) Benchmark Dose (mg/kg) Half-life (h) Benchmark Dose (mg/kg) Half-life (h)

Aldicarb BMD 10: 0.052

BMDL 10 : 0.035 1.5 BMD 10 : 0.031

BMDL 10 : 0.020 1.1 BMD 10 : 0.016

BMDL 10 : 0.013 1.7

Methomyl BMD 10 : 0.486

BMDL 10 : 0.331 1.0 BMD 10 : 0.204

BMDL 10 : 0.112 0.8 BMD 10 : 0.040

BMDL 10 : 0.028 1.6

Oxamyl BMD 10 : 0.165 0.9 BMD 10 : 0.278 0.8 BMD 10 : 0.083 2.4METHOMYL NAC Proposed 1: June 2009/ Page 16 of 35

BMDL 10 : 0.127 BMDL 10 : 0.158 BMDL 10 : 0.068 Benchmark dose data for brain cholinesterase activity for al dicarb and oxamyl are the average of male and female rat 1

values. 2

The BMDL 10 for 10% brain cholinesterase activity inhibition was used as the point of departure for U.S. EPA (2007) 3

risk assessment. 4 Source: Table 1.B-9, page 50, U.S. EPA 2007. 5 6
4.4. Other Relevant Information 7 4.4.1. Species Variability 8
9 Inhalation studies were conducted only with ra ts. Subchronic and chronic feeding studies 10 with the rat, mouse, and dog showed little difference in toxicity among the species. The extent 11 of hydrolysis of carbamate ester insecticides varies between species, ranging from 30 to 95%, 12 and is chemical specific (Costa 2008). Baseline erythrocyte acetylcholinesterase activity is 13 higher in humans than in other species (Ellin 1981). The U.S. EPA Office of Pesticide Programs 14 (U.S. EPA 2007) compared the toxicity (endpoint cholinesterase activity inhibition) of three N

15 methyl carbamate pesticides, oxamyl, methomyl , and aldicarb, using oral dosing in humans and 16 in juvenile and adult rats. Most data were available for oxamyl which was used as the index 17 chemical. Benchmark doses were calculated for brain and erythrocyte acetylcholinesterase 18 activity inhibition in juvenile and adult rats and erythrocyte cholinesterase activity inhibition in 19 humans. Based on the comparative erythrocyte acetylcholinesterase activity inhibition for equal 20 oral doses in adult rats and humans, the U.S. EPA calculated a chemical-specific interspecies 21 uncertainty factor of 5 for methomyl. For most of these chemicals, the interspecies uncertainty 22 factor is used for all routes of exposure. The half-lives for regeneration of erythrocyte 23 acetylcholinesterase activity in rats and humans were 0.8 and 1.6 hours, respectively. 24
25 4.4.2. Susceptible Populations 26
27 Humans are known to vary by gender, age, and genetic make-up in their sensitivity to 28 cholinesterase inhibitors. The erythrocyte acetylcholinesterase activity of adults (153±24 29 activity units; substrate acetylthiocholine) is greater than that of healthy newborn infants (97±15 30 activity units) by a factor of 1.6 (Herz et al. 1975). The U.S. EPA (2007) identified infants and 31 juveniles as the population most sensitive to the anticholinesterase effects of N -methyl carbamate 32 pesticides. In so doing, they evaluated the relative sensitivity of juvenile and adult rats to N

33 methyl carbamate pesticides including methomyl. Developmental neurotoxicity studies showed 34 that protection of the rat dam against cholinesterase activity inhibition is protective against pup 35 acetylcholinesterase activity inhibition in utero . Therefore, intraspecies uncertainty factors were 36 based on relative juvenile and adult rat sensitivity to brain acetylcholinesterase activity 37 inhibition. Based on comparative brain acetylcholinesterase activity inhibition in methomyl38 treated post-natal day 11 juvenile rats and adult rats, the U.S. EPA calculated a Food Quality 39 Protection Act (FQPA) uncertainty factor for children of 3.05 . This uncertainty factor 40 corresponds to an AEGL intraspecies uncertainty f actor. The estimated half-life for recovery of 41 brain acetylcholinesterase activity in juvenile rats was 0.4 hours (U.S. EPA 2007). 42
43 4.4.3. Concentration-Exposure Duration Relationship 44
45 No data were available for evaluating the relationship between ambient concentrations of 46 methomyl and exposure duration for a single endpoi nt. The concentration-time relationship for a 47METHOMYL NAC Proposed 1: June 2009/ Page 17 of 35

single endpoint for many irritant and systemica lly acting vapors and gases may be described by 1
C n x t = k. In the absence of empirical data, the time scaling factors of n = 3 and n = 1 are used 2 to scale to shorter and longer exposure durations respectively (NRC 2001). 3

4 4.4.4. Concurrent Exposure Issues 5
6 Dermal absorption may occur, but toxicity is low compared to inhalation exposure as 7 indicated by a dermal LD 50 of >5000 mg/kg in rabbits (Kaplan and Sherman 1977). Concurrent 8 exposure to other N-methyl carbamates in proportion to their potency indicates that they follow a 9 dose-additive model of brain cholinesterase inhibition (Padilla et al. 2006; U.S. EPA 2007). 10

11
5. DATA ANALYSIS FOR AEGL-1 12 5.1. Summary of Human Data Relevant to AEGL-1 13
14 No human inhalation studies were located in the available literature. No occupational 15 monitoring data were presented by U.S. EPA (1998). 16
17 5.2. Summary of Animal Data Relevant to AEGL-1 18
19 Ta’naka et al. (1987) exposed rats to an atmosphere of methomyl powder for 4 hours. 20 Rats inhaling 9.9 mg/m 3 for 4 hours showed plasma cholinesterase activity inhibited by 21 approximately 50%, but erythrocyte acetylcholinesterase activity was reported as either not 22 affected or only slightly inhibited. No clinical signs were described. In the human oral dosing 23 study (McFarlane et al. 1998), plasma cholinesterase activity inhibition was accompanied by a 24 corresponding inhibition in erythrocyte acetylcholinesterase activity. These results raise some 25 questions about the rat inhalation study in which plasma but not erythrocyte activity was 26 significantly inhibited. 27
28
5.3. Derivation of AEGL-1 29
30 The study of Ta’naka et al. (1987) in which rats inhaled 9.9 mg/m 3 methomyl powder 31 for 4 hours was considered inadequate for derivation of AEGL-1 values. The study did not 32 appear to accurately report erythrocyte acetylcholinesterase activity inhibition. In addition, the 33 presence or absence of clinical signs was not clear ly stated. No other studies addressed effects 34 defined by the AEGL-1. Therefore, AEGL-1 values are not recommended. 35
36

TABLE 4. AEGL-1 Values for Methomyl

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

Not recommended Not recommended Not recommended Not recommended Not recommended
Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 37
38
6. DATA ANALYSIS FOR AEGL-2 39 6.1. Summary of Human Data Relevant to AEGL-2 40
41
No human inhalation studies were located in the available literature. 42
43

44METHOMYL NAC Proposed 1: June 2009/ Page 18 of 35

6.2. Summary of Animal Data Relevant to AEGL-2 1
2 No inhalation studies with methomyl dust that addressed effects consistent with the 3 definition of the AEGL-2 were reported in the available literature. One of six rats exposed to a 4 nominal concentration of 36 mg/m 3 of methomyl vapor showed mild signs of cholinesterase 5 activity inhibition. These signs included face-pa wing, slight salivation and slight lacrimation 6 and mild dyspnea (DuPont 1966a). At the higher concentration of 44 mg/m 3 , all six rats showed 7 these clinical signs, and the signs were more severe, but recovery within 14 days was complete. 8 Higher vapor atmospheres could not be attained. 9
10 The lethality study with an aqueous aerosol of methomyl (DuPont 1991; Panepinto 11 1991), showed a steep concentration-response relationship. No mortality occurred at 181 mg/m 3

, 12 but six of ten rats died at 232 mg/m 3

. 13

14
6.3. Derivation of AEGL-2 15
16 Lethality data show that methomyl has a steep concentration-response curve. In the 17 absence of other relevant data, AEGL-2 values for chemicals with a steep concentration18 response curve may be derived by dividing the AEGL-3 values by 3 (NRC 2001). For 19 consistency with the study used to derive AEGL-3 values, the AEGL-2 values were derived by 20 dividing the AEGL-3 values by 3. Values are summarized in Table 5, calculations are in 21 Appendix A, and a category graph of the toxicity da ta in relation to AEGL values is in Appendix 22

B. 23

24

TABLE 5. AEGL-2 Values for Methomyl

10-min 30-min 1-h 4-h 8-h 7.0 mg/m 3 7.0 mg/m 3 5.7 mg/m 3 3.3 mg/m 3 1.7 mg/m 3

25 The vapor study of DuPont (1966a) supports the values derived by dividing the AEGL-3 26 by 3. Inhalation exposure of rats to of 44 mg/m 3 over a period of 4 hours induced clinical signs 27 consistent with the definition of the AEGL-2. Dividing the 4-hour 44 mg/m 3 value by 15 (see 28 Section 7.3 for discussion of uncertainty factors) and time-scaling using the default values of 3 29 and 1 for shorter and longer exposure durations, respectively, results in 10-minute through 8- 30 hour values of 5.9, 5.9, 4.7, 2.9, and 1.5 mg/m 3 . These values are comparable with the derived 31
values shown in Table 5. The fact that no rats died at the lowest tested concentration of 137 32 mg/m 3 in the study by DuPont (1991) also supports the AEGL-2 values. 33
34
7. DATA ANALYSIS FOR AEGL-3 35 7.1. Summary of Human Data Relevant to AEGL-3 36
37 No human inhalation studies relevant to development of AEGL-3 values were located in 38
the available literature. 39
40 7.2. Summary of Animal Data Relevant to AEGL-3 41
42 Three studies with methomyl as a mist or liquid aerosol addressed lethality in the rat. All 43
studies were for 4 hours. Four-hour LC 50 values were 258 mg/m 3 (DuPont 1991; Panepinto 44METHOMYL NAC Proposed 1: June 2009/ Page 19 of 35

1991), 300 mg/m 3 (DuPont 1966b), and 450 mg/m 3 (DuPont 1967; Hornberger 1967). Although 1 performed at different times, the three studies by DuPont give consistent values. The 1991 GLP 2 study by DuPont used both sexes of rats and provides good dose-response information. There 3 was little difference in toxicity between the sexes. Tested concentrations were 137, 181, 182, 4 232, and 326 mg/m 3 and respective mortalities were 0/10, 0/10, 1/10, 6/10, and 7/10 rats. 5
6
7.3. Derivation of AEGL-3 7
8 The GLP study of DuPont 1991 (Panepinto 1991) was chosen as the basis for AEGL-3 9 values. In that study, male and female rats inhaled an aerosol of methomyl generated by 10 suspending the solid in water. Benchmark concentrations were calculated (1) using all of the 11 data and (2) deleting the highest value of 326 mg/m 3 . Omitting the highest value provided a 12
better mathematical fit of the data to a curve. With omission of the highest value, the calculated 13
4-hour BMCL 05 is 157.26 mg/m 3 , and the BMC 01 is 166.51 mg/m 3 (Appendix C). The 14 NAC/AEGL committee generally uses the BMCL 05 as the estimate at which lethality is not 15 likely to be observed (NRC 2001). 16
17 The 157.3 mg/m 3 value was divided by inter- and intraspecies uncertainty factors of 5 18 and 3.05, respectively, for a total of 15. The U.S. EPA (2007) derived an interspecies 19 uncertainty factor of 5 for methomyl based on differences in modeled red blood cell values for 20 acetylcholinesterase activity inhibition between the rat and humans (See section 4.4.1). Based 21 on comparative brain cholinesterase activity inhibition in post-natal day 11 juvenile rats and 22 adult rats, the U.S. EPA calculated an uncertainty factor of 3.05 to protect sensitive young (See 23 section 4.4.2). The combined uncertainty factor is 15. The data set with application of an 24 uncertainty factor that protects sensitive juveniles provides a reasonable estimate of lethality. 25 The resulting value of 10.49 mg/m 3 (157.3 mg/m 3 /15) was time-scaled (C n x t = k) from the 4- 26 hour data point to 1 hour and to 30 minutes using the default n value of 3 and to the 8-hour 27 exposure duration using the default value of 1 (NRC 2001). Because the key study was 4 hours, 28 the 10-minute value was set equal to the 30-minute value. Values are summarized in Table 6, 29 calculations are in Appendix A, and a category graph of the toxicity data in relation to AEGL 30 values is in Appendix B. 31 32

TABLE 6. AEGL-3 Values for Methomyl

10-min 30-min 1-h 4-h 8-h 21 mg/m 3 21 mg/m 3 17 mg/m 3 10 mg/m 3 5.2 mg/m 3

33
The BMCL 05 value of 157.3 mg/m 3 is higher than the lowest concentration causing no 34 mortality (137 mg/m 3 ) in the key study. No deaths occurred at 181 mg/m 3 , but this value is 35 virtually identical with the 182 mg/m 3 value that resulted in the death of 1 of 10 rats. 36
37
8. SUMMARY OF AEGLs 38 8.1. AEGL Values and Toxicity Endpoints 39
40 AEGL values are summarized in Table 7. Derivations are summarized in Appendix D. 41

42
43

44METHOMYL NAC Proposed 1: June 2009/ Page 20 of 35

TABLE 7. Summary of AEGL Values for Methomyl
Exposure Duration Classification 10-min 30-min 1-h 4-h 8-h

AEGL-1 (Nondisabling) Not
recommended Not
recommended Not
recommended Not
recommended Not
recommended

AEGL-2 (Disabling) 7.0 mg/m 3 7.0 mg/m 3 5.7 mg/m 3 3.3 mg/m 3 1.7 mg/m 3

AEGL-3 (Lethal) 21 mg/m 3 21 mg/m 3 17 mg/m 3 10 mg/m 3 5.2 mg/m 3

Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 1
2 8.2. Comparison with Other Standards and Guidelines 3
4 Standards and guidelines for methomyl are listed in Table 8. The American Conference of 5 Government Industrial Hygienists (ACGIH 1992) Threshold Limit Value-Time Weighted 6 Average (TLV-TWA) is 2.5 mg/m 3 . Although far less than the no-adverse-effect-level identified 7 in animal studies, this value incorporates a margin of safety in view of doses associated with 8 human poisoning. This 8-hour value is for healthy adults, whereas the lower AEGL-2 value of 9 1.7 mg/m 3 is protective of infants and children. The ACGIH has derived a Biological Exposure 10 Index (BEI) for workers based on erythrocyte cholinesterase activity of acetylcholinesterase 11 inhibiting chemicals (ACGIH 2008). The value is ≤ 70% of an individual’s baseline red blood 12 cell acetylcholinesterase activity. 13

14

TABLE 8. Standards and Guidelines for Methomyl
Exposure Duration Guideline 10 min 30 min 1 h 4 h 8 h

AEGL-1 Not
recommended Not
recommended Not
recommended Not
recommended Not
recommended AEGL-2 7.0 mg/m 3 7.0 mg/m 3 5.7 mg/m 3 3.3 mg/m 3 1.7 mg/m 3
AEGL-3 21 mg/m 3 21 mg/m 3 17 mg/m 3 10 mg/m 3 5.2 mg/m 3
ERPG-1 (AIHA) a

─ ERPG-2 (AIHA)

─ ERPG-3 (AIHA)

─ IDLH (NIOSH) b ─

REL-TWA (NIOSH) c 2.5 mg/m 3

OSHA PEL (NIOSH) d ─

TLV-TWA (ACGIH) e 2.5 mg/m 3

MAK (Germany) f

─ MAC (The Netherlands) g 2.5 mg/m 3

Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 15 16

a ERPG (Emergency Response Planning Guide lines, American Industrial Hygiene Association 17

The ERPG-1 is the maximum airborne concentration belo w which it is believed nearly all individuals could be 18 exposed for up to one hour without experiencing other than mild, transient adverse health effects or without 19 perceiving a clearly defined objectionable odor. 20

The ERPG-2 is the maximum airborne concentration belo w which it is believed nearly all individuals could be 21 exposed for up to one hour without experiencing or devel oping irreversible or other serious health effects or 22METHOMYL NAC Proposed 1: June 2009/ Page 21 of 35

symptoms that could impair an individual = s ability to take protective action. 1

The ERPG-3 is the maximum airborne concentration belo w which it is believed nearly all individuals could be 2 exposed for up to one hour without experiencing or developing life-threatening health effects. 3 4

b IDLH (Immediately Dangerous to Life and Health, Nati onal Institute of Occupational Safety and Health) 5 represents the maximum concentration from which one could escape within 30 minutes without any escape6 impairing symptoms, or any irreversible health effects. 7 8

c NIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits - 9 Time Weighted Average) (NIOSH 2008) is defined analogous to the ACGIH-TLV-TWA. 10 11

d OSHA PEL-TWA (Occupational Safety and Health Ad ministration, Permissible Exposure Limits - Time 12 Weighted Average) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of no more than 10 13 hours/day, 40 hours/week. 14 15

e ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - 16 Time Weighted Average) (ACGIH 1992) is the time-weighted averag e concentration for a normal 8-hour workday 17 and a 40-hour workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse 18

effect. 19 20

f MAK (Maximale Arbeitsplatzkonzentrat ion [Maximum Workplace Concentration]) (Deutsche 21 Forschungsgemeinschaft [German Research Associa tion]) is defined analogous to the ACGIH-TLV-TWA. 22 23

g MAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration]) (SDU Uitgevers [under the 24 auspices of the Ministry of Social Affairs and Employmen t], The Hague, The Netherlands 2000) is defined similar to 25

the ACGIH TLV. 26
27 8.3. Data Adequacy and Research Needs 28
29 Methomyl has a low vapor pressure and no suitable studies involving inhalation exposure 30 of humans were located in the available literature. An oral dosing study with human volunteers 31
addressed effects consistent with cholinesterase activity inhibition. Five inhalation studies with 32 rats as the test species were sufficient for deri vation of two AEGL levels for five timepoints. 33 Studies involving comparisons of cholinesterase activity inhibition between juvenile and adult 34 rats and between rats and humans addressed chemical-specific uncertainty factors. Metabolism 35 pathways and mode of action are well understood. 36
37
9. REFERENCES 38
39 ACGIH (American Conference of Government and Industrial Hygienists). 1992. Methomyl. 40 Documentation of the Threshold Limit Values and Biological Exposure Indices. Cincinnati, OH: 41

ACGIH. 42
43 ACGIH (American Conference of Government and Indus trial Hygienists). 2008. TLVs and BEIs Based 44
on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents & 45 Biological Exposure Indices. Cincinnati, OH: ACGIH. 46 47 Costa, L.G. 2008. Chapter 22: Toxic Effects of Pes ticides. In Casarett & Doull’s Toxicology, The Basic 48
Science of Poisons. 7 th Ed. New York: McGraw-Hill. 49
50 de Vreede, J.A.F., D.H. Brouwer, H. Stevenson, and J.J. van Hemmen. 1998. Exposure and risk 51 estimation for pesticides in high-volume sp raying. Ann. Occup. Hyg. 42:151-157. 52
53METHOMYL NAC Proposed 1: June 2009/ Page 22 of 35

Driskell, W.J., D.F. Groce, R.H. Hill, Jr., and M.M. Birky. 1991. Methomyl in the blood of a pilot who 1 crashed during aerial spraying. J. Anal. Toxicol. 15:339-340. 2
3 DuPont. 1966a. Acute Inhalation Toxicity. Haske ll Laboratory Report No. 214-66. Haskell Laboratory 4 for Toxicology and Industrial Medicine, Newark, DE. 5 6 DuPont. 1966b. Acute Inhalation Toxicity (Progr ess Report). Haskell Laboratory Report No. 73-66. 7 Haskell Laboratory for Toxicology a nd Industrial Medicine, Newark, DE. 8 9 DuPont. 1967. Acute Inhalation Toxicity Study of Aqueous Spray Mist. Haskell Laboratory Report No. 10 171-67. Haskell Laboratory for Toxicology a nd Industrial Medicine, Newark, DE. (Same as 11 Hornberger 1967). 12
13 DuPont. 1991. Acute Inhalation Toxicity Study with DPX-X1179-427 in Rats. Haskell Laboratory 14 Report No. 678-91. Haskell Laboratory for Toxico logy and Industrial Medicine, Newark, DE. 15 (Same as Panepinto 1991). 16 17 DuPont. 2007. Material Safety Data Sheet: DuPont Lannate SP Insecticide. Available online, Dupont 18
Chemical Co. 19
20 Ellin, R.I. 1981. Anomalies in theories and therapy of intoxication by potent organophosphorus 21 anticholinesterase compounds. U.S. Army Medical Research and Development Command, 22 Biomedical Laboratory Report No. USABML-SP-81-003. Available from the Defense Technical 23 Information Center, AD A1013364. 24
25 Harvey, J., A.G. Jeinek and H. Sherman. 1973. Metabolism of methomyl in the rat. Agric. Food Chem. 26

21:769-775. 27
28 Herz, F., E. Kaplan, and E.S. Scheye. 1975. A long itudinal study of red cell enzymes in infants of low 29 birth weight. Z. Kinderheilk. 120: 217-221. 30
31 Hornberger, C.S. 1967. Acute Inhalation Toxicity Study of Aqueous Spray Mist. Haskell Laboratory 32 Report No. 171-67. Haskell Laboratory for Toxico logy and Industrial Medicine, Newark, DE. 33 (Same as DuPont 1967). 34
35 HSDB (Hazardous Substances Data Bank). 2009. Methom yl. National Library of Medicine. Available 36
online: http://toxnet/nlm.nih.gov/cgi-bin/sis/download.txt

. 37
38 HSRB (Human Studies Review Board). 2006. Report of the Human Studies Review Board April 4-6, 39 2006, regarding chemicals aldicarb, methomyl, oxamyl, azinphos-methyl, DDVP, ethephon, 40 hydrogen cyanide, and amitraz. Available online: http://www.epa.gov/osa/hsrb/files/meeting41 materials/apr-4-6-2006-public-meeti ng/april2006mtgfinalreport62606.pdf. 42
43 IPCS (International Program on Chemical Safety). 1996. Environmental Health Criteria 178: Methomyl. 44 World Health Organization. Available online: 45 http://www.inchem.org/documents/ehc/ehc/ehc178.htm

. 46 47 IPCS (International Program on Chemical Safety). 2001. Pesticide residues in food – 2001- 48 Toxicological Evaluations: Methomyl (addendum). Joint Meeting on Pesticide Residues. World 49 Health Organization. Available online: 50 http://www.inchem.org/documents/jmpr/jmpmono/2001pr08.htm

. 51
52METHOMYL NAC Proposed 1: June 2009/ Page 23 of 35

Jaglan, P.S. and T.S. Arnold. 1984. Meta bolism of the insecticidal carbamate methyl N -[[[[[(1,1- 1 dimethylethyl)(5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2yl)- 2 amino]thio]methylamino]carbonyl]oxy]ethanimidothioate in rats. J. Agric. Food Chem. 32:618-622. 3
4 Kaplan, A.M. and H. Sherman. 1977. Toxicity studies with methyl N

5 [[(methylamino)carbonyl]oxy]ethanimidothioate. Toxicol. Appl. Pharmacol. 40:1-17. 6
7 McDaniel, K.L., S. Padilla, R.S. Marshall, P.M. Ph illips, L. Podhorniak, Y. Qian, and V.C. Moser. 2007. 8 Comparison of acute neurobehavioral and cholinesterase inhibitory effects of N -methylcarbamates in 9
rat. Toxicol. Sci. 98:552-560. 10
11 McFarlane, P., J.B. Sanderson, and S. Freestone. 1998. A randomized double blind ascending oral dose 12 study with methomyl to establish a no adverse effect level. Inveresk Clinical Research, Riccarton, 13 Edinburgh, Scotland. HLO-1998-00969. (Summarized in U.S. EPA 2005, MRID 44721401). 14
15 NIOSH (National Institute for Occupational Safety and Health). 2008. NIOSH Pocket Guide to 16
Chemical Hazards. Available online: http://www.cdc.gov/niosh/npgd0455.html

. 17
18 NRC (National Research Council). 2001. Standi ng Operating Procedures for Developing Acute 19 Exposure Guideline Levels for Hazardous Chemical s. Washington, DC: National Academy Press. 20
21 O’Neil, M.J., A. Smith, and P.E. Heckelman. 2001. Methomyl. The Merck Index. Whitehouse Station, 22 NJ: Merck & Co., Inc., p. 6015. 23
24 Padilla, S., W. Setzer, R.S. Marshall, D. Hunter, P. Phillips, K. McDaniel, V.C. Moser, and A. Lowit. 25 2006. A dose-response study of the toxicity of a mixture of 7 N -methyl carbamates in adult, male 26
rats. Presented at the 45 th Annual Meeting of the Society of Toxicology, San Diego, CA. 27
28 Padilla, S., R.S. Marshall, D.L. Hunter, and A. Low it. 2007. Time course of cholinesterase inhibition in 29 adult rats treated acutely with carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl, or 30 propoxur. Toxicol. Appl. Pharmacol. 219:202-209. 31
32 Panepinto, A.S. 1991. Acute Inhalation Toxic ity Study with DPX-X1179-427 in Rats. Haskell 33 Laboratory Report No. 678-91. Haskell Laboratory fo r Toxicology and Industrial Medicine, Newark, 34 DE. (Same as DuPont 1991). 35
36 SDU Uitgevers. 2000. Nationale MAC List. Under the auspices of the Ministry of Social Affairs and 37 Employment. The Netherlands: The Hague. 38 39 Ta’naka, I., H. Igisu, J. Haratake, S. Cho, K. Mori , K. Fujishiro, N. Inoue, A. Horie, and T. Akiyama. 40 1987. Cumulative toxicity potential of methomyl aeros ol by repeated inhalation. Am. Ind. Hyg. J. 41

48:330-334. 42
43 Tsatsakis, A.M., G.K. Bertsias, I.N. Mammas, I. S tiakakis, and D.B. Georgopoulos. 2001. Acute fatal 44 poisoning by methomyl caused by inhalation and transdermal absorption. Bull. Environ. Contam. 45
Toxicol. 66:415-420. 46 47 U.S. EPA (U.S. Environmental Protection Agency). 1991. Methomyl. In Drinking Water Health 48 Advisory: Pesticides. Chelsea, MI: Lewis Publishers, pp. 521-539. 49
50 U.S. EPA (U.S. Environmental Protection Agency). 1998. Reregistration Eligibility Decision (RED) for 51 Methomyl. Available online: www.epa.gov/pesticides/reregistration/REDs/methomyl_red.pdf

. 52METHOMYL NAC Proposed 1: June 2009/ Page 24 of 35

1 U.S. EPA (U.S. Environmental Protection Agency). 2000. Office of Pesticide Programs Science Policy 2
on The Use of Data on Cholinesterase Inhibiti on for Risk Assessments of Organophosphorous and 3 Carbamate Pesticides. Washington, DC: U.S. Envi ronmental Protection Agency. Available online: 4 http://www.epa.gov/pesticides/trac/science/cholin.pdf. 5 6 U.S. EPA (U.S. Environmental Protection Agency). 2005. Data Evaluation Record: Methomyl/90301 7 (MRID 44721401). Available online: Regulations.gov/me thomyl 90301. Citation: McFarlane et al. 8 1998. A randomized double blind ascending oral dose study with methomyl. Inveresk Clinical 9 Research, Riccarton, Edinburgh, Scotland. Labor atory Project ID: HLO-1998-00969, November 30, 10

1998. 11
12 U.S. EPA (U.S. Environmental Protection Agency). 2007. Revised N -Methyl Carbamate Cumulative 13 Risk Assessment. Office of Pesticide Programs. Available online: 14 http://www.epa.gov/oppsrrd1/REDs/nmc_revised_cra.pdf

. 15
16 17METHOMYL NAC Proposed 1: June 2009/ Page 25 of 35

1 APPENDIX A: Derivation of Methomyl AEGLs 2
3
Derivation of AEGL-1 Values 4

5 No human inhalation studies or adequately reported animal studies were located that 6 reported effects consistent with the definition of the AEGL-1. Therefore, AEGL-1 values are not 7
recommended. 8
9
10
Derivation of AEGL-2 Values 11
12 Key Study: DuPont. 1991. Acute Inhalati on Toxicity Study with DPX-X1179-427 in 13 Rats. Haskell Laboratory Report No . 678-91. Haskell Laboratory for 14 Toxicology and Industrial Medicine, Newark, DE. (same as Panepinto 1991). 15
16 Toxicity endpoint: AEGL-3 values divided by 3. The steep concentra tion-response line curve 17 by the DuPont 1991 data justifies deriving AEGL-2 values by dividing the 18 AEGL-3 values by 3 (NRC 2001). 19
20 Time scaling See AEGL-3 derivation, next page 21
22 Uncertainty factors: Total uncertainty factor: 15 (See AEGL-3 derivation, next page). 23
24 Calculations: AEGL-3 values divided by 3 25
26 10-min AEGL-2: C = 21 mg/m 3 /3 = 7.0 mg/m 3 27
28 30-min AEGL-2: C = 21 mg/m 3 /3 = 7.0 mg/m 3 29
30 1-h AEGL-2: C = 17 mg/m 3 /3 = 5.7 mg/m 3 31
32 4-h AEGL-2: C = 10 mg/m 3 /3 = 3.3 mg/m 3 33
34 8-h AEGL-2: C = 5.2 mg/m 3 /3 = 1.7 mg/m 3 35
36METHOMYL NAC Proposed 1: June 2009/ Page 26 of 35

1
Derivation of AEGL-3 Values 2
3 Key Study: DuPont. 1991. Acute Inhalati on Toxicity Study with DPX-X1179-427 in 4 Rats. Haskell Laboratory Report No . 678-91. Haskell Laboratory for 5 Toxicology and Industrial Medicine, Newark, DE (same as Panepinto 1991). 6
7 Toxicity endpoint: Threshold for lethality in rats at the BMCL 05 of 157.264 mg/m 3 calculated 8 from the rat lethality data of DuPont (1991) (with omission of the highest 9 value). 10
11 Time scaling C n x t = k where n = 3 and 1 for s horter and longer exposure durations, 12 respectively 13
14 Uncertainty factors: Total uncertainty factor: 15 15 Interspecies: 5 – Based on differences in modeled values for red blood cell 16 cholinesterase activity inhibition between rats and humans following oral 17 ingestion of methomyl (U.S. EPA 2007). 18 Intraspecies: 3.05 – Based on comparative brain acetylcholinesterase activity 19 inhibition in post-natal day 11 juvenile rats and adult rats exposed to 20 methomyl (U.S. EPA 2007). 21
22 Modifying factor: None applied 23
24 Calculations: (157.264 mg/m 3 /15) 3 x 240 minutes = (27.66 x 10 4 ) mg/m 3 •min 25 (157.264 mg/m 3 /15) 1 x 240 minutes = 2516.22 mg/m 3 •min 26 27 10-min AEGL-3: C = 21 mg/m 3 (set equal to the 30-minute value because of the long study 28 duration) 29
30
30-min AEGL-3: C = 3 √ (27.66 x 10 4 mg/m 3 •min) = 21 mg/m 3 31
32
1-h AEGL-3: C = 3 √ (27.66 x 10 4 mg/m 3 •min) = 17 mg/m 3 33
34 4-h AEGL-3: C = 157.264 mg/m 3 /15 = 10 mg/m 3 35
36 8-h AEGL-3: C = 2516.22 mg/m 3 •min/480 min = 5.2 mg/m 3 37
38METHOMYL NAC Proposed 1: June 2009/ Page 27 of 35



### APPENDIX B: Category Graph of AE GL Values and Toxicity Data 1

2

0 1 10 100 1000mg/m3

0 60 120 180 240 300 360 420 480 Minutes No Effect

Discomfort

Disabling

Some Lethality

Lethal

AEGL Category Graph - Animal Data Methomyl

AEGL-3

AEGL-2

3 4

5
Data: 6

For Category: 0 = No effect, 1 = Discomfort, 2 = Disabling, SL = Some Lethality, 3 = Lethal
Source Species mg/m 3 Minutes Category

NAC/AEGL-1 NR 10 AEGL

NAC/AEGL-1 NR 30 AEGL

NAC/AEGL-1 NR 60 AEGL

NAC/AEGL-1 NR 240 AEGL

NAC/AEGL-1 NR 480 AEGL

NAC/AEGL-2 7.0 10 AEGL

NAC/AEGL-2 7.0 30 AEGL

NAC/AEGL-2 5.7 60 AEGL

NAC/AEGL-2 3.3 240 AEGL

NAC/AEGL-2 1.7 480 AEGL

NAC/AEGL-3 21 10 AEGL

NAC/AEGL-3 21 30 AEGL

NAC/AEGL-3 17 60 AEGL

NAC/AEGL-3 10 240 AEGL

NAC/AEGL-3 5.2 480 AEGLMETHOMYL NAC Proposed 1: June 2009/ Page 28 of 35

Ta’naka et al. 1987 rat 9.9 240 0 (clinical signs either absent or not described) DuPont 1966a rat 36 240 1 (slight lacrimation, salivation, mild dyspnea in 1 of 6 rats) rat 44 240 1 (slight lacrimation, salivation, mild dyspnea in 6 of 6 rats) DuPont 1966b rat 250 240 2 (lacrimation, salivation, mild to moderate dyspnea, tremor, convulsions) rat 300 240 SL (death of 3 of 6 rats) rat 350 240 3 (death of 6 of 6 rats) rat 560 240 3 (death of 6 of 6 rats)
DuPont 1967; Hornberger 1967 rat 97 240 2 (tremors, lacrimation, salivation) rat 130 240 2 (tremors, lacrimation, salivation) rat 333 240 SL (death of 1 of 6 rats) rat 420 240 SL (death of 2 of 6 rats) rat 540 240 SL (death of 5 of 6 rats) rat 600 240 SL (death of 5 of 6 rats) rat 950 240 3 (death of 6 of 6 rats) DuPont 1991 rat 137 240 2 (diarrhea, ruffled fur) rat 181 240 2 (diarrhea, ruffled fur) rat 182 240 SL (death of 1 of 10 rats)) rat 232 240 SL (death of 6 of 10 rats) rat 326 240 SL (death of 7 of 10 rats)

Atmospheres of methomyl include powder (Ta’naka et al. 1987), vapor (DuPont 1966a), and mist or liquid aerosol (DuPont 1966b; 1967; 1991).
NR = not recommended. Absence of AEGL-1 values doe s not imply that exposure below AEGL-2 levels is
without effect.METHOMYL NAC Proposed 1: June 2009/ Page 29 of 35



### APPENDIX C: Benchmark Co ncentration Calculations 1

2
Calculation of BMCL 05 3 Rat lethality data (DuPont 1991; Panepinto 1991) 4

=============================================================== 5 Probit Model. (Version: 2.8; Date: 02/20/2007) 6 Input Data File: C:\BMDS\UNSAVED1.(d) 7 Gnuplot Plotting File: C:\BMDS\UNSAVED1.plt 8 Thu Apr 23 09:12:05 2009 9

=============================================================== 10

11
BMDS MODEL RUN 12

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 13 The form of the probability function is: 14 P[response] = Background + (1-Background) CumNorm(Intercept+Slope*Log(Dose)), 15 where CumNorm(.) is the cumulative normal distribution function 16
17 Dependent variable = COLUMN3 18 Independent variable = COLUMN1 19 Slope parameter is not restricted 20

21
Total number of observations = 5 22 Total number of records with missing values = 0 23
Maximum number of iterations = 250 24 Relative Function Convergence has been set to: 1e-008 25 Parameter Convergence has been set to: 1e-008 26
27 User has chosen the log transformed model 28
29 Default Initial (and Specified) Parameter Values 30 Background = 0 31 intercept = -19.7475 32 slope = 3.59092 33
34 Asymptotic Correlation Matrix of Parameter Estimates 35 The model parameter(s) -background have been estimated at a boundary point, or 36 have been specified by the user, and do not appear in the correlation matrix ) 37
38 intercept slope 39 intercept 1 -1 40 slope -1 1 41

42
Parameter Estimates 43

44
95.0% Wald Confidence Interval 45 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 46 background 0 NA 47METHOMYL NAC Proposed 1: June 2009/ Page 30 of 35

intercept -42.1724 13.4943 -68.6207 -15.7242 1 slope 7.78999 2.52426 2.84253 12.7374 2
3 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus 4
has no standard error. 5
6 Analysis of Deviance Table 7 Model Log(likelihood) # Param's Deviance Test d.f. P-value 8
Full model -9.98095 5 9
Fitted model -10.6556 2 1.34926 3 0.7175 10
Reduced model -20.2482 1 20.5345 4 0.0003916 11
AIC: 25.3112 12
13

14
Goodness of Fit 15
Scaled 16 Dose Est._Prob. Expected Observed Size Residual 17

------------------------------------------------------------------------ 18
0.0000 0.0000 0.000 0 10 0.000 19
137.0000 0.0001 0.001 0 10 -0.025 20
181.0000 0.0468 0.468 0 10 -0.701 21
182.0000 0.0512 0.512 1 10 0.700 22
232.0000 0.6016 6.016 6 10 -0.011 23
Chi^2 = 0.98 d.f. = 3 P-value = 0.8055 24
25 Benchmark Dose Computation 26 Specified effect = 0.05 27 Risk Type = Extra risk 28
Confidence level = 0.95 29
BMC 05 = 181.73 30
BMCL 05 = 157.264 31
32

0 0.2 0.4 0.6 0.8

0 50 100 150 200Fraction Affected

dose Probit Model with 0.95 Confidence Level

09:12 04/23 2009 BMDL BMD Probit

BMD Lower Bound

33METHOMYL NAC Proposed 1: June 2009/ Page 31 of 35

Calculation of BMCL 01 1 Rat lethality data (DuPont 1991; Panepinto 1991) 2

============================================================== 3 Probit Model. (Version: 2.8; Date: 02/20/2007) 4 Input Data File: C:\BMDS\UNSAVED1.(d) 5 Gnuplot Plotting File: C:\BMDS\UNSAVED1.plt 6 Thu Apr 23 09:21:15 2009 7

============================================================== 8
9
BMDS MODEL RUN 10

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 11

12 The form of the probability function is: 13 P[response] = Background + (1-Background) * 14 CumNorm(Intercept+Slope*Log(Dose)), where CumNorm(.) is the cumulative normal 15
distribution function 16
17 Dependent variable = COLUMN3 18 Independent variable = COLUMN1 19 Slope parameter is not restricted 20

21
Total number of observations = 5 22 Total number of records with missing values = 0 23
Maximum number of iterations = 250 24 Relative Function Convergence has been set to: 1e-008 25 Parameter Convergence has been set to: 1e-008 26
27 User has chosen the log transformed model 28
29 Default Initial (and Specified) Parameter Values 30 Background = 0 31 Intercept = -19.7475 32 Slope = 3.59092 33
34 Asymptotic Correlation Matrix of Parameter Estimates 35 The model parameter(s) -background have been estimated at a boundary point, or have been 36 specified by the user, and do not appear in the correlation matrix ) 37
38 intercept slope 39 intercept 1 -1 40 slope -1 1 41

42
Parameter Estimates 43
95.0% Wald Confidence Interval 44 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 45 background 0 NA 46 intercept -42.1724 13.4943 -68.6207 -15.7242 47METHOMYL NAC Proposed 1: June 2009/ Page 32 of 35

slope 7.78999 2.52426 2.84253 12.7374 1

2 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and 3
thus has no standard error. 4

5 Analysis of Deviance Table 6 Model Log(likelihood) # Param's Deviance Test d.f. P-value 7
Full model -9.98095 5 8
Fitted model -10.6556 2 1.34926 3 0.7175 9
Reduced model -20.2482 1 20.5345 4 0.0003916 10
AIC: 25.3112 11

12
Goodness of Fit 13
Scaled 14 Dose Est._Prob. Expected Observed Size Residual 15

------------------------------------------------------------------------ 16
0.0000 0.0000 0.000 0 10 0.000 17
137.0000 0.0001 0.001 0 10 -0.025 18
181.0000 0.0468 0.468 0 10 -0.701 19
182.0000 0.0512 0.512 1 10 0.700 20
232.0000 0.6016 6.016 6 10 -0.011 21

22
Chi^2 = 0.98 d.f. = 3 P-value = 0.8055 23

24 Benchmark Dose Computation 25 Specified effect = 0.01 26 Risk Type = Extra risk 27
Confidence level = 0.95 28
BMC 01 = 166.508 29
BMCL 01 = 133.852 30
31

0 0.2 0.4 0.6 0.8

0 50 100 150 200Fraction Affected

dose Probit Model with 0.95 Confidence Level

09:21 04/23 2009 BMDL BMD Probit

BMD Lower Bound

32
33METHOMYL NAC Proposed 1: June 2009/ Page 33 of 35

1 

### APPENDIX D: Derivation Summary for Methomyl AEGLs 2 Acute Exposure Guideline Levels for Methomyl 3 (CAS Reg. No. 16752-77-5) 4

5

AEGL-1 VALUES

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

Not recommended Not recommended Not recommended Not recommended Not recommended
Key Reference : Insufficient data Test Species/Strain/Sex/Number : Exposure Route/Concentration/Duration : Effects : Endpoint/Concentration/Rationale : Uncertainty Factors/Rationale : Total uncertainty factor:

Interspecies : Intraspecies : Modifying Factor : Animal to Human Dosimetric Adjustment : Time Scaling : Data Adequacy : Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 6 7 8METHOMYL NAC Proposed 1: June 2009/ Page 34 of 35

1

AEGL-2 VALUES

10-min 30-min 1-h 4-h 8-h 7.0 mg/m 3 7.0 mg/m 3 5.7 mg/m 3 3.3 mg/m 3 1.7 mg/m 3

Key Reference : DuPont. 1991. Acute Inhalation Toxicity Study with DPX-X1179-427 in Rats. Haskell Laboratory Report No. 678-91. Haskell Laborat ory for Toxicology and Industrial Medicine, Newark, DE. Test Species/Strain/Number : Rat/CrL-CD/6 males per group Exposure Route/Concentration/Duration : Inhalation/137, 181, 182, 232, and 326 mg/m 3 /4 hours

Effects : acetylcholinesterase activity inhibition es timated at 1/3 of the AEGL-3 values. Endpoint/Concentration/Rationale : One-third of the AEGL-3 values based on the steep concentrationresponse curve in the key AEGL-3 study (NRC 2001). Uncertainty Factors/Rationale : Total uncertainty factor : 15 (See AEGL-3 summary)

Interspecies: Intraspecies: : Modifying Factor : None applied Animal to Human Dosimetric Adjustment : Not applicable Time Scaling : See AEGL-3 summary Data Adequacy : Four studies performed in the same labor atory at different times provided consistent, concentration-related results, regardless of the physical st ate of the test material. The values are supported by the 4-hour vapor study of DuPont 1966a in which rats inhaling 44 mg/m 3 for 4 hours exhibited clinical signs
consistent with the definition of the AEGL-2.
2 3 4METHOMYL NAC Proposed 1: June 2009/ Page 35 of 35

1

AEGL-3 VALUES

10-min 30-min 1-h 4-h 8-h 21 mg/m 3 21 mg/m 3 17 mg/m 3 10 mg/m 3 5.2 mg/m 3

Key References: DuPont. 1991. Acute Inhalation Toxicity Study with DPX-X1179-427 in Rats. Haskell Laboratory Report No. 678-91. Haskell Laboratory for Toxicology and Industrial Medicine, Newark,

DE. Test Species/Strain/Number : Rat/Crl-CD/groups of 5 male and 5 female Exposure Route/Concentration/Duration: Inhalation/137, 181, 182, 232, or 326 mg/m 3 liquid aerosol/ 4
hours

Effect : Concentration-related clinical signs and mortality Endpoint/Concentration/Rationale : Threshold for lethality, BMCL 05 calculated using the benchmark dose computer program (highest data point omitted for better curve fitting). Uncertainty Factors/Rationale : Total uncertainty factor : 15

Interspecies: 5, Based on differences in modeled values for red blood cell cholinesterase activity inhibition between rats and humans following or al ingestion of methomyl (U.S. EPA 2007). Intraspecies : 3.05, Based on comparative brain acetylcholines terase activity inhibition in post-natal day 11 juvenile rats and adult rats exposed to methomyl (U.S. EPA 2007). Modifying Factor : None applied Animal to Human Dosimetric Adjustment : Not applicable Time Scaling : C n x t = k where n = 3 and 1 for shorter and longer exposure durations, respectively (NRC 2001) Data Adequacy: Four studies performed in the same laborator y but at different times provided consistent, concentration-related results, regardless of the physical state of the test material.

2