## ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs)
FOR
DIMETHYL PHOSPHITE CAS Reg. No. 868-85-9

PROPOSEDDIMETHYL PHOSPHITE Proposed: October, 2009

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## ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 2 

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## DIMETHYL PHOSPHITE 4 

## CAS Reg. No. 868-85-9 5

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23DIMETHYL PHOSPHITE Proposed: October, 2009

3 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 Acut e Exposure Guideline Levels for Hazardous 5 Substances (NAC/AEGL Committee) has been established to identify, review and interpret 6 relevant toxicologic and other sc ientific data and develop AEGLs for high priority, acutely toxic 7
chemicals. 8

9 AEGLs represent threshold exposure limits for the general public a nd are applicable to 10 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels

C AEGL-1, 11
AEGL-2 and AEGL-3

Care developed for each of five e xposure 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 (expres sed as parts per million or milligrams per 16 cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general 17 population, including susceptible indi viduals, could experience notab le 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 (expresse d as ppm or mg/m3) of a substance above 22 which it is predicted that th e general population, including su sceptible individuals, could 23 experience irreversible or other serious, long-lasting adverse hea lth effects or an impaired ability 24
to escape. 25

26 AEGL-3 is the airborne concentration (expres sed as ppm or mg/m3) of a substance above 27 which it is predicted that th e general population, including su sceptible individuals, could 28 experience life-threatening health effects or death. 29

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Airborne concentrations below the AEGL-1 re present exposure levels that could produce 31 mild and progressively increas ing but transient and nondisab ling odor, taste, and sensory 32 irritation or certain asymptomatic , non-sensory effects. With incr easing airborne concentrations 33 above each AEGL, there is a progressive increase in the likelihood of occu rrence and the severity 34
of effects described for each corresponding AEGL. Although the AEGL values represent 35 threshold levels for the general public, including susceptible subpopulations, such as infants, 36 children, the elderly, persons with asthma, and thos e with other illnesses, it is recognized that 37 individuals, subject to unique or idiosyncratic responses, could experience the effects described 38
at concentrations belo w the corresponding AEGL 39

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41DIMETHYL PHOSPHITE Proposed: October, 2009

4 TABLE OF CONTENTS 1

PREFACE........................................................................................................................ ............................3 2

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

1. INTRODUCTION................................................................................................................... ...........8 4

2. HUMAN TOXICITY DATA............................................................................................................ .8 5

2.1. Acute Lethality................................................................................................................ ...............8 6

2.2. Nonlethal Toxicity............................................................................................................. .............8 7

2.3. Developmental/Reproduc tive Toxicity.........................................................................................9 8

2.4. Genotoxicity................................................................................................................... .................9 9

2.5. Carcinogenicity ................................................................................................................ ..............9 10

2.6. Summary........................................................................................................................ .................9 11

3. ANIMAL TOXICITY DATA........................................................................................................... .9 12

3.1. Acute Lethality................................................................................................................ ...............9 13

3.2. Non-lethal Toxicity............................................................................................................ .............9 14

3.3. Repeated-Expos ure Studies...................................................................................................... ...10 15

3.4. Developmental/Reproductive Toxicity.......................................................................................11 16

3.5. Genotoxicity................................................................................................................... ...............11 17

3.6. Chronic Toxicity/Carcinogenicity ..............................................................................................1 1 18

3.7. Summary........................................................................................................................ ...............11 19

4. SPECIAL CONSIDERATIONS .....................................................................................................12 20

4.1. Metabolism and Disposition..................................................................................................... ...12 21

4.2. Mechanism of Toxicity .......................................................................................................... ......12 22

4.3. Structure Activity Relationships ............................................................................................... .12 23

4.4. Other Relevant Information ..................................................................................................... ..12 24

4.4.1. Species Vari ability............................................................................................................ ...12 25

4.4.2. Susceptible Populations ......................................................................................................12 26

4.4.3. Concentration-Exposure Duration Relationship..............................................................12 27

4.4.4. Concurrent Exposure Issues ..............................................................................................13 28

5. DATA ANALYSIS FOR AEGL-1 ..................................................................................................13 29

5.1. Summary of Human Data Relevant to AEGL-1 .......................................................................13 30

5.2. Summary of Animal Data Relevant to AEGL-1 .......................................................................13 31

5.3. Derivation of AEGL-1 ........................................................................................................... ......13 32

6. DATA ANALYSIS FOR AEGL-2 ..................................................................................................13 33

6.1. Summary of Human Data Relevant to AEGL-2 .......................................................................13 34

6.2. Summary of Animal Data Relevant to AEGL-2 .......................................................................13 35

6.3. Derivation of AEGL-2 ........................................................................................................... ......13 36

7. DATA ANALYSIS FOR AEGL-3 ..................................................................................................14 37

7.1. Summary of Human Data Relevant to AEGL-3 .......................................................................14 38

7.2. Summary of Animal Data Relevant to AEGL-3 .......................................................................14 39

7.3. Derivation of AEGL-3 ........................................................................................................... ......14 40

8. SUMMARY OF AEGLS ............................................................................................................... ..15 41

8.1. AEGL Values and Toxicity Endpoints.......................................................................................15 42

8.2. Comparison with Other Standards and Guidelines..................................................................15 43

8.3. Data Adequacy and Research ..................................................................................................... 15 44

9. REFERENCES..................................................................................................................... ............17 45

APPENDIX A: DERIVATION OF AEGL VALUES...........................................................................19 46

APPENDIX B: DERIVATION SUMMARY FOR DIMETHYL PHOSPHITE AEGLS .................22 47

APPENDIX C: CATEGORY PLOT FOR DIMETHYL PHOSPHITE.............................................25 48DIMETHYL PHOSPHITE Proposed: October, 2009

5 LIST OF TABLES 1

2 Table 1. Summary of AEGL Values for Dimethyl Phosphite ....................................................... 7 3 Table 2. Chemical and physical pr operties for dimethyl phosphite.............................................. 8 4 TABLE 3. AEGL-1 values for dimethyl phosphite...................................................................... 13 5 TABLE 4. AEGL-2 values for dimethyl phosphite...................................................................... 14 6 TABLE 5. AEGL-3 values for dimethyl phosphite...................................................................... 15 7 TABLE 6. Summary of AEGL values......................................................................................... 15 8

9DIMETHYL PHOSPHITE Proposed: October, 2009

6 EXECUTIVE SUMMARY 1

2 Dimethyl phosphite (DMP) is a colorless liquid with a mild odor ; it is a degradation product 3 of trimethyl phosphite (TMP). It is used as an intermediate in the manuf acture of insecticides 4 and herbicides. It is also used as a fireproof ing agent in the production of textiles. Dimethyl 5 phosphite is manufactured in a closed system by reacting phosphorus trichloride with methanol 6 or sodium methoxide, and is listed as a High Production Volume (HPV) chemical. 7
8
Data are insufficient for derivation of AEGL-1 values; therefore AEGL-1 values are not 9
recommended. Absence of AEGL-1 values does not imply that concentrations below AEGL-2 10
are without effect. 11

12 Clinical signs (labored breathing and ptosis ) in mice exposed to 1575 ppm DMP for 6 hours 13 (Hazleton, 1962) were used as the point-of-departure for AEGL-2 values. Inter- and intraspecies 14 uncertainty factors of 3 each (total 10) were ap plied because DMP is irritating, and much of the 15 toxicity is likely caused by a direct chemical e ffect on the tissue; this type of portal-of-entry 16 effect is not expected to vary greatly between species or among individuals. The interspecies 17 uncertainty factor of 3 is also considered sufficien t because no clinical signs were noted in rats or 18 guinea pigs exposed to 1575 ppm for 6 hours. A m odifying factor of 3 was also applied because 19 of the sparse database and because the point-o f-departure is a nominal concentration. The 20 concentration-exposure time relationship for many irritant and systemi cally-acting vapors and 21 gases may be described by C n x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et 22 al., 1986). To obtain conservative and protective AEGL values in the absence of an empirically 23 derived chemical-specific scaling exponent, tempor al scaling may be performed using n=3 when 24 extrapolating to shorter time points and n = 1 wh en extrapolating to longer time points using the 25

C n x t = k equation (NRC, 2001). The 30-minute AEGL-2 value was adopted as the 10-min 26 value because of the added uncertainty of extrap olating from the 6-hr point-of-departure. 27

28 The highest concentration causing no mortality in rats (843 ppm for 6 hr) was used as the 29 point-of-departure for AEGL-3 (Biodymanics, 1980a ). Excessive lacrima tion, partially closed 30 eyes, red nasal discharge, red-brown materi al around the nares, labored breathing, and 31 unresponsiveness to sound stimuli were noted in rats exposed to 843 ppm DMP 6 hr/day for 5 32 days. Death was noted at the next concentra tion tested (934 ppm) esse ntially after one exposure 33
because one rat was killed in extremis after day 1 of the study. Inter- and intrapsecies 34 uncertainty factors of 3 each (total 10) were ap plied because DMP is irritating, and much of the 35 toxicity is likely caused by a direct chemical e ffect on the tissue; this type of portal-of-entry 36 effect is not expected to vary greatly between species or among individuals. The concentration37 exposure time relationship for many irritant an d systemically-acting vapors and gases may be 38 described by C n x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al., 1986). 39 To obtain conservative and protective AEGL valu es in the absence of an empirically derived 40 chemical-specific scaling exponent, temporal scaling may be performed using n=3 when 41 extrapolating to shorter time points and n = 1 wh en extrapolating to longer time points using the 42

C n x t = k equation (NRC, 2001). The 30-minute AEGL -3 value will also be adopted as the 10- 43 min value because of the added uncertainty of extr apolating from the 6-hr point-of-departure. 44

45
The calculated values are lis ted in Table 1 below. 46DIMETHYL PHOSPHITE Proposed: October, 2009

7 1 Table 1. Summary of AEGL Values for Dimethyl Phosphite

Classification 10-minute 30-mi nute 1-hour 4-hour 8-hour Endpoint (Reference)

AEGL

B 1 (Nondisabling) NR NR NR NR NR Insufficient data

AEGL

B 2 (Disabling) 120 ppm (540 mg/m 3 ) 120 ppm (540 mg/m 3 ) 95 ppm (430 mg/m 3 ) 60 ppm (270 mg/m 3 ) 39 ppm (180 mg/m 3 ) Labored breathing and ptosis in mice (Hazleton, 1962)

AEGL

B 3 (Lethal) 190 ppm (850 mg/m 3 ) 190 ppm (850 mg/m 3 ) 150 ppm (670 mg/m 3 ) 96 ppm (430 mg/m 3 ) 63 ppm (240 mg/m 3 ) NOEL for mortality in rats (Biodynamics, 1980a) NR: Not Recommended due to insufficient data. Absence of AEGL-1 values does not imply that concentrations 2

below AEGL-2 are without effect. 3 4 5 6DIMETHYL PHOSPHITE Proposed: October, 2009

8 1
1. INTRODUCTION 2
3 Dimethyl phosphite (DMP) is a colorless liquid with a mild odor ; it is a degradation product 4 of trimethyl phosphite (TMP). It is used as an intermediate in the manuf acture of insecticides 5 and herbicides. It is also used as a fireproof ing agent in the production of textiles. Dimethyl 6 phosphite is manufactured in a closed system by reacting phosphorus trichloride with methanol 7 or sodium methoxide, and is listed as a High Production Vo lume (HPV) chemical. HPV 8 chemicals were produced or imported into the U. S. in quantities of > 1 million pounds in 1990 9 and/or 1994; estimated US manufacturing cap acity was 1000-5000 tons/year in 2002 (UNEP, 10 2004). Chemical and physical proper ties are presented in Table 2. 11

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Table 2. Chemical and physical properties for dimethyl phosphite

Parameter Value References

Synonyms Dimethyl phosphonate; dimethylhydrogen phosphite; DMPH; DMP; Phosphonic acid, dimethyl ester; Dimethyl phosphonus acid; Phosphorus acid dimethyl ester; Hydrogen dimethyl phosphite UNEP, 2004

Chemical formula C 2 H 7 O 3 P HSDB, 2009 Molecular weight 110.05 HSDB, 2009 CAS Reg. No. 868-85-9 HSDB, 2009 Physical state Colorl ess liquid HSDB, 2009

Solubility in water Soluble; >10 g/100 ml at 25oC; Decomposes to monomethyl phosphite

and methanol UNEP, 2004

Vapor pressure 1.5 mm Hg at 20oC HSDB, 2009 Vapor density (air =1) 7.9 HSDB 2009 Specific gravity 1.2002 g/cm 3 at 20oC HSDB, 2009 Melting point -60oC HSDB, 2009 Boiling point 170.5oC UNEP, 2004 Flash point 70oC HSDB, 2009 Explosive limits Lower: 5.8%; Upper: 38.1% UNEP, 2004

Conversion factors 1 ppm = 4.49 mg/m 3
1 mg/m 3 = 0.22 ppm

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2. HUMAN TOXICITY DATA 15 2.1. Acute Lethality 16

17 No information concerning acute lethality was located. 18
19 2.2. Nonlethal Toxicity 20

21 Albright and Wilson, Inc. (1985) reported the results of an ai r and health monitoring study on 22 DMP conducted in a manufacturing facility in Ch arleston, South Carolina. The maximum partial 23 shift (approximately 3- to 4-hours) employee exposure to DMP was 1.9 ppm and the average 24 exposure was 0.22 ppm. The maximum 8-hour TWA concentration was 1.1 ppm and the 25 average exposure was 0.16 ppm. A single maxi mum area sample of 3 ppm DMP was reported in 26DIMETHYL PHOSPHITE Proposed: October, 2009

9 the immediate production area. The report did no t describe the duration of the monitoring, but 1 noted that exposure information had been obtained on an “ongoing basis.” It was also stated that 2 standard practice was to obtain separate employee samples in the morning and afternoon from 3 which an eight hour time weighted average was determined. Albright and Wilson, Inc. (1985) 4 reported that medical surveillance of the workers did not indicate any significant adverse health 5 effects related to historical expos ures to DMP at this facility. The report states that respiratory 6 protection is provided to employ ees during operations with highest exposure potential, to reduce 7 actual exposure. 8

9 2.3. Developmental/Reproductive Toxicity 10

11 No human developmental/reproductive data were located. 12

13 2.4. Genotoxicity 14
15 No human genotoxicity data were located. 16

17 2.5. Carcinogenicity 18
19 No human carcinogenicity data were located. 20

21 2.6. Summary 22
23 Human data are limited to one workplace monitoring report where an average exposure of 24 0.22 ppm did not show health effects. No other human data were located. 25

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3. ANIMAL TOXICITY DATA 27 3.1. Acute Lethality 28
29
A 1-hour rat LC 50 of >5112 ppm was reported (Albright and Wilson, Inc., 1985). No other 30 details were reported. 31

32 3.2. Non-lethal Toxicity 33
34 Groups of ten male Swiss albino mice, ten male Wistar rats, and ten male English short-hair 35 guinea pigs were exposed to a “mean theoretic al concentration” of 1575 ppm DMP for 6 hours 36 (Hazleton, 1962). Concentrations we re calculated from air flow and net loss of test material. 37 Exposures were conducted in a 500 lit er stainless steel chamber with one or two fritted-disc glass 38 bubblers at the inlet containing the DMP. A gla ss trap was placed between the vapor generator 39 and chamber to collect liquid. Air flow was 18 L/minute with one bubbler and 35 L/min with 40
two bubblers. Animals were observed continua lly during exposure for signs of toxicity and 41 mortality. At the end of the seven day obs ervation period, animals were sacrificed and 42 necropsies were performed. There were no deaths during exposure or during the 7-day 43 observation period. There were no c linical signs in rats or guinea pigs. Two mice had labored 44 breathing after 1 hr- 50 min of exposure, and a ll mice had ptosis after 5 hours exposure. No 45 other clinical signs were noted. Necropsies showed only lung congestion with pulmonary 46 hemorrhage in rats and small hemorrhagic areas on the lungs of two guinea pigs. 47

48DIMETHYL PHOSPHITE Proposed: October, 2009

10 1 3.3. Repeated-Exposure Studies 2
3 In a range-finding study, groups of five male and five female Sprague-Dawley rats were 4 repeatedly exposed to 0, 431, 843, or 934 ppm DMP for six hours per day for five consecutive 5 days (Biodymanics, 1980a). Animals were expose d in one cubic meter stainless steel and glass 6 dynamic chambers, with an airflow of 83 L/min. The test atmosphere was generated by passing 7 a nitrogen stream through a bubbler containing the DMP, varying the amount of nitrogen to 8 volatilize the appropriate amount of test material. Test atmospheres were sampled four times per 9 exposure (at 1, 2.5, 4, and 5.5 hours) for infrared an alysis. Mortality was observed only in the 10 934 ppm group. None of the female rats in the 934 ppm group survived beyond day three of 11 exposure (1 was killed in extremis on day one, 3 died on day two, and 1 died on day three). 12
Two males died and one was killed in extremis on day three, while one died and another was 13
killed in extremi s on day 4 prior to exposure. Clinical signs were observed in all DMP-exposed 14 animals at all exposure levels. Excessive lacrimation, partially cl osed eyes, red nasal discharge, 15 labored breathing, and unresponsiveness to sound stimuli were recorded during exposure in all 16 treated groups. The time to observation of effect s decreased with exposure concentration; effects 17 were noted on day 1 for the 934 ppm group, day 2 for the 843 ppm group, and day 4 for the 431 18 ppm group. On day 3, swelling of the limbs with re d discoloration, fresh or dried ocular or nasal 19 discharge, and dull, dry and/or cloudy corneal surfaces were observed in animals exposed to 431 20 and 843 ppm, with the incidence of these eff ects increasing until termination. The authors 21 suggested that the degradation of DMP to phosphor us acid was likely respons ible for the irritant 22 effects observed. Body weight lo ss or decreased body weight gain were noted in both sexes in 23 the 843 and 934 ppm groups. Increased absolute a nd relative lung weights were noted in males 24 from all treatment groups. Lung discoloration was noted in both sexes at all treatment levels, 25 and congestive changes were noted only in high-concentration animals. 26

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28 Groups of twenty male and twenty female Sp rague-Dawley rats were exposed to 0, 12, 35, 29 119, or 198 ppm DMP 6 h/d, 5 d/wk, for up to 4 wks, followed by a 4-week follow-up period 30 (Biodymanics, 1980b). Exposure me thods were similar to those described above (Biodymanics, 31 1980a). Up to five rats/sex/concentration were sacrificed 2, 4, and 6 w eeks after the start of 32 exposure, with the remaining survivors being sacr ificed after 8 weeks. Lethality occurred at 33 concentrations of 119 and 198 ppm. In the 198-ppm group, 13 males and 14 females died or 34
were killed in extremis before day 27; in the 119-ppm group, one male died on day 23 and one 35 female died on day 14. Neurological impairment , which was usually reversed by the following 36 morning, was noted in the rats e xposed to 119 and 198 ppm. Physi cal signs of irritation of the 37 skin, mucous membranes, eyes, eyelids, and conjunctiva, and inflammation of the cornea 38 (keratitis) were noted at concen trations of 35 ppm and above dur ing clinical observation periods, 39 and signs of respiratory irritation (rales) occu rred at 119 ppm and above. Body weight reduction 40 (8%) was reported for both male and female rats at concentrations of 119 and 198 ppm for much 41 of the study period. Hemoglobin and hematocrit were decrease d in males at 119 and 198 ppm 42 and in females at 198 ppm. Increased SGPT, alka line phosphatase, and urea levels were noted in 43 males and females at 198 ppm, and increased SGPT (males) and decreased glucose concentration 44 (males and females) were also noted at 119 ppm. Irritation of superficial ocular structures was 45 observed in all treatment groups, and was associat ed with inflammatory changes of intraocular 46 structures. Lenticular opaciti es were observed at concentrat ions of 35 ppm and above, and 47 progressed to cataracts in the 119 and 198 pp m groups during the post-exposure period. 48DIMETHYL PHOSPHITE Proposed: October, 2009

11 Increased absolute and relative kidney weight s were observed in all treatment groups. Red 1 discoloration of the lungs and nasal turbinates and involution of the thymus were seen in 2 decedents at 198 ppm. An increased inciden ce of hypospermatogenesis (decreased epididymal 3 sperm content) was also reported in the two highest concentration groups. 4

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7 3.4. Developmental/Reproductive Toxicity 8

9 No inhalation studies designed specifically to look at reproductive or developmental toxicity 10 in animals were located. However, hyposperm atogenesis was observed in 3/20 and 4/19 rats 11 exposed via inhalation to 119 a nd 198 ppm DMP, respectively, for 6 hr/d, 5 d/wk for 4 weeks 12 (Biodymanics, 1980b). 13

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15 3.5. Genotoxicity 16

17 Dimethyl phosphite was not mutagenetic in Salmonella typhimurium strains TA98, 18 TA100, TA1535, or TA1537 in the presence or abcence of exogenous metabolic activation 19 (NTP, 1985). DMP was positive with metabolic activation and negative without metabolic 20
activation in the L5178Y tk+/- mouse lymphoma cell forward mu tation assay (McGregor et al., 21 1988). DMP caused chromosomal aberrations and sister chromatid exchanges in the Chinese 22 hamster ovary assay with and without metabolic activation (Tennant et al., 1987). DMP was 23 positive in a mouse bone marrow micronucleus test (Shelby et al., 1993). DMP did not induce 24
sex linked recessive lethals in Drosophila melanogaster (NTP, 1995; Woodruff, 1985). 25

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27 3.6. Chronic Toxicity/Carcinogenicity 28
29
No inhalation data were located. Dimet hyl phosphite was administered for 103 weeks by 30 gavage in corn oil to groups of 50 male F 344/N rats and groups of 50 male and 50 female 31 B6C3F1 mice at doses of 0, 100, or 200 mg/kg (N TP, 1985; Dunnick et al., 1986). Groups of 50 32 female F344/N rats were administered 0, 50, or 100 mg/kg. Dose-related toxicity was noted in 33 the lungs of treated male and female rats, with lung lesions being most prevalent in high-dose 34 male rats. Lung lesions included alveolar epithelial hyperplasia, chemical pneumonia, 35 alveolar/bronchiolar adenoma and carcinoma, and squamous cell carcinoma. Neoplastic and 36 non-neoplastic lesions were noted in the forestomachs of male and female rats, with males more 37 severely affected. Mineralizati on of the cerebellum in male rats and focal calcification of the 38
testes in male mice were also noted. 39

40 3.7. Summary 41

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Animal inhalation data are limited. Clinical signs from both acute and repeated-exposure 43 studies suggest that DMP is an irritant; effects in cluded lacrimation, exophthalmos, respiratory 44 distress, ocular opaciti es, cataracts, and pulmonary congestio n. Genotoxicity testing yielded 45 both positive and negative results. Hypospermatogene sis was noted in rats repeatedly exposed to 46
DMP for 4-weeks. No inhalation data on chro nic toxicity/carcinogenicity were located. 47

48DIMETHYL PHOSPHITE Proposed: October, 2009

12 4. SPECIAL CONSIDERATION S 1 4.1. Metabolism and Disposition 2
3 Studies in rats and mice suggest that DMP is oxidatively demethyl ated to monomethyl 4 hydrogen phosphite and the methanol formed is further oxidized via formaldehyde to CO 2

. 5 Nomeir and Matthews (1997) ad ministered 10-200 mg/kg 14 C -labeled DMP to male F-344/N 6 rats and male B6C3F1 mice. The compound was readily and essentially completely absorbed 7
from the GI tract of both rats and mice a nd was eliminated primarily as expired CO 2 (44-57%) 8 and urine (28-49%). Only 1-2% was collected from feces and only 2-3% as volatile organics. 9 Radioactivity was primarily distributed to the liver, kidneys, spleen, l ungs and forestomach. 10 Absorption, metabolism, and disposition were linear in both species. The clearance rate was two 11
times faster in the mouse than in the rat. The monomethyl hydrogen phosphite metabolite was 12 excreted in the urine of both species and suggests that DMP is demethylated in vivo . In vitro 13 studies suggest that DMP is meta bolized to formaldehyde in the liver, lung, kidney, forestomach 14 and stomach of rats (Nomeir and Matthews, 1997). 15

16 4.2. Mechanism of Toxicity 17
18 Information concerning the mechanism of toxicity of DMP was not located; however, 19 repeated-exposure studies in rats su ggest that it is an ir ritant when inhaled. Clinical signs noted 20 in rat inhalation studies include lacrimation, exopht halmos, respiratory distress, ocular opacities, 21 cataracts, and pulmonary congestion. 22

23

24 4.3. Structure Activity Relationships 25
26 DMP is structurally similar to organophosphate insecticides that in hibit cholinesterase 27 activity; however, DMP does not app ear to be a cholinesterase i nhibitor. Repeated-exposure 28 inhalation studies in rats (Biodym anics, 1980a,b) did not indicate systemic or cumulative toxic 29 effects suggesting cholinesterase inhibition, but suggested the e ffects were indicative of local 30
irritation. 31

32
4.4. Other Relevant Information 33
34

35

36 4.4.1. Species Variability 37
38 Data are not sufficient for determining species sensitivity. However, because DMP is an 39 irritant via the inhalation route, little interspecies variability is expected. 40

41 4.4.2. Susceptible Populations 42
43 No information was available on populations esp ecially sensitive to DMP toxicity. However, 44
because DMP is an irritant via the inhalation rout e, little intraspecies variability is expected. 45

46 4.4.3. Concentration-Exposure Duration Relationship 47
48DIMETHYL PHOSPHITE Proposed: October, 2009

13 The concentration exposure time relationship for many irritant and systemically acting 1 vapors and gases may be described by C n x t = k, where the exponent ranges from 0.8 to 3.5 (ten 2 Berge et al. 1986). In lieu of a definitive data set allowing empirical derivation of the exponent 3 n, temporal scaling was performed, using n = 3 wh en extrapolating to sh orter time points and n = 4 1 when extrapolating to l onger time points using the C n x t = k equation (NRC, 2001). 5

6 4.4.4. Concurrent Exposure Issues 7
8 No concurrent exposure issues were identified. 9
10
5. DATA ANALYSIS FOR AEGL-1 11 5.1. Summary of Human Data Relevant to AEGL-1 12
13 No human data relevant to developm ent of AEGL-1 values were identified. 14

15 5.2. Summary of Animal Data Relevant to AEGL-1 16

17 No animal data relevant to developmen t of AEGL-1 values were identified. 18
19
5.3. Derivation of AEGL-1 20

21
Data are insufficient to derive AEGL-1 values for dimethyl phosphite. Therefore, AEGL-1 22 values are not recommended (Table 3). 23

24

TABLE 3. AEGL-1 values for dimethyl phosphite

10-minute 30-minute 1-hour 4-hour 8-hour

NR NR NR NR NR
NR: Not Recommended due to insufficient data. Absence of AEGL-1 values does not imply that concentrations 25

below AEGL-2 are without effect. 26
27

28
6. DATA ANALYSIS FOR AEGL-2 29 6.1. Summary of Human Data Relevant to AEGL-2 30
31 No human data relevant to developm ent of AEGL-2 values were identified. 32

33 6.2. Summary of Animal Data Relevant to AEGL-2 34
35 Mice exposed to 1575 ppm DMP for 6 hrs exhi bited labored breathing and ptosis. No 36 clinical signs were noted in rats and guinea pigs simila rly exposed (Hazleton, 1962). 37

38 Irritation of superficial ocular structures associated with inflammatory changes of intraocular 39 structures was observed in rats exposed to 12 ppm DMP 6 hr/day, 5 days/week for 4-weeks 40 (Biodynamics, 1980b). 41

42
6.3. Derivation of AEGL-2 43

44 The clinical signs (labored breathing and pt osis) in mice exposed to 1575 ppm DMP for 6 45DIMETHYL PHOSPHITE Proposed: October, 2009

14 hours (Hazleton, 1962) will be used as the point-of-departure fo r AEGL-2 values. Inter- and 1 intraspecies uncertainty factors of 3 each (total 10) will be applied because DMP is irritating, and 2 much of the toxicity is likely caused by a direct chemical effect on the tissu e; this type of portal3 of-entry effect is not expect ed to vary greatly between sp ecies or among individuals. The 4 interspecies uncertainty factor of 3 is also cons idered sufficient because no clinical signs were 5 noted in rats or guinea pigs exposed to 1575 ppm for 6 hours. A modifying factor of 3 will also 6 be applied because of the sparse database and because the point-of-departure is a nominal 7 concentration. The concentration-exposure time relationship for many irri tant and systemically8 acting vapors and gases may be described by C n x t = k, where the exponent, n, ranges from 0.8 9 to 3.5 (ten Berge et al., 1986). To obtain co nservative and protective AEGL values in the 10 absence of an empirically derived chemical-sp ecific scaling exponent, te mporal scaling may be 11 performed using n=3 when extrapolating to shorte r time points and n = 1 when extrapolating to 12 longer time points using the C n x t = k equation (NRC, 2001). The 30-minute AEGL-2 value 13 will also be adopted as the 10-min value because of the added uncertainty of extrapolating from 14 the 6-hr point-of-departure. AEGL-2 values are presented in Table 4, and calculations are 15 presented in Appendix A. 16

17

TABLE 4. AEGL-2 values for dimethyl phosphate

10-minute 30-minute 1-hour 4-hour 8-hour

120 ppm (540 mg/m 3 ) 120 ppm (540 mg/m 3 ) 95 ppm (430 mg/m 3 ) 60 ppm (270 mg/m 3 ) 39 ppm (180 mg/m 3 )

18
19
7. DATA ANALYSIS FOR AEGL-3 20 7.1. Summary of Human Data Relevant to AEGL-3 21

22 No human data relevant to developmen t of AEGL-3 values were identified. 23

24 7.2. Summary of Animal Data Relevant to AEGL-3 25
26
A 1-hr rat LC 50 of >5112 ppm was reported (Alb right and Wilson Inc., 1985). 27

28 Excessive lacrimation, partially closed eyes, red nasal discharge, labored breathing, and 29 unresponsiveness to sound stimuli were noted in rats exposed to 843 ppm DMP 6 hr/day for 5 30 days (Biodymanics, 1980a). Swelling of the limb s with red discoloration, fresh or dried ocular 31 or nasal discharges, and dull, dry and/or cloudy corneal surfa ces were also noted as was 32 decreased body weight gain. Deat h was noted at the next highes t concentration tested (934 ppm) 33
as one rat was killed in extremis after day 1 of exposure. 34

35

36
7.3. Derivation of AEGL-3 37

38 The highest concentration causing no mortality in rats (843 ppm for 6 hr) will be used as 39 the point-of departure for AEGL-3 (Biodymani cs, 1980a). Excessive lacrimation, partially 40 closed eyes, red nasal discharg e, red-brown material around the nares, labored breathing, and 41 unresponsiveness to sound stimuli were noted in rats exposed to 843 ppm DMP 6 hr/day for 5 42 days. Death was noted at the next concentra tion tested (934 ppm) esse ntially after one exposure 43
because one rat was killed in extremis after day 1 of the study. Inter- and intraspecies 44DIMETHYL PHOSPHITE Proposed: October, 2009

15 uncertainty factors of 3 each (total 10) will be applied because DMP is irritating, and much of the 1 toxicity is likely caused by a direct chemical e ffect on the tissue; this type of portal-of-entry 2 effect is not expected to vary greatly between species or among individuals. The concentration3 exposure time relationship for many irritant an d systemically-acting vapors and gases may be 4 described by C n x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al., 1986). 5 To obtain conservative and protective AEGL valu es in the absence of an empirically derived 6 chemical-specific scaling exponent, temporal scaling may be performed using n=3 when 7 extrapolating to shorter time points and n = 1 wh en extrapolating to longer time points using the 8

C n x t = k equation (NRC, 2001). The 30-minute AEGL -3 value will also be adopted as the 10- 9 min value because of the added uncertainty of ex trapolating from the 6-hr point-of-departure. 10 AEGL-3 values are presented in Table 5, a nd calculations are presented in Appendix A. 11

12

TABLE 5. AEGL-3 values for dimethyl phosphate

10-minute 30-minute 1-hour 4-hour 8-hour

190 ppm (850 mg/m 3 ) 190 ppm (850 mg/m 3 ) 150 ppm (670 mg/m 3 ) 96 ppm (430 mg/m 3 ) 63 ppm (240 mg/m 3 )

13 The AEGL-3 values are considered pr otective. Dividing the 1-hr rat LC 50 of >5112 ppm 14 (Albright and Wilson Inc., 1985) by 3, yields an estimated 1- hr lethality threshold of >1701 ppm. 15 Applying a total uncertainty factor of 10, yields a value of 170 ppm; this concentration is 16
consistent with the derived 1-hr AEGL-3 value. 17

18
8. SUMMARY OF AEGLS 19 8.1. AEGL Values and Toxicity Endpoints 20

21
AEGL values are summarized in Table 6. AEGL-1 values are not recommended due to 22
insufficient data. AEGL-2 values are based on la bored breathing and ptosis in mice exposed to 23
DMP for 6-hr. AEGL-3 values are based on th e highest concentration causing no mortality in 24 rats exposed to DMP for 6-hr. 25

26

TABLE 6. Summary of AEGL values
Exposure Duration Classification 10-minute 30-minute 1-hour 4-hour 8-hour

AEGL-1 (Nondisabling) NR NR NR NR NR

AEGL-2 (Disabling) 120 ppm (540 mg/m 3 ) 120 ppm (540 mg/m 3 ) 95 ppm (430 mg/m 3 ) 60 ppm (270 mg/m 3 ) 39 ppm (180 mg/m 3 )

AEGL-3 (Lethal) 190 ppm (850 mg/m 3 ) 190 ppm (850 mg/m 3 ) 150 ppm (670 mg/m 3 ) 96 ppm (430 mg/m 3 ) 63 ppm (240 mg/m 3 )
NR: Not Recommended due to insufficient data. Absence of AEGL-1 values does not imply that concentrations 27

below AEGL-2 are without effect. 28
29

30 8.2. Comparison with Other St andards and Guidelines 31

32 No other standards or guidelines were located for dimethyl phosphite. 33

34 8.3. Data Adequacy and Research 35DIMETHYL PHOSPHITE Proposed: October, 2009

16 1
Human and animal data are both limited. Hu man data are limited to one workplace 2 monitoring report. Acute animal inhalation data are limited to studies with nominal 3 concentrations. Repeated-exposure analytical data are available. A dditional acute inhalation 4 toxicity studies would be helpful. 5DIMETHYL PHOSPHITE Proposed: October, 2009

17 1
9. REFERENCES 2
3

4 Albright and Wilson, Inc. 1985. Chemical H azard Information File. Dimethyl Hydrogen 5 Phosphite (DMHP) with 4 attachments. OTS05850379. 6

7 Biodynamics, 1980a. A five day inhalation toxicity study of MCTR-174-79 in the rat. Project 8 No. 79-7344. March 4, 1980. 9
10 Biodynamics, 1980b. A four week inhalation toxi city study of MCTR-242-79 in the rat with 11 pathology report and cover letter da ted 122281. Project No. 79-7328. OTS02048661. 12

13 Dunnick, J.K., G.A. Boorman, J.K. Haseman, J. Langlos, R.H. Cardy, and A.G. Manus. 1986. 14 Lung Neoplasms in Rodents after Chronic Admi nistration of Dimethyl Hydrogen Phosphite. 15

Cancer Res. 46: 264-270. 16

17 Hazleton, 1962. Initial Submission: Letter submitti ng acute inhalation exposure in mice, rat, 18 and guinea pigs, on hexachloro-2-cyclopentanone (final report) with attachments. Hazelton 19 Laboratories, Inc. Falls Chur ch, VA. November 1, 1962. OTS0537047. 20

21 HSDB (Hazardous Substances Data Bank). 2009. Di methyl Phosphite. [Online] Available. 22 http://toxnet.nlm.nih.gov/ [02/09/ 2009]. TOXNET, Toxicology Data Network. US. Natl. Library 23
of Medicine. 24

25 McGregor, D.B., Brown, A., Cattanach, P., Edward s, I., McBride, D. and Caspary, W.J. 1988. 26 Responses of the L5178Y tk + /tk - mouse lymphoma cell forward mutation assay II: 18 coded 27 chemicals. Environ. Mol. Mutagen. 11:91-118. 28
29 Nomeir, A.A. and Matthews, H.B. 1997. Meta bolism and disposition of dimethyl hydrogen 30 phosphite in rats and mice. J. T oxicol. Environ. Health. 51: 489-501. 31

32 NTP (National Toxicology Program). 1985. Toxicology and Carcinogenesis Studies of 33 Dimethyl Hydrogen Phosphite in F344/N Rats and B6C3F 1 Mice. Technical Report Series 34
No. 287. Available online at http://ntp.niehs.nih.gov/nt p/htdocs/LT_rpts/tr287.pdf

. 35

36 NRC (National Research Council). 2001. Standing operating procedures for developing acute 37 exposure guideline levels for hazardous chemicals. Committee on Toxicology, Board on 38 Toxicology and Environmental Health Hazards , Commission on Life Sciences, National 39 Research Council. National Academy Press, Washington, DC. 40

41 Shelby, M.D., G.L. Erexson, G.J. Hook, and R.R. Tice. 1993. Evaluation of a Three-Exposure 42
Mouse Bone Marrow Micronucleus Prot ocol: Results with 49 Chemicals

. Environ. Mol. 43 Mutagen

. 21: 160-179. 44

45 ten Berge, W.F., A. Zwart, and L.M. Appelman . 1986. Concentration-time mortality response 46 relationship of irritant and sy stemically acting vapours and gase s. J. Hazard. Materials: 13: 47
301-309. 48DIMETHYL PHOSPHITE Proposed: October, 2009

18 1 Tennant, R.W., Spalding, J.W., Stasiewicz, S., Ca spary, W.D., Mason, J.M. and Resnick, M.A. 2 1987. Comparative evaluation of genetic toxicity patterns of carcinogens and noncarcinogens: 3 strategies for predictive use of short-term assays. Environ. Health Perspect. 75: 87-95. 4

5 UNEP (United Nations Environmen tal Program Publications). 2004. Dimethyl Phosphonate. 6
CAS No. 868-85-9. OECD SIDS Initial Assessment Report. 7
8 Woodruff, R.C., Mason, J.M., Valencia, R., a nd Zimmering, S. 1985. Chemical mutagenesis 9 testing in Drosophila. V. Results of 53 code d compounds tested for the National Toxicology 10 Program. Environ. Mutagen. 7: 677-702. 11

12

13DIMETHYL PHOSPHITE Proposed: October, 2009

19 1
APPENDIX A: Derivation of AEGL Values 2
3
Derivation of AEGL-1 4
5

6
AEGL-1 values are not recommended due to insu fficient data. Absence of AEGL-1 values does 7 not imply that concentrations be low AEGL-2 are without effect. 8DIMETHYL PHOSPHITE Proposed: October, 2009

20 Derivation of AEGL-2 1

2 Key Study: Hazleton, 1962. Initial Submission: Letter submitting acute inhalation exposure 3 in mice, rat, and guinea pigs, on hexachlo ro-2-cyclopentanone (final report) with 4 attachments. Hazelton Laboratories, Inc. Falls Church, VA. November 1, 1962. 5

OTS0537047. 6

7 Toxicity endpoint: Labored breathing and ptosis in mice exposed to 1575 ppm DMP for 6 8
hours. 9
10 Uncertainty factors: Interspecies : 3, DMP is irritating, and much of the toxicity is likely caused 11 by a direct chemical effect on the tissues ; this type of portal-of-entry effect 12 is not expected to vary greatly between species. The interspecies 13 uncertainty factor of 3 is also considered sufficient because no clinical 14 signs were noted in rats or guinea pigs exposed to 1575 ppm for 6 hours. 15

16 Intraspecies: 3, DMP is irritating, and mu ch of the toxicity is likely caused 17 by a direct chemical effect on the tissues ; this type of portal-of-entry effect 18 is not expected to vary greatly among individuals. 19

20 Modifying factor: 3: Sparse data base and nominal concen tration for point-of-departure 21

22 Time scaling: C 3 x t = k (30-min, 1-hr, 4-hr) 23 1575 ppm 3 x 6 hr = 2.34 x 10 10 ppm 3 -hr 24

25

C 1 x t = k (8-hr) 26 1575 ppm x 6 hr = 9450 ppm-hr 27

28 10-minute AEGL-2: 30-min value adopted as 10-min value = 120 ppm 29

30
30-minute AEGL-2: C 3 x 0.5 hr = 2.34 x 10 10 ppm 3 ·hr 31

C 3 = 4.68 x 10 10 ppm 32 C = 3604 ÷ 30 = 120 ppm 33

34
1-hour AEGL-2: C 3 x 1 hr = 2.34 x 10 10 ppm 3 ·hr 35

C 3 = 5.85x 10 9 ppm 36 C = 2860 ÷ 30 = 95 ppm 37

38
4-hour AEGL-2: C 3 x 4 hr = 2.34 x 10 10 ppm 3 ·hr 39

C 3 = 5.85 x 10 9 ppm 40 C = 1802 ÷ 30 = 60 ppm 41

42
8-hour AEGL-2: C 1 x 8 hr = 9450 ppm 3 ·hr 43

C 1 = 1181 ppm 44 C = 1181 ÷ 30 = 39 ppm 45

46

47DIMETHYL PHOSPHITE Proposed: October, 2009

21 1
Derivation of AEGL-3 2
3 Key Study: Biodynamics, 1980a. A five day inhalation toxicity study of MCTR-174- 4 79 in the rat. Projec t No. 79-7344. March 4, 1980. 5

6 Toxicity endpoint: Highest concentration caus ing no mortality in rats (843 ppm for 6 hr). 7 Excessive lacrimation, partially clos ed eyes, red nasal discharge, red8 brown material around the nares, la bored breathing, and unresponsiveness 9 to sound stimuli were noted in rats exposed to 843 ppm DMP 6 hr/day for 10 5 days. Death was noted at the next concentration tested (934 ppm) 11 essentially after one exposure because one rat was killed in extremis after 12 day 1 of the study. 13

14 Uncertainty factors: Interspecies : 3, DMP is irritating, and much of the toxicity is likely caused 15 by a direct chemical effect on the tissues ; this type of portal-of-entry effect 16 is not expected to vary greatly between species. 17

18 Intraspecies: 3, DMP is irritating, and mu ch of the toxicity is likely caused 19 by a direct chemical effect on the tissues ; this type of portal-of-entry effect 20 is not expected to vary greatly among individuals. 21

22 Modifying factor: None 23

24 Time scaling: C 3 x t = k (30-min, 1-hr, 4-hr) 25 843 ppm 3 x 6 hr = 3.59 x 10 9 ppm 3 -hr 26

27

C 1 x t = k (8-hr) 28 843 ppm x 6 hr = 5058 ppm-hr 29

30 10-minute AEGL-3: 190 ppm: 30-min value adopted as 10-min value 31

32
30-minute AEGL-3: C 3 x 0.5 hr = 3.59 x 10 9 ppm 3 ·hr 33

C 3 = 7.18 x 10 9 ppm 34 C = 1929 ÷ 10 = 190 ppm 35

36
1-hour AEGL-3: C 3 x 1 hr = 3.59 x 10 9 ppm 3 ·hr 37

C 3 = 3.59 x 10 9 ppm 38 C = 1531 ÷ 10 = 150 ppm 39

40
4-hour AEGL-3: C 3 x 4 hr = 3.59 x 10 9 ppm 3 ·hr 41

C 3 = 8.98 x 10 8 ppm 42 C = 964 ÷ 10 = 96 ppm 43

44
8-hour AEGL-3: C 1 x 8 hr = 5058 ppm 3 ·hr 45

C 1 = 632 ppm 46 C = 632 ÷ 10 = 63 ppm 47DIMETHYL PHOSPHITE Proposed: October, 2009

22 1

2 APPENDIX B: Derivation Summary for Dimethyl Phosphite AEGLs 3

4

5
AEGL-1 VALUES 6

10-minute 30-minute 1-hour 4-hour 8-hour

NR NR NR NR NR
Key Reference: Test Species/Strain/Number: Exposure Route/Concentrations/Durations:

Effects:

Endpoint/Concentration/Rationale: Uncertainty Factors/Rationale: Total uncertainty factor: Interspecies: Intraspecies:

Modifying Factor: NA Animal to Human Dosimetric Adjustment: NA Time Scaling: Data Adequacy: Not Recommended due to insufficient data. Absence of AEGL-1 values does not imply that
concentrations below AEGL-2 are without effect.DIMETHYL PHOSPHITE Proposed: October, 2009

23 1
AEGL-2 VALUES 2

10-minute 30-minute 1-hour 4-hour 8-hour 120 ppm (540 mg/m 3 ) 120 ppm (540 mg/m 3 ) 95 ppm (430 mg/m 3 ) 60 ppm (270 mg/m 3 ) 39 ppm (180 mg/m 3 )
Key Reference: Hazleton, 1962. Initial Submission: Letter submitting acute inhalation exposure in mice, rat, and guinea pigs, on hexachloro-2-cyclopentanone (final report) with attachments. Hazelton Laboratories, Inc. Falls Church, VA. November 1, 1962. OTS0537047. Test Species/Strain/Number: Mouse/Swiss albino/10 males Exposure Route/Concentrations/Durations: Inhalation/1575 ppm/6-hr Effects: Labored breathing (2/10) and ptosis (10/10).

Endpoint/Concentration/Rationale: Labored breathing and ptosis/1575 ppm Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 DMP is highly irritating, and much of the toxicity is likely caused by a direct chemical eff ect on the tissue; this type of portal-of-entry effect is not expected to vary greatly between species or among individuals. The interspecies uncertainty factor of 3 is also considered sufficient beca use no clinical signs were noted in rats and guinea pigs exposed to 1575 ppm for 6 hr.

Modifying Factor: 3: Sparse data base and nominal concentration point-of-departure Animal to Human Dosimetric Adjustment: NA Time Scaling: C n x t = k. To obtain conservative and protective AEGL values in the absence of an empirically derived chemical-specific scaling exponent, temporal scaling was performed using n=3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the C n x t = k equation (NRC, 2001). The 30-min AEGL-2 value was adopted as the 10-min value because the point-of-departure is 6-hr. Data Adequacy: Sparse data set.

3DIMETHYL PHOSPHITE Proposed: October, 2009

24 1

2
AEGL-3 VALUES 3

4 5

10-minute 30-minute 1-hour 4-hour 8-hour 190 ppm (850 mg/m 3 ) 190 ppm (850 mg/m 3 ) 150 ppm (670 mg/m 3 ) 96 ppm (430 mg/m 3 ) 63 ppm (240 mg/m 3 )
Key Reference: Biodynamics, 1980a. A five day inhalation toxicity study of MCTR-174-79 in the rat. Project No. 79-7344. March 4, 1980. Test Species/Strain/Number: Rat/Sprague-Dawley/ 5/sex/group Exposure Route/Concentrations/Durations: Inhalation/ 431, 843, 934 ppm/6-hr for up to five days Effects: All Concentration Groups: Excessive lacrimation, partially closed eyes, red nasal discharge, red-brown material around the nares, labored breathing, and unresponsiveness to sound.

934 ppm: Mortality. One rat killed in extremis on day 1, 8/9 remaining rats died before study termination. Endpoint/Concentration/Rationale: Highest concentration causin g no mortality in rats. Death was noted at the next concentration tested (934 ppm) essentially after one exposure because one rat was killed in extremis after day 1 of the study. /843 ppm for 6-hr Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 DMP is highly irritating, and much of the toxicity is likely caused by a direct chemical eff ect on the tissue; this type of portal-of-entry effect is not expected to vary greatly between species or among individuals.

Modifying Factor: NA: Animal to Human Dosimetric Adjustment: NA Time Scaling: C n x t = k. To obtain conservative and protective AEGL values in the absence of an empirically derived chemical-specific scaling exponent, temporal scaling was performed using n=3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the C n x t = k equation (NRC, 2001). The 30-min AEGL-3 value was adopted as the 10-min value because the point-of-departure is 6-hr. Data Adequacy: Sparse data set. However, the AEGL-3 values are considered protective. Dividing the 1-hr rat

LC 50 of >5112 ppm (Albright and Wilson Inc., 1985) by 3, yields an estimated 1-hr lethality threshold of >1701 ppm. Applying a total uncertainty factor of 10, yields a value of 170 ppm; this concentration is consistent with the
derived 1-hr AEGL-3 value.DIMETHYL PHOSPHITE Proposed: October, 2009

25 1 APPENDIX C: Category Plot for Dimethyl Phosphite 2
3

4 5

1 10 100 1000 10000ppm

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

Human - Discomfort

Human - Disabling

Animal - No Effect

Animal - Discomfort

Animal - Disabling

Animal - Partially Lethal

Animal - Lethal

AEGL Chemical Toxicity Dimethyl Phosphite

AEGL-2

6 7 8 9 Note: Animal partially lethal data points at 360 minu tes are from repeated exposure studies. Lethality was 10 not noted until after 14-27 days of exposure. 11DIMETHYL PHOSPHITE Proposed: October, 2009

26 Category Plot Data 1 2 3

Source Species Sex # Exposures ppm Minutes Category Comments

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-2 120 10 AEGL
NAC/AEGL-2 120 30 AEGL
NAC/AEGL-2 95 60 AEGL
NAC/AEGL-2 60 240 AEGL
NAC/AEGL-2 39 480 AEGL

NAC/AEGL-3 190 10 AEGL
NAC/AEGL-3 190 30 AEGL
NAC/AEGL-3 150 60 AEGL
NAC/AEGL-3 96 240 AEGL
NAC/AEGL-3 63 480 AEGL

Rat 1 5112 60 pl free standing LC50 >5112 ppm Rat 1 1575 360 0 no clinical signs Gp 1 1575 360 0 no clinical signs Mouse 1 1575 360 2 labored breathing (1/10), ptosis (10/10) Rat 5 431 360 2 lacrimation, nasal discharge, labored breathing, unresponsive to sound, corneal effects Rat 5 843 360 2 lacrimation, nasal discharge, labored breathing, unresponsive to sound, corneal effects, increased lung weight
Rat 5 934 360 3 10/10 morta lity, days 1-4 of 5 day exposure protocol Rat 20 12 360 1 Irritation of superficial ocular structure Rat 20 35 360 1 skin, mucous membrane, ocular irritation Rat 20 119 360 pl 2/40 mortalit y days 14-23; signs of irritation, rales, decreased BW, hematological effects, ocular opacity, cataract Rat 20 198 360 pl 27/40 mortality before day 27; signs of irritation, rales, decreased BW, hematological effects, ocular opacity, cataract 4