NAC Proposed 1: June 2009 1
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## ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 5



## FOR 6



## ALDICARB 7


## (CAS Reg. No. 116-06-3) 8

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10 11
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## PROPOSED 14

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17ALDICARB NAC Proposed 1: June 2009/ Page 2 of 33

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
40ALDICARB NAC Proposed 1: June 2009/ Page 3 of 33

TABLE OF CONTENTS 1

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

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

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

1. INTRODUCTION................................................................................................................ ................7 5

2. HUMAN TOXI CITY DATA......................................................................................................... ......8 6

3. ANIMAL TOXI CITY DATA........................................................................................................ ......9 7

3.1. Acute Toxicity ............................................................................................................ .................9 8

3.2. Repeat-Exposure Studies................................................................................................... ........10 9

3.3. Neurotoxicity............................................................................................................. ................10 10

3.4. Developmental/Reproductive Toxicity......................................................................................1 1 11

3.5. Genotoxicity .............................................................................................................. ................11 12

3.6. Chronic Toxicity/Carcinogenicity .......................................................................................... ...11 13

3.7. Summary................................................................................................................... .................11 14

4. SPECIAL CONS IDERATIONS ...................................................................................................... ..12 15

4.1. Metabolism and Disposition................................................................................................ ......12 16

4.2. Mechanism of Toxicity..................................................................................................... .........12 17

4.3. Structure-Activity Relationships .......................................................................................... .....13 18

4.4. Other Relevant Information................................................................................................ .......14 19 4.4.1. Species Variability ..................................................................................................... ...........14 20 4.4.2. Susceptible Populations ................................................................................................. .......15 21 4.4.3. Concentration-Exposur e Duration Relationship ...................................................................15 22 4.4.4. Concurrent Exposure Issues.............................................................................................. ....16 23

5. DATA ANALYSIS FOR AEGL-1 .................................................................................................... 16 24

5.1. Summary of Human Data Relevant to AEGL-1........................................................................16 25

5.2. Summary of Animal Data Relevant to AEGL-1........................................................................16 26

5.3. Derivation of AEGL-1...................................................................................................... .........16 27

6. DATA ANALYSIS FOR AEGL-2 .................................................................................................... 16 28

6.1. Summary of Human Data Relevant to AEGL-2........................................................................16 29

6.2. Summary of Animal Data Relevant to AEGL-2........................................................................16 30

6.3. Derivation of AEGL-2...................................................................................................... .........16 31ALDICARB NAC Proposed 1: June 2009/ Page 4 of 33

7. DATA ANALYSIS FOR AEGL-3 .................................................................................................... 17 1

7.1. Summary of Human Data Relevant to AEGL-3........................................................................17 2

7.2. Summary of Animal Data Relevant to AEGL-3........................................................................17 3

7.3. Derivation of AEGL-3...................................................................................................... .........17 4

8. SUMMARY OF AEGLs............................................................................................................ ........18 5

8.1. AEGL Values and Toxicity Endpoints......................................................................................18 6

8.2. Comparison with Other Standards and Guidelines....................................................................18 7

8.3. Data Adequacy and Research Needs .........................................................................................2 0 8

9. REFERENCES.................................................................................................................. .................20 9

APPENDIX A: Derivation of Aldicarb AEGLs ...................................................................................... ..23 10

APPENDIX B: Category Graph of AE GL Values and Toxicity Data.......................................................25 11

APPENDIX C: Benchmark Concentra tion Calculations for Aldicarb.......................................................27 12

APPENDIX D: Derivation Summary for Aldicarb AEGLs.......................................................................31 13ALDICARB NAC Proposed 1: June 2009/ Page 5 of 33

LIST OF TABLES 1

TABLE ES 1. Summary of AE GL Values fo r Aldi carb ............................................................................... ...........7 2

TABLE 1. Chemical and Physical Pr operties..................................................................................... ......................8 3 TABLE 2. Acute Toxicity of Aldicarb to Rats................................................................................... .....................10 4

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

5 Methyl Carbamate Pestic ides (Oral Dosing)...................................................................................... ............13 6 TABLE 4. Comparison of Erythrocyt e Acetylcholinesterase Activity I nhibition in Rats and Hu mans............14 7
TABLE 5. AEGL-1 Va lues for Aldicarb........................................................................................... ......................16 8

TABLE 6. AEGL-2 Va lues for Aldicarb........................................................................................... ......................17 9

TABLE 7. AEGL-3 Va lues for Aldicarb........................................................................................... ......................18 10 TABLE 8. Summary of AEGL Values fo r Aldi carb.................................................................................. ............18 11

TABLE 9. Standards and Gu idelines fo r Aldi carb................................................................................ ................19 12 13ALDICARB NAC Proposed 1: June 2009/ Page 6 of 33

SUMMARY 1
2 Technical aldicarb (CAS No. 116-06-3) is a crystalline solid N -methyl carbamate 3 pesticide with a slight sulfur smell. Aldicarb is registered as a systemic insecticide, acaricide, 4 and nematocide for use on a wide range of crops. Aldicarb, sold under the trade name TemikTM, 5 is a granular formulation containing 5, 10, or 15% active ingredient. TemikTM is usually applied 6 below the soil surface for absorption by plant root systems. Moisture is required to release the 7 active ingredient from the granules. Two so il degradates, aldicarb sulfoxide and aldicarb 8 sulfone, retain some of the toxic property of the parent compound. Approximately 4.5 million 9 pounds of aldicarb are used annually in the United States. 10
11 Aldicarb and other carbamate pesticides are neurotoxic in that they are inhibitors of 12 cholinesterase enzymes. Inhibition of acetylcholinesterase, responsible for termination of the 13 biological activity of the neurotransmitter acetylcholine at various nerve endings, results in 14 sustained stimulation of electrical activity. Depending on concentration administered, signs 15 following acute exposure of rats to aldicarb ma y include facial fasciculations, tremors, 16 salivation, lacrimation, gasping and convulsions . In humans, inhibition of erythrocyte 17 acetylcholinesterase activity, the form found in human erythrocytes, is used as a biomarker of 18 exposure to methyl carbamates. No inhalation studies involving human subjects were located. 19 Given that methyl carbamate pesticides do not ha ve a port of entry effect, are expected to be 20 rapidly absorbed, and do not require activation, relative acetylcholinesterase activity inhibition 21 levels measured from oral studies with humans and adult and juvenile rodents are applicable for 22 determination of interspecies and intraspecies uncertainty factors. 23
24
No human data relevant to derivation of AEGL values were found. No animal studies 25
were located that addressed effects of aldicarb consistent with the definition of the AEGL-1. 26 Therefore, AEGL-1 values are not recommended. 27
28
No studies that addressed effects consistent with the definition of the AEGL-2 were 29 found. The concentration-response curve for lethality in rats is steep as shown by the studies of 30 Risher et al. (1987) and UCC (1985). Mortality went from 0 to 83% with the doubling of 31 exposure duration (Risher et al. 1987). Therefore, according to Standard Operating Procedures 32 (NRC 2001), the AEGL-2 values were derived by dividing the AEGL-3 values by 3. 33
34 The study with aldicarb aerosol (UCC 1985) was chosen as the key study for AEGL-3 35 development. The 4-hour study used a sufficient number of rats and five concentrations. The 36
calculated 4-hour BMCL 05 is 0.97 mg/m 3 and the BMC 01 is 1.9 mg/m 3 . The 4-hour BMCL 05 was 37 chosen as the threshold for lethality. The 4-hour 0.97 mg/m 3 value was divided by inter- and 38 intraspecies uncertainty factors of 2 and 3, resp ectively, for a total of 6. The aldicarb-specific 39 interspecies inhalation uncertainty factor of 2 was based on differences in modeled values for red 40 blood cell acetylcholinesterase activity inhibition between rats and humans (U.S. EPA 2007b). 41 The intraspecies uncertainty factor of 3, derived by U.S. EPA (2007b) for the related methyl 42 carbamates, oxamyl and methomyl, was applied. The intraspecies uncertainty factor was based 43 on comparative brain acetylcholinesterase activity inhibition in juvenile and adult rats 44 administered the pesticides by the oral route. The combined uncertainty factor is 6. No 45 information was available for time-scaling. Values were time-scaled (C n x t = k) from the 4-hour 46ALDICARB NAC Proposed 1: June 2009/ Page 7 of 33

data point using n values of 3 and 1 for extra polation to shorter and longer exposure durations, 1 respectively (NRC 2001). 2
3
The calculated values are listed in the table below. 4
5
TABLE ES 1. Summary of AEGL Values for Aldicarb

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 Insufficient data

AEGL

B 2 (Disabling) 0.16 mg/m 3 0.11 mg/m 3 0.087 mg/m 3 0.053 mg/m 3 0.027 mg/m 3 AEGL-3 values divided by 3

AEGL

B 3 (Lethal) 0.47 mg/m 3 0.32 mg/m 3 0.26 mg/m 3 0.16 mg/m 3 0.081 mg/m 3 BMCL 05 for lethality –
rat - calculated from UCC (1985) data Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 6
1. INTRODUCTION 7
8 Technical aldicarb (CAS No. 116-06-3) is a white crystalline solid with a slight sulfur 9 smell (AIHA 1993). Aldicarb is registered for use as a systemic insecticide, acaricide, and 10 nematocide on a wide range of crops (O’Neil et al. 2001; U.S. EPA 2007a). Aldicarb is sold in 11 the United States under the trade name TemikTM, a gr anular formulation of aldicarb containing 5, 12 10, or 15% a.i. (active ingredient by weight) aldicarb in corn cob grit or gypsum; 13 dichloromethane may be present up to 0.2% (UCC 1986). TemikTM is usually applied below the 14 soil surface for absorption by plant root systems. Moisture is required to release the active 15 ingredient from the granules. Two soil degradat es, aldicarb sulfoxide and aldicarb sulfone retain 16 anti-cholinesterase activity. Chemical and physical properties are listed in Table 1. 17
18 Aldicarb is manufactured commercially by the reaction of methyl isocyanate with 2- 19 methyl-2-(methylthio) propionaldehyde (HSDB 2005). According to U.S. EPA (2007a), 20 approximately 4.5 million pounds of aldicarb are used annually in the United States, primarily on 21 cotton (64%). Other high use crops include peanut s, potatoes, sugar, beets, and citrus. World 22 production figures are not available (IPCS 1991). Al dicarb is a restricted use pesticide and can 23 be applied only by certified applicators. 24
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TABLE 1. Chemical and Physical Properties

Parameter Value Reference Synonyms 2-Methyl-2-(methylthio)-propanal O

- [(methylamino)carbonyl]oxime; 2- methyl-2-(methylthio)- propionaldehyde O

- (methylcarbamoyl)oxime; TemikTM O’Neil et al. 2001

Chemical formula C 7 H 14 N 2 O 2 S O’Neil et al. 2001 Molecular weight 190.27 O’Neil et al. 2001 CAS Reg. No. 116-06-3 O’Neil et al. 2001 Physical state Aldicarb: white crystalline solid Temik 15G pesticide: brown to black crystals AIHA 1993
UCC 1986

Solubility in water Soluble, 6 g/L at 25oC O’Neil et al. 2001; AIHA 1993 Vapor pressure, saturated 0.0001 mm Hg at 25oC AIHA 1993 Vapor density, saturated (air =1) 0.1 ppm at 25oC AIHA 1993 Liquid density (water =1) 1.195 at 25oC AIHA 1993 Melting point 99-100 oC O’Neil 2001 Boiling point Decomposes AIHA 1993 Flammability limits in air No data Conversion factors 1 ppm = 7.78 mg/m 3 1 mg/m 3 = 0.13 ppm Calculated

1
2
2. HUMAN TOXICITY DATA 3
4 No inhalation studies other than descriptions of accidental exposures were located. 5 These reports lacked information on concentrations and exposure durations. Symptoms of 6 cholinesterase activity inhibition have been observed following ingestion of food containing 7 aldicarb or aldicarb degradates (HSDB 2005). 8
9 A double-blind human oral dosing study incl uded 47 volunteers (38 men and 9 women) 10 (Wyld et al. 1991, reviewed in U.S. EPA 1992). Groups of 4-8 males were administered doses 11 of 0, 0.01, 0.025, 0.05, 0.06 (one subject), or 0.075 mg/kg of aldicarb in orange juice during a 12 light breakfast. Females received 0, 0.025, or 0.05 mg/kg under the same protocol. Clinical 13 signs and symptoms were observed by trained res earchers. Blood plasma and erythrocytes were 14 analyzed for cholinesterase activity at 1, 2, 4, 6, 8, and 21 hours after dosing; these values were 15 compared with each subject’s pre-exposure values taken at -16 and -3 hours and immediately 16 predose. Peak effects were noted at 1 hour after the dose. Males, but not females developed 17 symptoms consistent with acetylcholinesterase activity inhibition. In males, erythrocyte 18 cholinesterase activity at one hour was inhibited by 3.8, 12, 29, and 38% in the 0.01, 0.025, 19 0.050, and 0.075 mg/kg dose groups, respectively. In females, the mean inhibition at one hour 20 post-dose was 20% at 0.025 mg/kg and 36% at 0.050 mg/kg. The U.S. EPA noted that the 21 erythrocyte cholinesterase activity inhibition may have been underestimated due to lack of 22 measurement of some membrane-bound enzyme. The U.S. EPA considered the LOAEL 0.25 23 mg/kg based on sweating in one male. The NOAEL was 0.01 mg/kg. However, the Human 24 Studies Review Board (HSRB 2006) considered acet ylcholinesterase activity inhibition a more 25 reliable endpoint than clinical signs. The HSRB (2006) reviewed the study and found it met 26 ethical considerations (required by EP A’s Human Subjects Protection Rule). 27
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3. ANIMAL TOXICITY DATA 1
2 Using protocols that were standard at the tim e, aldicarb was tested for dermal and ocular 3 irritation in the rabbit, and dermal sensitizati on in the guinea pig (IPCS 1991). Aldicarb was not 4 irritating to the skin (500 mg moistened in saline solution) or eye (0.1 mL of a 25% suspension 5 in propylene glycol). There was no sensitization response in male guinea pigs. Dermal LD 50 6 doses in rats range from 2.5 to 3 mg/kg (Risher et al. 1987). Ranges for oral LD 50 values for 7 aldicarb, aldicarb sulfoxide, and aldicarb su lfone in the rat are 0.62-1.23, 0.49-1.13, and 20-25 8 mg/kg body weight, respectively (IPCS 1992). The L OAEL for acute oral neurotoxicity in rats 9 was 0.05 mg/kg/day based on 23% and 10% i nhibition of whole blood and erythrocyte 10 cholinesterase activity, respectively in female rats (U.S. EPA 2005). 11
12 3.1. Acute Toxicity 13
14 Early inhalation studies were summarized in several reviews including Risher et al. 15 (1987) and IPCS (1991). These summaries lacked details of exposure conditions and number 16 and sex of animals. Carpenter and Smyth (1965) conducted inhalation studies with rats, mice, 17 and guinea pigs. A concentration of 200 mg/m 3 aldicarb dust was lethal to all species within 5 18 minutes. Rats and mice were more sensitive than guinea pigs. Rats survived a dust 19 concentration of 6.7 mg/m 3 for 15 minutes, but five of six rats died after a 30-minute exposure. 20 All rats survived a saturated vapor concentration (not further described) for 8 hours. Two of six 21 rats survived an 8-hour exposure to an aerosol concentration of 7.6 mg/m 3 (Weil and Carpenter 22 1970). Studies are summarized in Table 2. 23
24 Groups of five male and five female Sprague -Dawley rats inhaled an aerosol of aldicarb 25 solution in dichloromethane for 4 hours (UCC 1985). Measured concentrations of aldicarb were 26 0.82, 2.0, 6.0, 8.7, and 46.3 mg/m 3 . The respective mean dichloromethane concentrations for the 27 same exposures were 43, 94, 183, 25, and 100 mg/m 3 . The dichloromethane concentrations were 28 considered low in toxicity compared to aldicarb [LC 50 values of 57,000-60,000 mg/m 3 in rats and 29 mice (NTP 1986)]. The mass median aerodynamic diameter ranged from 2.0 to 3.8 μ. Ataxia 30 and tremors were seen at all concentrations during exposure. Additional signs of hypoactivity, 31 increased respiration rate, lacrimation, exophthalmos, and periocular encrustation were observed 32 at the two higher concentrations. Mortalities were seen at all concentrations except the lowest, 33 0.82 mg/m 3 . Mortalities in males were 0/5, 0/5, 3/5, 5/5, and 5/5, respectively. Mortalities in 34 females were 0/5, 1/5, 2/5, 5/5, and 5/5, respectively. The 4-hour LC 50 was 3.9 mg/m 3 with 35 confidence limits of 2.8-5.5 mg/m 3 . At necropsy, discoloration of the lungs, perinasal 36 encrustation and staining and eye abnormalities were observed. Survivors initially lost body 37 weight, but body weight gains were observed by the end of the 14-day post-exposure observation 38 period. 39
40 In studies conducted by Union Carbide Corporation from 1973-1977 (summarized in 41 UCC 1992), rats were also exposed to the degradate aldicarb sulfone (Temik ® sulfone). An 42 aerosol of 120 mg/m 3 , 0.5% in distilled water, for 8 hours failed to induce lethality in six rats. 43
The LC 50 for a 4-hour inhalation exposure to aldicarb sulfone dust was 420 mg/m 3 . However, in 44 the same summary report, a 4-hour LC 50 for rats of 120 mg/m 3 was reported. Signs observed 45 during exposure were indicative of cholinesterase activity inhibition and, at necropsy, congestion 46 and hemorrhage of the lungs were noted. 47ALDICARB NAC Proposed 1: June 2009/ Page 10 of 33

1
Additional aerosol studies with aldicar b sulfone were conducted (UCC 1992). An 2 aerosol of 6.9% technical aldicarb sulfone in dimethyl sulfoxide (approximately 2 mg/L) was 3 lethal to half of tested rats in 47.6 minutes whereas an aerosol of 0.5% in DMSO (approximately 4 184 mg/m 3 ) was lethal to one of six rats in 4 hours. An aerosol of 0.5% in water (approximately 5 148 mg/m 3 ) was not lethal to any of six rats in 4 hours. Signs of cholinesterase activity 6 inhibition were seen during exposure. 7
8
9
TABLE 2. Acute Toxicity of Aldicarb to Rats

Concentration (mg/m 3 ) Exposure Duration Effect/LC 50 (mg/m 3 ) Reference

Dust

6.7 15 minutes
30 minutes Survival: 6 of 6 mortality: 5 of 6 Risher et al. 1987

Liquid Aerosol

0.82 a

2.0
6.0
8.7
46.3
3.9 4 hours No mortality mortality: 1 of 10 mortality: 5 of 10 mortality: 10 of 10 mortality: 10 of 10
calculated LC 50 UCC 1985

Vapor Saturated vapor No mortality – 8 hours

─ Risher et al. 1987

a Aldicarb aerosol solutions in dichloromethane. 10
11 3.2. Repeat-Exposure Studies 12
13 No repeat-exposure inhalation studies with aldicarb were located. In a nine-day repeat14 exposure inhalation study, groups of six male and six female Wistar rats inhaled 0, 1.4, 6, or 18 15 mg/m 3 of the metabolite aldicarb sulfone as particulates for 6 hours/day for 9 days (UCC 1977; 16 U.S. EPA 1992). The test material was a 75% wettable powder. “Dust clouds” were generated 17 by a baffled dust feed through which air was passed at 20 liters/minute. Airborne dust 18 concentrations were measured gravimetrically. Exposure took place in a 120-L Plexiglas 19 chamber. Body weight was measured and liv er, kidney and brain were weighed. Plasma, 20 erythrocyte, and brain were assayed for cholinesterase activity levels. No clinical signs were 21 evident in rats inhaling 1.4 or 6 mg/m 3 ; there were no effects on body or organ weight. Rats 22 inhaling 18 mg/m 3 displayed tremor and salivation. Body weight was decreased and blood 23 cholinesterase activity was significantly inhibited at 19 hours following termination of the 24 experiment (data not presented). Correction for percent active ingredient in the test material was 25
not mentioned. 26
27 3.3. Neurotoxicity 28
29 Acute toxicity studies showed that aldicarb is neurotoxic. Ataxia and tremors were 30 observed in rats inhaling aldicarb for 4 hours (UCC 1985). See Section 4.2 for mechanism of 31 toxicity of N -methyl carbamates. 32
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3.4. Developmental/Reproductive Toxicity 1
2 No inhalation studies were conducted that addressed the developmental or reproductive 3 toxicity of aldicarb. Reproductive and developmental toxicity studies that used the oral route of 4 administration were reviewed by Risher et al. (1987), IPCS (1991), and HSDB (2005). In 5 developmental studies with the rat and rabbit, aldicarb showed neither developmental toxicity 6 nor teratogenicity. Fetotoxicity manifest as reduced litter weight was apparent at maternally 7 toxic doses in Sprague Dawley rats (0.5 mg/kg/ day from gestation days 6-15). No congenital 8 malformations were observed in offspring of rats administered aldicarb in the diet at 9 concentrations up to 1.0 mg/kg throughout pregnanc y, or in offspring of Dutch Belted rabbits 10 administered aldicarb by gavage at doses up to 0.50 mg/kg on days 7 through 27 of gestation. 11 No reproductive parameters were affected in any of three generations of rats fed aldicarb in the 12 diet at doses up to 0.7 mg/kg body weight per day. 13
14 3.5. Genotoxicity 15
16 The genetic toxicology of aldicarb was re viewed by the National Toxicology Program 17 (NTP 1979) and the International Program on Chemical Safety (IPCS 1991). Bacterial assays 18 were conducted with and without metabolic activation. Assay results were negative for 19 mutagenicity in Salmonella typhimurium (TA97, TA100, TA1535, and TA1537) and 20
Escherichia coli WP2 uvrA. In an in vitro test for gene mutation in mouse L5178Y lymphoma 21 cells, results were inconclusive in the absence of metabolic activation, but aldicarb induced 22 mutations in the presence of S9 mix. Assays with aldicarb were negative for chromosome and 23 chromatid breaks in human peripheral lymphocytes, but a significant increase in sister chromatid 24 exchanges was seen in the same system. In in vivo clastogenicity assays, intraperitoneal 25 injections with aldicarb induced damage in bone marrow cells in rats, but not in mice. There 26
was no increased incidence of dominant lethal mutations in male rats treated with aldicarb in the 27 diet and mated with untreated virgin females. 28
29 3.6. Chronic Toxicity/Carcinogenicity 30
31
Technical aldicarb was tested for chronic toxi city and carcinogenicity in two-year dietary 32 studies with male and female F344 rats and B6C3F1 mice (NTP 1979). Groups of 50 rats and 50 33
mice of each sex were administered aldicarb in th e diet at concentrations of 0, 2, or 6 ppm for 34 103 weeks and then observed for an additional 0 to 2 weeks. Body weight and survival were 35 unaffected in both rats and mice. Dosed mice appeared hyperactive. No tumors occurred in 36 either rats or mice at incidences that could clearly be related to administration of aldicarb. 37
38 Because the cholinesterase activity inhibition caused by aldicarb exposure is transient, 39
the U.S. “EPA had concluded that the cumulative risks associated with the N -methyl carbamate 40 pesticides are below the Agency’s level of concern” (U.S. EPA 2007a). 41
42 3.7. Summary 43
44 Acute inhalation lethality studies were conducted primarily with the rat. The 4-hour LC 50 45 value for an aerosol of aldicarb in dichloromethane was 3.9 mg/m 3 (UCC 1985). During 46 exposure rats showed signs of cholinesterase activity inhibition. No rats died following a 15- 47ALDICARB NAC Proposed 1: June 2009/ Page 12 of 33

minute exposure to 6.7 mg/m 3 aldicarb dust, but mortality was 100% after 30 minutes (Risher et 1 al. 1987). No details were available in the latter study. 2
3 Although considered highly acutely toxic, ev idence indicates aldicarb does not affect 4 fetal development, impair reproductive performance, conclusively induce genotoxic effects, or 5 produce significant subchronic or chronic effects including cancer. 6
7
4. SPECIAL CONSIDERATIONS 8 4.1. Metabolism and Disposition 9
10
Inhalation studies with aldicarb that addressed metabolism were not located. The N

11 methyl carbamates do not have a port of entry eff ect, are expected to be rapidly absorbed, and do 12 not require activation (U.S. EPA 2007b). Oral absorption is rapid and nearly complete (Risher et 13 al. 1987; IPCS 1991; AIHA 1993). The metabolic fate of aldicarb is similar in all species 14 examined (IPCS 1992). Clinical signs in rats appear at approximately 5 minutes after 15 administration. Unlike some organophosphate pesticides that are metabolized by A-esterases 16 which show great inter-individual variation, the metabolism of the carbamate pesticide aldicarb 17 involves both hydrolysis of the carbamate ester (t o aldicarb oxime) and oxidation of the sulfur to 18 the sulfoxide and sulfone derivatives. Hydrolysis is a minor pathway and results in compounds 19 with little or no insecticidal activity (aldicarb oxime and aldicarb nitrile). Aldicarb is S-oxidized 20 by flavin-containing monooxygenases to form aldi carb sulfoxide (Tang et al. 2006). Aldicarb 21 sulfoxide is slowly degraded by both oxidative and hydrolytic mechanisms to yield the 22 corresponding aldicarb sulfone and sulfoxide oxime. The sulfoxide and sulfone metabolites are 23 active cholinesterase inhibitors. Excretion of these metabolites takes place via the urine (80- 24 90%) within the first 24-hours post-exposure. The major urinary metabolites are aldicarb 25 sulfoxide (40% of the dose) and aldicarb sulfoxi de oxime and nitriles (over 30% of the dose). 26 Only a small amount is expired as CO 2 . Half-lives in rats and humans following oral dosing are 27 1.1 and 1.7 hours, respectively. Absorption through the skin can be extensive, and dermal LD 50 28 doses in rats range from 2.5 to 3 mg/kg (Risher et al. 1987). 29
30 4.2. Mechanism of Toxicity 31
32
Aldicarb is an N -methyl carbamate insecticide. The mode of action of carbamate 33 pesticides involves cholinesterase inhibiti on (U.S. EPA 2007b; Costa 2008). Carbamic acid 34 esters attach to the serine hydroxyl group of the active site of acetylcholinesterase, the enzyme 35 responsible for the destruction and termination of the biological activity of the neurotransmitter 36 acetylcholine. When unbound acetylcholine accumulates at the cholinergic nerve endings, there 37 is continual stimulation of electrical activity. Th e resulting signs of toxicity from stimulation of 38 the muscarinic receptors of the parasympathetic autonomic nervous system are manifest as 39 increased secretions, bronchoconstriction, miosis, gastrointestinal cramps, diarrhea, urination, 40 and bradycardia. Stimulation of the parasympathetic junctions of the autonomic nervous system 41 as well as the junctions between nerves and muscles cause tachycardia, hypertension, muscle 42 fasciculation, tremors, muscle weakness, and flaccid paralysis. Signs and symptoms resulting 43 from effects on the central nervous system include restlessness, emotional lability, ataxia, 44 lethargy, mental confusion, loss of memory, generalized weakness, convulsions, cyanosis, and 45 coma. Inhibition of acetylcholinesterase activity is transient and rapidly reversible (minutes to 46 hours) because there is rapid reactivation of the carbamylated enzyme in the presence of water. 47ALDICARB NAC Proposed 1: June 2009/ Page 13 of 33

Maximum inhibition typically occurs between 15 and 45 minutes after exposure. The major 1 metabolites of aldicarb, aldicarb sulfoxide and aldicarb sulfone are also cholinesterase inhibitors 2 (Risher et al. 1987; U.S. EPA 2007a). Aldicarb sulf oxide is considered to have similar potency 3 to the parent in terms of toxicity, while aldicarb sulfone is less potent. At the maximally 4 tolerated oral doses of 0.18, 0.26, and 0.35 mg/kg for PND 17, PND 27, and adult rats, brain 5 cholinesterase activity was 30-40% of the control value and blood cholinesterase activity was 6 <10% of the control value (Moser 1999). 7
8 Carbamates also inhibit butylcholinesterase, the primary form of cholinesterase found in 9 blood plasma. The toxicological significance of butylcholinesterase activity inhibition is 10 unknown. Acetylcholinesterase is the primary form of cholinesterase found in erythrocytes and 11 is present at neuromuscular and nerve-nerve junctions. A review of studies submitted to U.S. 12 EPA (2007b) for pesticide registration show that clinical signs and behavioral effects are not 13 evident below 10% cholinesterase activity inhibition. Due to human variability, it is difficult to 14 measure inhibition of <20% (U.S. EPA 2000) . At greater than 30% erythrocyte 15 acetylcholinesterase activity inhibition or 50% pl asma activity inhibition, workers are withdrawn 16 from pesticide application areas (U.S. EPA 2000; ACGIH 2008). Other enzymes such as 17 carboxylesterases are non-target enzymes to which cholinesterase activity inhibitors such as 18 aldicarb may bind. 19
20 4.3. Structure-Activity Relationships 21
22 Organophosphate and carbamate pesticides have a common mode of action (Costa 2008). 23 Compared to organophosphate ester pesticides, the carbamic acid esters are poor substrates for 24 cholinesterase-type enzymes. The carbamic acid esters which attach to the reactive site of acetyl 25 cholinesterase undergo fairly rapid hydrolysis, i.e., the carbamylated (inhibited) enzyme is 26 decarbamylated with the generation of the free, active enzyme. 27
28 Information is available on the relative oral toxicity of three carbamate pesticides (HSRB 29 2006; U.S. EPA 2007b). Aldicarb is considered the most toxic of the N -methyl carbamates. 30 Based on an assigned potency of 1 for oxamyl, aldicarb is considered 4 times more toxic by the 31 oral route. The endpoints for relative oral toxi city were brain and erythrocyte cholinesterase 32 activity inhibition in the rat and erythrocyte acetylcholinesterase activity inhibition in humans. 33 Raw data on erythrocyte cholinesterase activity inhibition were not provided for all three 34 chemicals, but relative toxicity can be derived from the benchmark doses (BMD 10 and BMDL 10 ) 35 calculated by U.S. EPA (2007b) from a range of oral doses (Table 3). For methomyl and 36 oxamyl, rat data on brain and erythrocyte cholinesterase activity are from McDaniel et al. 37 (2007). 38
39

TABLE 3. Adult Rat and Human BMD 10 and BMDL 10 Values for Cholinesterase Activity Inhibition for 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 1.0 BMD 10 : 0.204 0.8 BMD 10 : 0.040 1.6ALDICARB NAC Proposed 1: June 2009/ Page 14 of 33

BMDL 10 : 0.331 BMDL 10 : 0.112 BMDL 10 : 0.028 Oxamyl BMD 10 : 0.165
BMDL 10 : 0.127 0.9 BMD 10 : 0.278
BMDL 10 : 0.158 0.8 BMD 10 : 0.083
BMDL 10 : 0.068 2.4

Benchmark dose data for brain cholinesterase data for aldi carb and oxamyl are presented as the average of male and 1
female rat values. 2
The BMDL 10 for 10% brain cholinesterase activity inhibition wa s used as the point of departure for U.S. EPA 3 (2007b) risk assessment. 4 Source: Table 1.B-9, U.S. EPA 2007b. 5 6 The major metabolites of aldicarb also have anticholinesterase activity. Compared to 7 oxamyl’s potency of 1, aldicarb, aldicarb sulfone, and aldicarb sulfoxide were assigned potencies 8 of 4, 3.44, and 3.68, respectively (U.S. EPA 2007b). These potencies were based on molecular 9 weight conversions from aldicarb. 10
11
4.4. Other Relevant Information 12 4.4.1. Species Variability 13
14 Inhalation studies with usable data were conducted only with rats. The extent of 15 hydrolysis of carbamate ester insecticides varies among species, ranging from 30 to 95%, and is 16 chemical specific (Costa 2008). Baseline erythrocyte acetylcholinesterase activity is higher in 17 humans than in other species (Ellin 1981). The U.S. EPA Office of Pesticide Programs (Taylor 18 and Reaves 2006) compared erythrocyte cholinesterase activity inhibition in human and adult rat 19 oral dosing studies following equivalent oral dos es. Enzyme activity was assayed at 1 hour post20 dose in humans and 0.75 hours post-dose in rats (Table 4). 21
22
TABLE 4. Comparison of Erythrocyt e Acetylcholinesterase Activity Inhibition in Rats and Humans

Oral Dose Species 0.01 mg/kg 0.025 mg/kg 0.05 mg/kg Human (acute)

Males
Females 3.8%

─ 12%
20% 29%
36% Rat (acute)

Males
Females ─

─ ─

─ ─ 10% Rat (subchronic)

Males
Females ─

─ ─

─ 32%
24% Source: Taylor and Reaves 2006. 23
24 The U.S. EPA Office of Pesticide Programs (2007b) compared the toxicity (endpoint 25 cholinesterase activity inhibition) of three N -methyl carbamate pesticides, oxamyl, methomyl, 26 and aldicarb, using oral dosing in humans and in juvenile and adult rats. Most data were 27 available for oxamyl which was used as the index chemical. Benchmark doses were calculated 28 for brain and erythrocyte cholinesterase activity inhibition in juvenile and adult rats and 29 erythrocyte cholinesterase activity inhibition in humans. Based on the comparative erythrocyte 30 acetylcholinesterase activity inhibition for equal oral doses in adult rats and humans, the U.S. 31 EPA calculated a chemical-specific interspecies uncer tainty factor for aldicarb of 2. For most of 32
the N -methyl carbamate pesticides, the interspecies uncertainty factor is used for all routes of 33

exposure. 34
35ALDICARB NAC Proposed 1: June 2009/ Page 15 of 33

4.4.2. Susceptible Populations 1
2 Humans are known to vary by gender, age, and genetic make-up in sensitivity to 3 cholinesterase inhibitors. The erythrocyte acetylcholinesterase activity of adults (153±24 4 activity units; acetylthiocholine substrate) is greater than that of healthy newborn infants (97±15 5 activity units) by a factor of 1.6 (Herz et al. 1975) . Developmental neurotoxicity studies showed 6 that protection of the rat dam against cholinesterase activity inhibition is protective against pup 7 acetylcholinesterase activity inhibition in utero

. 8
9 The U.S. EPA (2007b) identified infants and juveniles as the population most susceptible 10 to the toxicity of carbamate pesticides. In the absence of human data, the relative sensitivity to 11 cholinesterase activity inhibition of adult and juvenile rats to aldicarb can be used as a surrogate 12 for a comparison of human adult and infant sensitivity. Using the oral route of exposure, Moser 13 (1999) evaluated age-related differences in sensitivity to aldicarb among preweanling (post-natal 14 day 17 [PND 17]), postweanling (PND 27) and adult (PND 70) Long Evans rats of both sexes. 15 Control data for cholinesterase activity (nmol 3 H-labeled acetylcholine iodide 16 hydrolyzed/min/mg/tissue) were (a) male brain: PND 17, 5.9; PND 27, 5.8; adult 7.0; male 17 blood: PND 17, 0.44; PND 27; 0.49, adult, 0.43; (b) female brain: PND 17, 4.9, PND 27, 6.1; 18 adult 6.9; female blood: PND 17, 0.50; PND 27, 0.52; adult, 0.59. Range-finding studies 19 determined the maximally tolerated doses (0.18, 0.26, and 0.35 mg/kg in the PND 17, 27, and 70 20 groups, respectively) and time of peak effect of blood cholinesterase activity inhibition, 1 hour in 21 all age groups. The U.S. EPA standard functional observational battery (FOB) and motor 22 activity observations were carried out. Pre-weanling rats were twice as sensitive to aldicarb as 23 adult rats, and dose-response data for brain acetylcholinesterase activity inhibition followed a 24 similar pattern of age-related differences. Blood cholinesterase activity inhibition measured with 25 a radiometric assay was greater than that of brain, with little age difference. At similar levels of 26 brain cholinesterase activity inhibition, young rats generally showed fewer signs of toxicity as 27 indicated by neurobehavioral parameters and motor activity than adult rats. 28
29 The U.S. EPA evaluated the relative sensitivity of juvenile and adult rats to N -methyl 30 carbamate pesticides including aldicarb (U.S. EPA 2007b). The U.S. EPA calculated benchmark 31 doses for brain cholinesterase activity inhibition in PND 17 and adult rats. The BMD 10 and 32
BMDL 10 in post-natal day 17 rats were 0.017 and 0.016 mg/kg, respectively. The BMD for adult 33 rats was 0.033 mg/kg. Based on comparative brain acetylcholinesterase activity inhibition in 34 aldicarb-treated post-natal day 17 juvenile rats and adult rats, the U.S. EPA calculated a Food 35 Quality Protection Act (FQPA) uncertainty factor for children of 2.0. This uncertainty factor 36 corresponds to an AEGL intraspecies uncertainty factor. A recovery half-life for brain 37 cholinesterase activity was not available for rats, but recovery was complete in juvenile and adult 38 rats by 24 hours (Moser 1999). 39
40 4.4.3. Concentration-Exposure Duration Relationship 41
42 No data were available for evaluating the relationship between ambient concentrations of 43 aldicarb and exposure duration for a single endpoint . The concentration-time relationship for a 44 single endpoint for many irritant and systemica lly acting vapors and gases may be described by 45
C n x t = k (ten Berge et al. 1986). In the absence of empirical data, the time scaling factors of n 46ALDICARB NAC Proposed 1: June 2009/ Page 16 of 33

= 3 and n = 1 are used to scale to shorter and longer exposure durations, respectively (NRC 1 2001). 2
3 4.4.4. Concurrent Exposure Issues 4
5 Dermal absorption may occur. Dermal LD 50 values in rats range from 2.5 to 3.0 mg/kg 6 (Risher et al. 1987). Concurrent exposure to other N -methyl carbamates in proportion to their 7 potency indicates that they follow a dose-additive model of brain cholinesterase inhibition 8 (Padilla et al. 2006; U.S. EPA 2007b). 9
10
5. DATA ANALYSIS FOR AEGL-1 11 5.1. Summary of Human Data Relevant to AEGL-1 12
13 No human inhalation studies were located in the available literature. No occupational 14 monitoring data were presented by U.S. EPA (2007a). 15
16 5.2. Summary of Animal Data Relevant to AEGL-1 17
18
No inhalation studies were located that addre ssed signs consistent with the definition of 19
the AEGL-1. 20
21
5.3. Derivation of AEGL-1 22
23 No human or animal studies were located that addressed symptoms and signs consistent 24 with the definition of the AEGL-1. Therefore, AEGL-1 values are not recommended (Table 5). 25
26

TABLE 5. AEGL-1 Values for Aldicarb

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. 27
28
6. DATA ANALYSIS FOR AEGL-2 29 6.1. Summary of Human Data Relevant to AEGL-2 30
31 No human inhalation studies relevant to development of AEGL-2 values were located in 32
the available literature. 33
34 6.2. Summary of Animal Data Relevant to AEGL-2 35
36 No animal studies relevant to deriving AEGL-2 values were located in the available 37 literature. All studies reviewed in Section 3.1 involved mortality. 38
39
6.3. Derivation of AEGL-2 40
41
No human or animal data on an aldicarb concentration that would result in effects 42
consistent with the definition of AEGL-2 were located. Therefore, consistent with Standard 43 Operating Procedures (NRC 2001), the AEGL-2 va lues were derived by dividing the AEGL-3 44ALDICARB NAC Proposed 1: June 2009/ Page 17 of 33

values by 3. This approach is justified when there is a steep concentration-response curve. As 1 shown by Risher et al. (1987) mortality went from 0 to 83% with the doubling of exposure 2 duration. In the study reported by UCC (1985) mortality went from 10% at 2.0 mg/m 3 to 50% 3 when concentration was increased 3-fold (6 mg/m 3 ). AEGL-2 values are summarized in Table 6. 4 Calculations are in Appendix A and a category gr aph of the toxicity data in relation to AEGL 5 values is in Appendix B. 6
7

TABLE 6. AEGL-2 Values for Aldicarb

10-min 30-min 1-h 4-h 8-h 0.16 mg/m 3 0.11 mg/m 3 0.087 mg/m 3 0.053 mg/m 3 0.027 mg/m 3

8
9
7. DATA ANALYSIS FOR AEGL-3 10 7.1. Summary of Human Data Relevant to AEGL-3 11
12
No human inhalation studies relevant to derivation of AEGL-3 values were located in the 13
available literature. 14
15 7.2. Summary of Animal Data Relevant to AEGL-3 16
17 A study with aldicarb dust lacked details of exposure and was of a short duration (Risher 18 et al. 1987). Vapor concentrations high enough to induce mortality were not attained in a second 19 study reported by Risher et al. (1987). One 4- hour study with aldicarb administered as an 20 aerosol in dichloromethane presented concentration-response information (UCC 1985). In that 21 study, mortality in rats inhaling 0.82, 2.0, 6.0, 8.7, or 46.3 mg/m 3 was 0/10, 1/10, 5/10, 10/10, 22 and 10/10, respectively. 23
24
7.3. Derivation of AEGL-3 25
26 The study with aldicarb aerosol was chosen as the key study for AEGL-3 development 27 (UCC 1985). The 4-hour study used a sufficient numbe r of rats and five concentrations. The 28
calculated 4-hour BMCL 05 is 0.97 mg/m 3 and the BMC 01 is 1.9 mg/m 3 (Appendix C). The 29 NAC/AEGL Committee generally uses the BMCL 05 as the estimate at which lethality is not 30 likely to be observed (NRC 2001). The 4-hour 0.97 mg/m 3 value was divided by inter- and 31 intraspecies uncertainty factors of 2 and 3, respectively, for a total of 6. U.S. EPA (2007b) 32 derived an uncertainty factor of 2 for aldicarb based on differences in modeled values for red 33 blood cell acetylcholinesterase activity inhibition between rats and humans (See section 4.4.1). 34 Based on comparative brain cholinesterase activity inhibition in post-natal day 17 juvenile rats 35 and adult rats, the U.S. EPA calculated an uncertainty factor of 2 to protect sensitive young (See 36 section 4.4.2). In keeping with intraspecies uncertainty factors applied to the related carbamate 37 pesticides, oxamyl and methomyl, the intraspecies uncertainty factor was raised to 3. The 38 combined uncertainty factor is 6. No differences were found in sensitivity between male and 39 female rats (UCC 1985). Values were time-scaled (C n x t = k) from the 4-hour data point using n 40 values of 3 and 1 for extrapolation to shorter and longer exposure durations, respectively (NRC 41 2001). Values are summarized in Table 7, calculations are in Appendix A, and a category graph 42 of the toxicity data in relation to AEGL values is in Appendix B. 43ALDICARB NAC Proposed 1: June 2009/ Page 18 of 33

1

TABLE 7. AEGL-3 Values for Aldicarb

10-min 30-min 1-h 4-h 8-h 0.47 mg/m 3 0.32 mg/m 3 0.26 mg/m 3 0.16 mg/m 3 0.081 mg/m 3

2 When AEGL-3 values are based on a 4-hour or longer exposure duration, the 10-minute 3 value is usually set equal to the 30-minute value. However, the 15-minute value of 6.7 mg/mg 3 4 for aldicarb dust that resulted in no mortality in rats can be used as justification for not setting 5 the 10- and 30-minute values equal. Application of a total uncertainty factor of 6 to the 6.7 6 mg/m 3 value results in a 15-minute value of 1.1 mg/m 3 . The 15-minute value time-scaled to 10 7 minutes (n = 3) with application of an uncertainty factor of 6 is 1.3 mg/m 3 , a value considerably 8 larger than that derived from the 4-hour data. 9
10 The derived AEGL-3 values are based on an aerosol which may be less toxic than the 11 dust. Because the 15-minute value derived from dust is larger than the calculated number using 12 the aerosol, the use of the study with aerosol is justified. The dust study was not used for AEGL 13 derivation because of the short exposure period and single concentration. 14
15
8. SUMMARY OF AEGLs 16 8.1. AEGL Values and Toxicity Endpoints 17
18 AEGL values are summarized in Table 8. Derivations summaries are in Appendix C. 19
20
TABLE 8. Summary of AEGL Values for Aldicarb 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) 0.16 mg/m 3 0.11 mg/m 3 0.087 mg/m 3 0.053 mg/m 3 0.027 mg/m 3

AEGL-3 (Lethal) 0.47 mg/m 3 0.32 mg/m 3 0.26 mg/m 3 0.16 mg/m 3 0.081 mg/m 3

Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 21
22 8.2. Comparison with Other Standards and Guidelines 23
24 Standards and guidelines for aldicarb are listed in Table 9. The American Conference of 25 Government Industrial Hygienists (ACGIH) has not derived a Threshold Limit Value-Time 26 Weighted Average for aldicarb. The ACGIH ha s calculated a Biological Exposure Index for 27 acetylcholinesterase inhibiting chemicals (ACGIH 2008). The value, based on erythrocyte 28 cholinesterase activity inhibition, is 70% of an individual’s baseline. 29
30 The American Industrial Hygiene Association Workplace Environmental Exposure Level 31 Guide is 0.07 mg/m 3 (AIHA 1993). This value corresponds to an inhaled amount of aldicarb of 32 0.01 mg/kg/day if one assumes inhalation of 10 m 3 of air per 8-hour day by a 70-kg person. This 33 dose is judged to provide sufficient protection from adverse health effects. A skin notation is 34
recommended. 35
36ALDICARB NAC Proposed 1: June 2009/ Page 19 of 33

TABLE 9. Standards and Guidelines for Aldicarb 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 0.16 mg/m 3 0.11 mg/m 3 0.087 mg/m 3 0.053 mg/m 3 0.027 mg/m 3 AEGL-3 0.47 mg/m 3 0.32 mg/m 3 0.26 mg/m 3 0.16 mg/m 3 0.081 mg/m 3 ERPG-1 (AIHA) a

─ ERPG-2 (AIHA)

─ ERPG-3 (AIHA)

─ IDLH (NIOSH) b ─

REL-TWA (NIOSH) c ─

OSHA PEL (NIOSH) d ─

TLV-TWA (ACGIH) e ─

WEEL (AIHA) f 0.07 mg/m 3 * MAK (Germany) g

─ MAC (The Netherlands) h ─

Not recommended: absence of AEGL-1 values does not imply that exposure below AEGL-2 levels is without effect. 1
* Skin notation. 2 3

a ERPG (Emergency Response Planning Guide lines, American Industrial Hygiene Association 4
The ERPG-1 is the maximum airborne concentration belo w which it is believed nearly all individuals could be 5 exposed for up to one hour without experiencing other than mild, transient adverse health effects or without 6 perceiving a clearly defined objectionable odor. 7
The ERPG-2 is the maximum airborne concentration belo w which it is believed nearly all individuals could be 8 exposed for up to one hour without experiencing or devel oping irreversible or other serious health effects or 9 symptoms that could impair an individual = s ability to take protective action. 10
The ERPG-3 is the maximum airborne concentration belo w which it is believed nearly all individuals could be 11 exposed for up to one hour without experiencing or developing life-threatening health effects. 12 13

b IDLH (Immediately Dangerous to Life and Health, Nati onal Institute of Occupational Safety and Health) 14 represents the maximum concentration from which one could escape within 30 minutes without any escape15 impairing symptoms, or any irreversible health effects. 16 17

c NIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits - 18 Time Weighted Average) is defined analogous to the ACGIH-TLV-TWA. 19 20

d OSHA PEL-TWA (Occupational Safety and Health Ad ministration, Permissible Exposure Limits - Time 21 Weighted Average) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of no more than 10 22 hours/day, 40 hours/week. 23 24

e ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - 25 Time Weighted Average) is the time-weighted average concentra tion for a normal 8-hour workday and a 40-hour 26 workweek, to which nearly all workers may be repeat edly exposed, day after day, without adverse effect. 27 28

f WEEL (Workplace Environmental Exposure Level Guide) (AIHA 1993) is the 8-hour time-weighted average 29 that is expected to be without adverse health effects during a normal 8-hour day and 40-hour workweek. 30 31

g MAK (Maximale Arbeitsplatzkonzentrat ion [Maximum Workplace Concentration]) (Deutsche 32 Forschungsgemeinschaft [German Research Associati on] is defined analogous to the ACGIH-TLV-TWA. 33ALDICARB NAC Proposed 1: June 2009/ Page 20 of 33

1

h MAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration]) (SDU Uitgevers [under the 2 auspices of the Ministry of Social Affairs and Employmen t], The Hague, The Netherlands is defined similar to the 3

ACGIH TLV. 4
5 8.3. Data Adequacy and Research Needs 6
7 Aldicarb has a low vapor pressure and no usab le studies involving inhalation exposure of 8 humans were located in the available literature. An oral dosing study with human volunteers 9 addressed effects consistent with cholinesterase activity inhibition. Inhalation studies with rats 10 as the test species involving several exposure durations and dust, aerosol, and vapor delivery 11
were sufficient for derivation of two AEGL le vels for five timepoints. Studies involving 12 comparisons of cholinesterase activity inhibition between juvenile and adult rats and between 13 rats and humans addressed chemical-specific uncertainty factors. Metabolism pathways and 14
mode of action are well understood. 15
16
9. REFERENCES 17 18 ACGIH (American Conference of Government and Indus trial Hygienists). 2008. TLVs and BEIs Based 19
on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents & 20 Biological Exposure Indices. Cincinnati, OH: ACGIH. 21 22 AIHA (American Industrial Health Association). 1993. Workplace Environmental Exposure Level 23 Guide: Aldicarb. Fairfax, VA: American Industrial Hygienists Association. 24 25 Carpenter, C.P. and H.F. Smyth. 1965. Recapitula tion of pharmacodynamic and acute toxicity studies on 26 Temik. Mellon Institute unpublished re port 28-75. (Reviewed in IPCS 1991). 27 28 Costa, L.G. 2008. Chapter 22: Toxic Effects of Pes ticides. In Casarett & Doull’s Toxicology, The Basic 29
Science of Poisons. 7 th Ed. New York: McGraw-Hill. 30 31 Ellin, R.I. 1981. Anomalies in theories and therapy of intoxication by potent organophosphorus 32 anticholinesterase compounds. U.S. Army Medical Research and Development Command, 33 Biomedical Laboratory Report No. USABML-SP-81-003. Available from the Defense Technical 34 Information Center, AD A1013364. 35 36 Herz, F., E. Kaplan, and E.S. Scheye. 1975. A long itudinal study of red cell enzymes in infants of low 37 birth weight. Z. Kinderheilk. 120: 217-221. 38 39 HSDB (Hazardous Substances Data Bank). 2005. Aldicarb. Available online: 40 http://toxnet/nlm.nih.gov/cgi-bin/sis/download.txt

. 41 42 HSRB (Human Studies Review Board). 2006. Report of the Human Studies Review Board April 4-6, 43 2006, regarding chemicals aldicarb, methomyl, oxamyl, azinphos-methyl, DDVP, ethephon, 44 hydrogen cyanide, and amitraz. Available online: http://www.epa.gov/osa/hsrb/files/meeting45 materials/apr-4-6-2006-public-meeti ng/april2006mtgfinalreport62606.pdf. 46 47 IPCS (International Program on Chemical Safety). 1991. Environmental Health Criteria 121: Aldicarb. 48 World Health Organization. Available online: 49 http://www.inchem.org/documents/ehc/ehc/ehc121.htm

. 50 51ALDICARB NAC Proposed 1: June 2009/ Page 21 of 33

IPCS (International Program on Chemical Safety). 1992. Pesticide Residues in Food: 1992 Evaluations 1 Part II: Toxicology. World Health Organization. Available online: 2 http://www.inchem.org/documents/jmpr/jmpmono/v92pr03.htm

. 3 4 McDaniel, K.L., S. Padilla, R.S. Marshall, P.M. Ph illips, L. Podhorniak, Y. Qian, and V.C. Moser. 2007. 5 Comparison of acute neurobehavioral and cholinest erase inhibitory effects of N-methylcarbamates in 6
rat. Toxicol. Sci. 98:552-560. 7 8 Moser, V.C. 1999. Comparison of aldicarb and metham idophos neurotoxicity at different ages in the rat: 9 behavioral and biochemical parameters. Toxicol. Appl. Pharmacol. 157:94-106. 10 11 NRC (National Research Council). 2001. Standi ng Operating Procedures for Developing Acute 12 Exposure Guideline Levels for Hazardous Chemical s. Washington, DC: National Academy Press. 13 14 NTP (National Toxicology Program). 1979. Bioassay of Aldicarb for Possible Carcinogenicity (CAS 15 No. 116-06-3). TR-136. Available online: http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr136.pdf

. 16 17 NTP (National Toxicology Program). 1986. Toxico logy and Carcinogenesis Studies of Dichloromethane 18 (Methylene Chloride) (CAS No. 75-09-2) in F 344/N Rats and B6C3F1 Mice (Inhalation Studies). 19
TR-No. 306. Available online: http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr306.pdf 20 21 O’Neil, M.J., A. Smith, and P.E. Heckelman. 2001. Aldicarb. The Merck Index. Whitehouse Station, 22 NJ: Merck & Co., Inc., p. 224. 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 Risher J.F., F.L. Mink, and J.F. Stara. 1987. The toxicologic effects of the carbamate insecticide aldicarb 29 in mammals: a review. Environ. Health Persp. 72:267-281. 30 31 Tang, J., R.L. Rose, and J.E. Chambers. 2006. Chapter 10: Metabolis m of organophosphorus and 32 carbamate pesticides. Pp. 127-143 in Gupta, R.C. (ed) Toxicology of Organophosphate and 33 Carbamate Compounds. Elsevier Academic Press, Burlington, MA. 34 35 Taylor, L. and E. Reaves. 2006. Aldicarb: WOE Comparison of Human and Animal Studies for Single 36
Chemical Assessment and NMC Cumulative Assessm ent. Presentation, U.S. Environmental 37 Protection Agency, Office of Pesticide Programs, April 4, 2006. Available online. 38 39 ten Berge, W.F., A. Zwart, and L.M. Appleman. 1986. Concentration-time mortality response 40 relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 13: 301-309. 41 42 UCC (Union Carbide Corporation). 1977. UC 21865- 75WP: 2-Methyl-s-(methylsulfonyl) propanol O43 [(methylamino)carbonyl] oxime: results of nine-day inhalation study on rats, Project Report 40-29, 44 March 16, 1977, Carnegie-Mellon University . OTS0539433; ID 88-920002674, 1992, available from 45 National Technical Information Service, Springfield, VA. 46 47 UCC (Union Carbide Corporation). 1985. Aldicarb Solution (in DMC) LC50 Aerosol Acute Inhalation 48 Toxicity Test. Bushy Run Research Center, Project Report 48-136, December 11, 1985. Initial 49 submission: Letter from Union Carbide Corp. to USEPA submitting enclosed information on aldicarb 50
solutions in dichloromethane aerosol inhalation and acute toxicity studies with attachment. 51ALDICARB NAC Proposed 1: June 2009/ Page 22 of 33

Submission dated 1992. OTS0543711; ID 88-920006638, 1992, available from National Technical 1 Information Service, Springfield, VA. 2 3 UCC (Union Carbide Corporation). 1986. Material Safety Data Sheet: Aldicarb. Research Triangle 4 Park, NC: Union Carbide Agricultural Produc ts Company, Inc. Available online. 5 6 UCC (Union Carbide Corporation). 1992. Initial Submission: Letter from Union Carbide submitting 7 reports describing a variety of toxicology studi es with Temik Sulfone with attachments. OTS 8 0539433, available from the National Technical Information Center, Springfield, VA. 9 10 U.S. EPA (U.S. Environmental Protection Agency). 1992. Data Evaluation Report: Aldicarb. Review of 11 Wyld et al., (1992) A Safety and Tolerability Study of Aldicarb at Various Dose Levels in Healthy 12
Male and Female Volunteers. Available from U.S. EPA. 13 14 U.S. EPA (U.S. Environmental Protection Agency). 2000. Office of Pesticide Programs Science Policy 15
on The Use of Data on Cholinesterase Inhibiti on for Risk Assessments of Organophosphorous and 16 Carbamate Pesticides. Washington, DC: U.S. Envi ronmental Protection Agency. Available online: 17 http://www.epa.gov/pesticides/trac/science/cholin.pdf. 18 19 U.S. EPA (U.S. Environmental Protection Agency). 2005. Memorandum (TXR No. 0052688) from 20 Linda Taylor, Health Effect Division to Mika H unter Special Review and Registration Division, 21 September 22, 2005. Available online. 22 23 U.S. EPA (U.S. Environmental Protection Agency). 2007a. Reregistration Eligibility Decision (RED) 24
for Aldicarb. Available online: www.epa.gov/pesticides/reregistration/REDs/aldicarb_red.pdf

. 25 26 U.S. EPA (U.S. Environmental Protection Agency). 2007b. Revised N -Methyl Carbamate Cumulative 27 Risk Assessment. Office of Pesticide Programs. Available online: 28 http://www.epa.gov/oppsrrd1/REDs/nmc_revised_cra.pdf

. 29 30 Weil, C.S. and C.P. Carpenter. 1970. Temik and ot her materials. Miscellaneous single dose peroral and 31 parenteral LD 50 assays and some joint action studies. U npublished Mellon Institute Report 33-7. 32 (Reviewed in IPCS 1991). 33 34 Wyld, P.J., C.E. Watson, W.S. Nimmo, and N. Wats on. 1991. A Safety and Tolerability Study of 35 Aldicarb at Various Dose Levels in Healthy Male a nd Female Volunteers. Inveresk Clinical Research 36 Limited, Riccarton, Edinburgh, Scotland, Re port No. 7786. (Reviewed in U.S. EPA 1992). 37 38ALDICARB NAC Proposed 1: June 2009/ Page 23 of 33

1 APPENDIX A: Derivation of Aldicarb AEGLs 2
3
Derivation of AEGL-1 Values 4
5 No human or animal studies were located that addressed symptoms and signs consistent 6 with the definition of the AEGL-1. Therefore, AEGL-1 values are not recommended. 7
8
Derivation of AEGL-2 Values 9 10 Key Study: UCC (Union Carbide Corporation). 1985. Aldicarb Solution (in DMC) LC 50 11 Aerosol Acute Inhalation Toxicity Test. Bushy Run Research Center, 12 Project Report 48-136, December 11, 1985. 13 14 Toxicity endpoint: AEGL-3 values divided by 3. The steep concentration-response line shown 15 by the Risher et al. (1987) and UCC (1985) data justifies deriving AEGL-2 16 values by dividing the AEGL-3 values by 3 (NRC 2001). 17 18 Time scaling See AEGL-3 derivation, next page 19 20 Uncertainty factors: Total uncertainty factor: 6 (See AEGL-3 derivation, next page) 21 22 Calculations: AEGL-3 values divided by 3 23 24 10-min AEGL-2: C = 0.47 mg/m 3 /3 = 0.16 mg/m 3 25 26 30-min AEGL-2: C = 0.32 mg/m 3 /3 = 0.11 mg/m 3 27 28 1-h AEGL-2: C = 0.26 mg/m 3 /3 = 0.087 mg/m 3 29 30 4-h AEGL-2: C = 0.16 mg/m 3 /3 = 0.053 mg/m 3 31 32 8-h AEGL-2: C = 0.081 mg/m 3 /3 = 0.027 mg/m 3 33 34 35 36ALDICARB NAC Proposed 1: June 2009/ Page 24 of 33

1
Derivation of AEGL-3 Values 2 3 Key Study: UCC (Union Carbide Corporation). 1985. Aldicarb Solution (in DMC) LC 50 4 Aerosol Acute Inhalation Toxicity Test. Bushy Run Research Center, 5 Project Report 48-136, December 11, 1985. 6 7 Toxicity endpoint: Threshold for lethality in rats at the BMCL 05 of 0.973753 mg/m 3 calculated 8 from the rat lethality data of UCC (1985). 9 10 Time scaling C n x t = k where n = 3 and 1 for s horter and longer exposure durations, 11 respectively (NRC 2001). 12 13 Uncertainty factors: Total uncertainty factor: 6 14 Interspecies: 2 – The U.S. EPA (2007b) Office of Pesticide Programs 15 calculated an oxamyl-specific inhalation interspecies uncertainty 16
factor of 2 based on differences in modeled red blood cell values for 17 cholinesterase activity inhibition between the rat and humans. 18 Intraspecies: 3 – The U.S. EPA (2007b) Office of Pesticide Programs 19 calculated an aldicarb-specific inhalation intraspecies uncertainty 20 factor of 2 based on comparative brain acetylcholinesterase activity 21 inhibition in post-natal day 17 juvenile rats and adult rats. For 22 consistency among the N-methyl carbamate pesticides, the chemical23 specific intraspecies uncertainty factor of 3, derived for the both of the 24
related N -methyl carbamate pesticides, oxamyl and methomyl, was 25 applied to aldicarb. 26 27 Modifying factor: None applied 28 29 Calculations: (0.973753 mg/m 3 /6) 3 x 240 minutes = 1.03 mg/m 3 •min 30 31
10-min AEGL-3: C = 3 √ (1.03 mg/m 3 •min /10) = 0.47 mg/m 3 32 33
30-min AEGL-3: C = 3 √ (1.03 mg/m 3 •min/30) = 0.32 mg/m 3 34 35
1-h AEGL-3: C = 3 √ (1.03 mg/m 3 •min/60) = 0.26 mg/m 3 36 37 4-h AEGL-3: C = 0.973753/6 = 0.16 mg/m 3 38 39 8-h AEGL-3: C = (0.16 mg/m 3 •min x 240 min)/480 minn = 0.081 mg/m 3 40 41 42 43ALDICARB NAC Proposed 1: June 2009/ Page 25 of 33

APPENDIX B: Category Graph of AEGL Values and Toxicity Data 1
2

0.0 0.1 1.0 10.0 100.0mg/m3

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

Discomfort

Disabling

Some Lethality

Lethal

AEGL Category Graph - Animal Data
Aldicarb

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 Not recommended 10 AEGL

NAC/AEGL-1 Not recommended 30 AEGL

NAC/AEGL-1 Not recommended 60 AEGL

NAC/AEGL-1 Not recommended 240 AEGL

NAC/AEGL-1 Not recommended 480 AEGL

NAC/AEGL-2 0.16 10 AEGL

NAC/AEGL-2 0.11 30 AEGL

NAC/AEGL-2 0.087 60 AEGL

NAC/AEGL-2 0.053 240 AEGL

NAC/AEGL-2 0.027 480 AEGL

NAC/AEGL-3 0.47 10 AEGL

NAC/AEGL-3 0.32 30 AEGL

NAC/AEGL-3 0.26 60 AEGL

NAC/AEGL-3 0.16 240 AEGL
NAC/AEGL-3 0.081 480 AEGLALDICARB NAC Proposed 1: June 2009/ Page 26 of 33

Risher et al. 1987 rat 6.7 15 2; survival of 6 of 6 rat 6.7 30 SL; mortality of 5 of 6

UCC 1985 rat 0.82 240 2; ataxia and tremors rat 2.9 240 SL; mortality of 1 of 10 rat 6.0 240 SL; mortality of 5 of 10 rat 8.7 240 3; mortality of 10 of 10 rat 46.3 240 3; mortality of 10 of 10

Not recommended: absence of AEGL-1 values does not im ply that exposure below AEGL-2 levels is without
effect.
1ALDICARB NAC Proposed 1: June 2009/ Page 27 of 33

1
APPENDIX C: Benchmark Concentrat ion Calculations for Aldicarb 2

3
Aldicarb BMCL 05 Derivation (data of UCC 1985) 4

============================================================== 5 Probit Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:53 $ 6 Input Data File: C:\BMDS\BCME_RAT.(d) 7 Gnuplot Plotting File: C:\BMDS\BCME_RAT.plt 8 Wed Apr 15 18:17:01 2009 9

============================================================== 10
BMDS MODEL RUN 11

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 12 The form of the probability function is: 13
14 P[response] = Background 15 + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 16
17 where CumNorm(.) is the cumulative normal distribution function 18
19 Dependent variable = COLUMN3 20 Independent variable = COLUMN1 21 Slope parameter is not restricted 22
23
Total number of observations = 6 24 Total number of records with missing values = 0 25
Maximum number of iterations = 250 26 Relative Function Convergence has been set to: 1e-008 27 Parameter Convergence has been set to: 1e-008 28
29 User has chosen the log transformed model 30 Default Initial (and Specified) Parameter Values 31 background = 0 32 intercept = -1.49047 33 slope = 0.948882 34
35 Asymptotic Correlation Matrix of Parameter Estimates 36
37 ( *** The model parameter(s) -background have been estimated at a boundary point, or 38 have been specified by the user, and do not appear in the correlation matrix ) 39
40 intercept slope 41 intercept 1 -0.95 42 slope -0.95 1 43
Parameter Estimates 44
Variable Estimate Std. Err. 45 background 0 NA 46 intercept -2.82566 0.882065 47ALDICARB NAC Proposed 1: June 2009/ Page 28 of 33

slope 1.84829 0.513275 1
2 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus 3
has no standard error. 4
5 Analysis of Deviance Table 6 Model Log(likelihood) Deviance Test DF P-value 7 Full model -10.1823 8
Fitted model -12.333 4.30146 4 0.3667 9
Reduced model -41.0539 61.7432 5 <.0001 10
11
AIC: 28.6661 12
Goodness of Fit Scaled 13 Dose Est._Prob. Expected Observed Size Residual 14

------------------------------------------------------------------------ 15
0.0000 0.0000 0.000 0 10 0 16
0.8200 0.0007 0.007 0 10 -0.08401 17
2.0000 0.0612 0.612 1 10 0.5114 18
6.0000 0.6865 6.865 5 10 -1.271 19
8.7000 0.8796 8.796 10 10 1.17 20
46.3000 1.0000 10.000 10 10 0.01005 21
22 Chi-square = 3.25 DF = 4 P-value = 0.5161 23
24 Benchmark Dose Computation 25 Specified effect = 0.05 26 Risk Type = Extra risk 27
Confidence level = 0.95 28
29
BMC 05 = 1.89433 30
BMCL 05 = 0.973753 31

0 0.2 0.4 0.6 0.8

1

0 10 20 30 40 50Fraction Affected

dose Probit Model with 0.95 Confidence Level

18:17 04/15 2009 BMDL BMD

Probit

32ALDICARB NAC Proposed 1: June 2009/ Page 29 of 33

Aldicarb BMC 01 Derivation (data of UCC 1985) 1

=============================================================== 2 Probit Model. (Version: 2.8; Date: 02/20/2007) 3 Input Data File: C:\BMDS\UNSAVED1.(d) 4 Gnuplot Plotting File: C:\BMDS\UNSAVED1.plt 5
Tue Mar 10 07:28:32 2009 6

=============================================================== 7
BMDS MODEL RUN 8

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 9 The form of the probability function is: 10 P[response] = Background + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 11 where CumNorm(.) is the cumulative normal distribution function 12
13 Dependent variable = COLUMN3 14 Independent variable = COLUMN1 15 Slope parameter is not restricted 16
17
Total number of observations = 6 18 Total number of records with missing values = 0 19
Maximum number of iterations = 250 20 Relative Function Convergence has been set to: 1e-008 21 Parameter Convergence has been set to: 1e-008 22
23 User has chosen the log transformed model 24 Default Initial (and Specified) Parameter Values 25 background = 0 26 intercept = -1.49047 27 slope = 0.948882 28
29 Asymptotic Correlation Matrix of Parameter Estimates 30
31 ( *** The model parameter(s) -background have been estimated at a boundary point, or 32 have been specified by the user, and do not appear in the correlation matrix ) 33
34 intercept slope 35 intercept 1 -0.95 36 slope -0.95 1 37
38
Parameter Estimates 39 95.0% Wald Confidence Interval 40 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 41 background 0 NA 42 intercept -2.82566 0.882065 -4.55448 -1.09685 43 slope 1.84829 0.513275 0.842291 2.85429 44
45 NA - Indicates that this parameter has hit a bound implied by some inequality constraint and thus 46
has no standard error. 47ALDICARB NAC Proposed 1: June 2009/ Page 30 of 33

Analysis of Deviance Table 1 Model Log(likelihood) # Param's Deviance Test d.f. P-value 2
Full model -10.1823 6 3
Fitted model -12.333 2 4.30146 4 0.3667 4
Reduced model -41.0539 1 61.7432 5 <.0001 5
6
AIC: 28.6661 7
8
Goodness of Fit Scaled 9 Dose Est._Prob. Expected Observed Size Residual 10

------------------------------------------------------------------------ 11
0.0000 0.0000 0.000 0 10 0.000 12
0.8200 0.0007 0.007 0 10 -0.084 13
2.0000 0.0612 0.612 1 10 0.511 14
6.0000 0.6865 6.865 5 10 -1.271 15
8.7000 0.8796 8.796 10 10 1.170 16
46.3000 1.0000 10.000 10 10 0.010 17
18
Chi^2 = 3.25 d.f. = 4 P-value = 0.5161 19
20 Benchmark Dose Computation 21 Specified effect = 0.01 22 Risk Type = Extra risk 23
Confidence level = 0.95 24
25
BMC 01 = 1.31016 26
BMCL 01 = 0.54285 27
28

0 0.2 0.4 0.6 0.8

1

0 10 20 30 40Fraction Affected

dose Probit Model with 0.95 Confidence Level

07:28 03/10 2009 BMDL BMD Probit

BMD Lower Bound

29ALDICARB NAC Proposed 1: June 2009/ Page 31 of 33

1 

### APPENDIX D: Derivation Su mmary for Aldicarb AEGLs 2 Acute Exposure Guideline Levels For Aldicarb 3 (CAS Reg. No. 23135-22-0) 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 7ALDICARB NAC Proposed 1: June 2009/ Page 32 of 33

1

AEGL-2 VALUES

10-min 30-min 1-h 4-h 8-h 0.16 mg/m 3 0.11 mg/m 3 0.087 mg/m 3 0.053 mg/m 3 0.027 mg/m 3

Key Reference : UCC (Union Carbide Corporation). 1985. Aldicarb Solution (in DMC) LC50 Aerosol Acute Inhalation Toxicity Test. Bushy Run Research Center, Project Report 48-136. Test Species/Strain/Number : Rat/Sprague-Dawley/groups of 5 per sex Exposure Route/Concentration/Duration : Inhalation/0.82, 2.0, 6.0, 8.7, 46.3 mg/m 3 /4 hours
Effects : acetylcholinesterase activity inhibition, estimate at 1/3 of the AEGL-3 values. Endpoint/Concentration/Rationale : One-third of the AEGL-3 values , based on the steep concentrationresponse curve Uncertainty Factors/Rationale : Total uncertainty factor : 6 (used for derivation of AEGL-3)

Interspecies: 2 Intraspecies : 3 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 Data Adequacy : The key study was well conducted, used adequate numbers of rats, and five concentrations. 2 3 4ALDICARB NAC Proposed 1: June 2009/ Page 33 of 33

1

AEGL-3 VALUES

10-min 30-min 1-h 4-h 8-h 0.47 mg/m 3 0.32 mg/m 3 0.26 mg/m 3 0.16 mg/m 3 0.081 mg/m 3

Key References: UCC (Union Carbide Corporation). 1985. Aldicarb Solution (in DMC) LC 50 Aerosol Acute Inhalation Toxicity Test. Bushy Run Research Center, Project Report 48-136. Test Species/Strain/Number : Rat/Sprague-Dawley/groups of 5 per sex Exposure Route/Concentration/Duration: Inhalation/0.82, 2.0, 6.0, 8.7, 46.3 mg/m 3 /4 hours
Effect : Mortalities: 0, 1, 5, 10, and 10 Endpoint/Concentration/Rationale : BMCL 05 , estimated as the threshold for lethality Uncertainty Factors/Rationale : Total uncertainty factor : 6

Interspecies: 2: The U.S. EPA (2007b) Office of Pestic ide Programs calculated an aldicarb-specific interspecies uncertainty factor of 2 based on differen ces in values of modeled red blood cell cholinesterase activity inhibition between the rat and humans. Intraspecies : 3: The U.S. EPA (2007b) Office of Pestic ide Programs calculated an aldicarb-specific intraspecies uncertainty factor of 3 for the relate d chemicals oxamyl and methomyl based on comparative brain acetylcholinesterase activity inhibition in pos t-natal day 17 juvenile rats and adult rats. 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 a nd longer exposure durations, respectively. Data Adequacy: The key study was well conducted, used adequate numbers of rats, and five concentrations.

2