## ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs)
FOR
TRIMETHYL PHOSPHITE CAS Reg. No. 121-45-9

PROPOSEDTRIMETHYL PHOSPHITE Proposed: October, 2009

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## ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 2 

## FOR 3 

## TRIMETHYL PHOSPHITE 4 

## CAS Reg. No. 121-45-9 5

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## PROPOSED 9

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21TRIMETHYL PHOSPHITE Proposed: October, 2009

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PREFACE 3
4 Under the authority of the Federal Adviso ry Committee Act (FACA) P. L. 92-463 of 5 1972, the National Advisory Committee for Acut e Exposure Guideline Levels for Hazardous 6 Substances (NAC/AEGL Committee) has been established to identify, review and interpret 7 relevant toxicologic and other sc ientific data and develop AEGLs for high priority, acutely toxic 8
chemicals. 9
10 AEGLs represent threshold exposure limits for the general public a nd are applicable to 11 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels

C AEGL-1, 12
AEGL-2 and AEGL-3

Care developed for each of five e xposure periods (10 and 30 minutes, 1 13 hour, 4 hours, and 8 hours) and are distinguished by va rying degrees of severity of toxic effects. 14
The three AEGLs are defined as follows: 15
16 AEGL-1 is the airborne concentration (expres sed as parts per million or milligrams per 17 cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general 18 population, including susceptible indi viduals, could experience notab le discomfort, irritation, or 19 certain asymptomatic, non-sensory effects. Ho wever, the effects are not disabling and are 20
transient and reversible upon cessation of exposure. 21

22 AEGL-2 is the airborne concentration (expresse d as ppm or mg/m3) of a substance above 23 which it is predicted that th e general population, including su sceptible individuals, could 24 experience irreversible or other serious, long-lasting adverse hea lth effects or an impaired ability 25
to escape. 26
27 AEGL-3 is the airborne concentration (expres sed as ppm or mg/m3) of a substance above 28 which it is predicted that th e general population, including su sceptible individuals, could 29 experience life-threatening health effects or death. 30
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Airborne concentrations below the AEGL-1 re present exposure levels that could produce 32 mild and progressively increas ing but transient and nondisab ling odor, taste, and sensory 33 irritation or certain asymptomatic , non-sensory effects. With incr easing airborne concentrations 34 above each AEGL, there is a progressive increase in the likelihood of occu rrence and the severity 35
of effects described for each corresponding AEGL. Although the AEGL values represent 36 threshold levels for the general public, including susceptible subpopulations, such as infants, 37 children, the elderly, persons with asthma, and thos e with other illnesses, it is recognized that 38 individuals, subject to unique or idiosyncratic responses, could experience the effects described 39
at concentrations belo w the corresponding AEGL 40

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42TRIMETHYL 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
2.2.1. Odor Threshold/Odor Awareness ........................................................................................8 8

2.2.2. Case Reports ..........................................................................................................................9 9

2.3. Developmental/Reproductive Toxicity .........................................................................................9 10

2.4. Genotoxicity

............................................................................................................................... .....9 11

2.5. Carcinogenicity ..............................................................................................................................9 12

2.6. Summary

............................................................................................................................... ..........9 13

3. ANIMAL TOXICITY DATA ............................................................................................................9 14

3.1. Acute Lethality

............................................................................................................................... 9 15

3.2. Repeated-Exposure Studies .........................................................................................................10 16

3.3. Developmental/Reproductive Toxicity .......................................................................................11 17

3.4. Genotoxicity

............................................................................................................................... ...11 18

3.5. Chronic Toxicity/Carcinogenicity ..............................................................................................12 19

3.6. Summary

............................................................................................................................... ........12 20

4. SPECIAL CONSIDERATION S .....................................................................................................12 21

4.1. Metabolism and Disposition ........................................................................................................12 22

4.2. Mechanism of Toxicity ................................................................................................................12 23

4.3. Structure Activity Relationships ................................................................................................12 24

4.4. Other Relevant Information .......................................................................................................12 25

4.4.1. Species Variability ...............................................................................................................13 26

4.4.2. Susceptible Populations ......................................................................................................13 27

4.4.3. Concentration-Exposure Duration Relationship ..............................................................13 28

4.4.4. Concurrent Exposure Issues ..............................................................................................13 29

5. DATA ANALYSIS FOR AEGL-1 ..................................................................................................13 30

5.1. Summary of Human Data Relevant to AEGL-1 .......................................................................13 31

5.2. Summary of Animal Data Relevant to AEGL-1 .......................................................................13 32

5.3. Derivation of AEGL-1 .................................................................................................................13 33

6. DATA ANALYSIS FOR AEGL-2 ..................................................................................................14 34

6.1. Summary of Human Data Relevant to AEGL-2 .......................................................................14 35

6.2. Summary of Animal Data Relevant to AEGL-2 .......................................................................14 36

6.3. Derivation of AEGL-2 .................................................................................................................14 37

7. DATA ANALYSIS FOR AEGL-3 ..................................................................................................15 38

7.1. Summary of Human Data Relevant to AEGL-3 .......................................................................15 39

7.2. Summary of Animal Data Relevant to AEGL-3 .......................................................................15 40

7.3. Derivation of AEGL-3 .................................................................................................................15 41

8. SUMMARY OF AEGLS .................................................................................................................15 42

8.1. AEGL Values and Toxicity Endpoints .......................................................................................15 43

8.2. Comparison with Other Standards and Guidelines ..................................................................16 44

8.3. Data Adequacy and Research .....................................................................................................16 45

9. REFERENCES

............................................................................................................................... ..17 46
APPENDIX A: DERIVATION OF AEGL VALUES ...........................................................................19 47
APPENDIX B: DERIVATION SUMMARY FOR TRIMETHYL PHOSPHITE AEGLS ...............22 48

APPENDIX C: CATEGORY PLOT FOR TRIMETHYL PHOSPHITE ..................................................25 49TRIMETHYL PHOSPHITE Proposed: October, 2009

5 LIST OF TABLES 1

2 Table 1. Summary of AEGL Values for Trimethyl Phosphite ................................................ 7 3 Table 2. Chemical and physical pr operties for trimethyl phosphite...................................... 8 4 Table 3. Time to death in mice and rats exposed to 6450 ppm TPM for 6 hours ................ 10 5 Table 4. AEGL-1 values for trimethyl phosphite.................................................................... 14 6 Table 5. AEGL-2 values for trimethyl phosphite.................................................................... 14 7 Table 6. AEGL-3 values for trimethyl phosphite.................................................................... 15 8 Table 7. Summary of AEGL values ......................................................................................... 16 9 Table 8. Extant standards and guidelines for trimethyl phosphite....................................... 16 10
11TRIMETHYL PHOSPHITE Proposed: October, 2009

6 EXECUTIVE SUMMARY 1
2 Trimethyl phosphite (TMP) is a colorless liqui d with an irritating, pungent, oily, pyridine3 like odor. Its primary use is as an intermediate in the manufacture of pesticides. It is also used 4 as a fireproofing agent in the pr oduction of textiles, as an intermediate in the production of 5 flame-retardant polymers for polyurethane fo ams, and as a catalyst (HSDB, 2009). 6

7 The no-effect-level for clinical signs in rats (10 ppm) exposed to TMP 6 hr/day, 5 days/week 8 for 4 weeks (Biodynamics, 1979) was used as the point-of-departure for AEGL-1 values. An 9 intraspecies uncertainty factor of 3 was applied b ecause the point-of-departure is from a repeated 10 exposure study and the endpoint is not likely the result of a single exposure. An interspecies 11 uncertainty factor of 1 was applied. Although an interspecies UF of 3 might normally be 12 applied, use of a total uncertainty factor of 10 yiel ds AEGL-1 values that are not compatible with 13 human occupational exposure data (AEGL-1 valu es derived with a to tal UF of 10 are 3.3, 2.3, 14 1.8, 1.1, and 0.60 ppm for 10-min, 30-min, 1-hr, 4-hr, a nd 8-hr, respectively). No effects were 15 noted in workers repeatedly exposed up to 15 ppm (ACGIH, 1991). The concentration-exposure 16 time relationship for many irritant and systemi cally-acting vapors and gases may be described by 17
C n x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al., 1986). To obtain 18 conservative and protective AEGL values in th e absence of an empirically derived chemical19 specific scaling exponent, temporal scaling was performed using n=3 when extrapolating to 20 shorter time points and n = 1 when extrap olating to longer time points using the C n x t = k 21 equation (NRC, 2001). Extrapolation was used to derive the 10-minute value because the 6-hour 22 point-of-departure is from a repeated exposure study. 23

24 The lens opacities in rats exposed to 1 01 ppm TMP 6 hours/day, 5 days/week for 4 weeks 25 (Biodynamics, 1979) were used as the point-of-depa rture for AEGL-2 values. This endpoint was 26 still present in some animals at 2-weeks post-exposure. An intras pecies uncertainty factor of 3 27 was applied because the point-of-departure is fr om a repeated exposure study and the endpoint is 28 not likely the result of a single exposure. The lens opacities ob served in rats repeatedly exposed 29 to 101 ppm TMP were noted after 2 weeks and c ontinued to increase in frequency and severity 30 after 4 weeks exposure, suggesting a cumulative eff ect. An interspecies uncertainty factor of 1 31 was applied. Although an interspecies UF of 3 might normally be applied, use of a total 32 uncertainty factor of 10 yields AEGL-2 values that are not compatible with human occupational 33 exposure data (AEGL-2 values derived with a total UF of 10 are 33, 23, 18, 12, and 6.0 ppm for 34 10-min, 30-min, 1-hr, 4-hr, and 8-hr, respectively). No effects were noted in workers repeatedly 35 exposed up to 15 ppm (ACGIH, 1991). Time s caling is as described above for AEGL-1. 36
37 Up to 50% lethality was observed in mice exposed to 6450 ppm TMP for approximately 3 38 hours (Hazleton, 1962). In the absence of other a ppropriate data for deriving AEGL-3 values, 39 this exposure concentration was divided by 3 to es timate a threshold for lethality (Rusch et al., 40 2009) (point-of-departure 2150 ppm). Inter- and in traspecies uncertainty f actors of 3 each (total 41 10) were applied because TMP is highly irritatin g, and much of the toxicity resulting from an 42 acute exposure is likely caused by a direct chemical effect on the tissue; this type of portal-of43 entry effect is not expected to vary greatly between species or among individuals. Temporal 44 scaling was performed using n=3 when extrapol ating to shorter time points and n = 1 when 45 extrapolating to longer time points using the C n x t = k equation (NRC, 2001). 46
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The calculated values are lis ted in Table 1 below. 48TRIMETHYL PHOSPHITE Proposed: October, 2009

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2 Table 1. Summary of AEGL Values for Trimethyl Phosphite

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

AEGL

B 1 (Nondisabling) 11 ppm (56 mg/m 3 ) 7.6 ppm (39 mg/m 3 ) 6.1 ppm (31 mg/m 3 ) 3.8 ppm (19 mg/m 3 ) 2.5 ppm (13 mg/m 3 ) NOEL for clinical signs in rats (Biodynamics, 1979)

AEGL

B 2 (Disabling) 110 ppm (560 mg/m 3 ) 77 ppm (390 mg/m 3 ) 61 ppm (310 mg/m 3 ) 38 ppm (190 mg/m 3 ) 25 ppm (128 mg/m 3 ) Lens opacities in rats (Biodynamics, 1979)

AEGL

B 3 (Lethal) 560 ppm (2900 mg/m 3 ) 390 ppm (2000 mg/m 3 ) 310 ppm (1600 mg/m 3 ) 160 ppm (820 mg/m 3 ) 81 ppm (410 mg/m 3 ) Estimated 3-hr lethality
threshold in mice (Hazleton, 1962) 3 4 5TRIMETHYL PHOSPHITE Proposed: October, 2009

8 1 1. INTRODUCTION 2
3 Trimethyl phosphite (TMP) is a colorless liqui d with an irritating, pungent, oily, pyridine4 like odor. Its primary use is as an intermediate in the manufacture of pesticides. It is also used 5 as a fireproofing agent in the pr oduction of textiles, as an intermediate in the production of 6 flame-retardant polymers for polyurethane foams, and as a catalyst (HSDB, 2009). It is 7 produced by reaction of phosphorus tr ichloride and methyl alcohol in the presence of a tertiary 8 amine. Trimethyl phosphite is manufactured prim arily overseas and is imported into the US for 9 domestic use; manufacture is in closed sy stems (HPV, 2005). No current quantitative 10 manufacturing information was located. Chemical and physical properties are presented in Table 11
2. 12
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14 Table 2. Chemical and physical properties for trimethyl phosphite

Parameter Value References

Synonyms Methyl phosphite; Phosphorus acid trimethyl ester; TMP; Trimethoxyphosphine ACGIH, 1991

Chemical formula C 3 H 9 O 3 P HSDB, 2009 Molecular weight 124.08 HSDB, 2009 CAS Reg. No. 121-45-9 HSDB, 2009 Physical state Colorl ess liquid HSDB, 2009

Solubility in water Insoluble- Decomposes to dimethyl phosphite and methanol ACGIH, 1991

Vapor pressure 24 torr at 25oC (saturates in air at 32,000 ppm) HSDB, 2009

Vapor density (air =1) 4.3 HSDB 2009 Specific gravity 1.046 at 20oC HSDB, 2009 Melting point -78oC HSDB, 2009 Boiling point 111.5oC ACGIH 1991 Flash point 37.8oC, open cup HSDB, 2009

Conversion factors 1 ppm = 5.1 mg/m 3 1 mg/m 3 = 0.20 ppm

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2. HUMAN TOXICITY DATA 16 2.1. Acute Lethality 17
18 No information concerning acute lethality was located. 19
20 2.2. Nonlethal Toxicity 21
2.2.1. Odor Threshold/Odor Awareness 22
23 An odor threshold of 0.0001 ppm was reported from a laboratory test panel. No further 24 information was available (Mobil Oil, 1979). 25
26 ACGIH (1991) reported that in an occupational setting, the odor of TMP was not generally 27 considered objectionable until concentrations appr oached 20 ppm. No further information was 28
available. 29
30TRIMETHYL PHOSPHITE Proposed: October, 2009

9 2.2.2. Case Reports 1
2 ACGIH (1991) reported that analyses of ai r in a TMP manufacturing plant from 1969 to 3 1971 showed an average concentration of up to 8 ppm. ACGIH (1991) also reported that 4 average workplace exposures in another TMP pl ant in 1979 usually ranged from 0.3 to 4 ppm, 5 with occupational exposures up to 15 ppm. Mon itoring of 179 employees in these plants showed 6
no ocular effects or other advers e effects associated with occupational exposure to TMP. No 7 further details were provided. 8
9
10 2.3. Developmental/Reproductive Toxicity 11
12 No human developmental/reproductive data were located. 13

14 2.4. Genotoxicity 15
16
No human data were located. 17
18 2.5. Carcinogenicity 19
20
No human data were located. 21

22 2.6. Summary 23
24
Human data are limited to odor threshold and occupational monitoring data, both of which 25 are available only from secondary sources. An odor threshold of 0.0001 ppm was reported, and 26 odor was not considered objectionabl e until concentrations approached 20 ppm. No effects were 27 reported from occupational exposure con centrations ranging from 0.3 to 15 ppm. 28
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3. ANIMAL TOXICITY DATA 30 3.1. Acute Lethality 31
32 Groups of ten male Swiss albino mice, ten male Wistar rats, and ten male English short-hair 33 guinea pigs were exposed to a “mean theoretic al concentration” of 6450 ppm TMP for 6 hours, 34 followed by a 24-hour observation period (Hazlet on, 1962). Concentrations were calculated 35
from air flow and net loss of test material. Exposures were conducted in a 500 liter stainless 36
steel chamber with one or two fritted-disc glass bubblers at th e inlet containing the TMP. A 37 glass trap was placed between the vapor generato r and chamber to collect liquid. Air flow was 38
18 L/minute with one bubbler and 35 L/min w ith two bubblers. Animals were observed 39 continually during exposure for signs of toxicity and mortalit y. At the end of the 24-hour 40 observation period, surviving animals were sacrifi ced and necropsies were performed; necropsies 41 were also performed on animals that died during exposure. Both cl inical signs and lethality data 42 suggest that mice are more sensitiv e than rats, and rats may be more sensitive than guinea pigs. 43 Clinical signs included an init ial increase in activity, followed by progressive depression. At 30 44 minutes, all mice were prostrate and rats and gu inea pigs were depressed. Lacrimation and 45 ptosis were observed in most animals, and after 3-hours, mice exhibited increasing 46 exophthalmos. Signs remained unchanged until the death of the animal or cessation of exposure 47 after 6 hours. No guinea pigs died during expos ure; whereas ten mice and six rats died during 48TRIMETHYL PHOSPHITE Proposed: October, 2009

10 exposure; times to death for mice and rats dyi ng during exposure are summarized in Table 3. 1 Additionally, one rat died the day after expos ure. Animals dying dur ing exposure showed a 2 foamy fluid in the stomachs and lungs and liver congestion. Four rats al so exhibited congestion 3 of the spleen and two rats had ad renal congestion. Mice all had distenti on of the large intestine. 4 Guinea pigs sacrificed at study termination had lung and liver congestion and gaseous distention 5 of the gastrointestinal tract. Necropsies of surviving rats s howed only lung congestion with 6 hemorrhage and kidney congestion. 7
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Table 3. Time to death in mice and rats exposed to 6450 ppm TPM for 6 hours

Number dead/Number exposed (cumulative) Time to death (hrs: mins) Mice Rats

2:55 2/10 -

2:58 4/10 -

3:01 5/10 -

3:02 - 2/10

3:05 6/10 -

3:11 - 3/10

4:03 8/10 5/10

4:07 9/10 -

4:20 - 6/10

4:44 10/10 -

LT 50 (hrs: mins) ( 95%CI) 3:08 (2:51-3:27) 4:03 (3:27-4:47)
Hazleton, 1962 10
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A nominal 1-hr rat LC 50 of 35,885 ppm was reported by Mobil Oil (1979); no further details 12 were provided. 13

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A nominal 4-hr rat LC 50 of > 10,000 ppm has also been re ported (Levin and Gabriel, 1973). 15 Animals showed a high degree of irritation, discomfort, and respir atory distress. No further 16 details were provided. 17
18 19
20 3.2. Repeated-Exposure Studies 21
22 Groups of Sprague-Dawley rats were repeatedly exposed to 0 (20 rats/sex), 105 (20 rats/sex), 23 or 600 ppm (36 rats/sex) TMP (Biodynamics, 1978) . Control and 105 ppm group animals were 24 exposed 6 hours/day, 5 days/week for four week s. Animals in the 600 ppm group were exposed 25 6 hours/day, 5 days/week for three weeks and r eceived three 6-hour exposures during the fourth 26 week. Animals were exposed in one cubic me ter stainless steel and glass dynamic chambers, 27
with an airflow of 132 L/min. The test atmos phere was generated by passing a nitrogen stream 28 through a bubbler containing the TMP, varyi ng the amount of nitr ogen to volatilize the 29 appropriate amount of test materi al. Test atmospheres were samp led four times per exposure for 30 infrared analysis. Additionally, periodic samp les were taken from the chambers each exposure 31 day and analyzed via gas chromatography. Th e purpose of the study wa s to determine if 32 lenticular cataracts would develop from TMP ex posure. No treatment-related mortality was 33 reported in the control or 105 ppm groups; howev er, 30/36 males and 19/36 females in the 600 34 ppm group died during the study. One male and one female in the 600 ppm group were 35TRIMETHYL PHOSPHITE Proposed: October, 2009

11 sacrificed in extremis. Deaths occurred between days 15 and 31 of the study. All rats in both 1 treatment groups showed concentration-related si gns of irritation during the 4-week exposure. 2 Additionally, animals exposed to 600 ppm e xhibited decreased ac tivity, poor condition, 3 excessive salivation, and ocular abnormalities. Ophthalmoscopic examinations revealed grooved 4 lens opacities in 7 of 30 rats exposed to 105 ppm ; these lesions were reve rsible within 8 weeks 5 post exposure. At 600 ppm, almost all rats devel oped mature (severe), irreversible cataracts. 6 Body weight in the 105 ppm group was comparable to controls throughout the study. Body 7 weight in the 600 ppm group was significantly de creased from week 1 through 5; body weights 8 then increased and became comparable with cont rols, thereafter. No treatment-related necropsy 9 findings were noted in rats in the 105 ppm group. However, there was an increase in absolute 10 and relative lung weights in the 600 ppm group, and gross necr opsy revealed lung congestion 11
and discoloration. 12
13 In another study, Biodynamics (1979) groups of twenty male and twenty female 14 Sprague-Dawley rats were exposed to 0, 10, 51, or 101 ppm TMP 6 hours/day, 5 days/week for 15 up to four weeks. Five rats/sex were sacrificed after two and f our weeks exposure, and after two 16 and eight weeks post-exposure. Exposure me thods are similar to those described above 17 (Biodynamics, 1978). No treatment-related deaths o ccurred at any concentr ation, and no clinical 18 signs were observed during the exposure period. Body and lung weights for all treatment groups 19
were similar to those of controls. No lens effects were noted at 10 ppm. Ocular surface 20 irregularities were noted at th e end of 4 weeks in rats exposed to 51 or 101 ppm, with females 21 affected more than males. Two weeks after expos ure, lens opacities were noted only in females 22 in the 51 ppm group (2/10), and 101 ppm group (6/10). 23

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Albino rats were administer ed 100, 300, or 600 ppm TMP 6 hours/ day, 5 days/week for four 25 weeks (Mobil Oil, 1979). There were no treatmen t-related deaths at 100 ppm. Approximately 26 10% mortality occurred in the 300 ppm group, and mortality exceeded 70% in the 600 ppm 27 group over the 4 week exposure period. No respir atory effects were noted at 100 or 300 ppm; 28 however, gross histological evidence of lung inflammation was noted at 600 ppm. Clinical signs 29
of ocular irritation were noted in all treatment groups. A few rats exposed to 100 ppm had mild 30 and reversible striate opacities of the lenses; however, these lesions were similar to those 31 occurring spontaneously in untreat ed rats. Mild cataracts were noted at 300 ppm, and severe 32 cataracts were reported at 600 ppm. No othe r experimental details were available. 33
34 Groups of five rats were exposed to 0 (5 male s) or 500 ppm (nominal concentration; 4 males, 35 1 female) TMP 7.5 hours/day, 5 days/week for 8 weeks (Levin and Gabriel, 1973). 36 Histopathological changes in the lungs were noted; however, a later review of this study deemed 37
the results unreliable because the effects were likely related to chr onic lung disease in the 38 laboratory rats (HPV, 2005). 39
40 3.3. Developmental/Reproductive Toxicity 41
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No inhalation data were located. 43

44 3.4. Genotoxicity 45
46 Trimethyl phosphite was negative for b acterial mutagenicity in a series of S. typhimurium 47
Ames tests both with and without activation. Trimethyl phosphite was positive both with and 48TRIMETHYL PHOSPHITE Proposed: October, 2009

12 without metabolic activation in the mouse lymphoma assay and was also positive in a battery of 1 Drosophila melanogaster mutagenicity assays. It gave both positive and negative results in 2 DNA damage and repair assays in vitro in E. coli and S. typhimurium strains, both with and 3 without exogenous metabolic activation and wa s negative for cell tran sformation in C3H/T101⁄2 4
cells in vitro (HSDB, 2009; HPV, 2005). 5

6 3.5. Chronic Toxicity/Carcinogenicity 7
8
No data were located. 9
10 3.6. Summary 11
12 Limited acute inhalation data suggest that trim ethyl phosphite is of low acute toxicity with 13 regard to lethality. Clinical signs from both acute and repeated-exposure studies suggest that 14 TMP is an irritant; effects in cluded lacrimation, exophthalmos, respiratory distress, ocular 15 opacities, cataracts, and pulmonary congestion. Cumulative effects we re also noted; lens 16 opacities observed in rats repeatedly exposed to approximately 100 ppm TMP were noted after 2 17 weeks and continued to increase in frequency and severity after 4 weeks exposure. Genotoxicity 18 testing yielded both positive and negative results . No data on developmental/ reproductive 19 toxicity or chronic toxicity /carcinogenicity were located. 20

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4. SPECIAL CONSIDERATION S 22 4.1. Metabolism and Disposition 23
24 Little information was located concerning the metabolism and disposition of trimethyl 25 phosphite. However, trimethyl phosphite may be hydrolyzed in the moist respiratory tract to 26 dimethyl phosphite and meth anol (ACGIH, 1991). 27
28 4.2. Mechanism of Toxicity 29
30 TMP is an acute irritant to the skin, eyes , and upper respiratory tract (ACGIH, 1991). 31 Clinical signs noted in rat i nhalation studies include lacrim ation, exophthalmos, respiratory 32 distress, ocular opaciti es, cataracts, and pulmonary congestio n. Cumulative effects were also 33 noted. Lens opacities observed in rats repeat edly exposed to approximately 100 ppm TMP were 34
noted after 2 weeks and continued to increase in frequency and severity after 4 weeks exposure 35 (Biodynamics, 1979). 36
37
38 4.3. Structure Activity Relationships 39
40 TMP is structurally similar to organophosphate insecticides that inhibit cholinesterase 41 activity. However, a study of c holinesterase inhibition followi ng intravenous administration of 42 TMP in rats, rabbits, and dogs and in vitro studies of cholinesterase inhibition potential showed 43
that TMP does not inhibit cholinesterase ac tivity (HPV, 2005). Repeated-exposure inhalation 44 studies in rats (Biodymanics, 1978, 1979; Mobi l Oil, 1979; Levin and Gabriel, 1973) did not 45 indicate systemic or cumulative toxic e ffects suggesting cholin esterase inhibition. 46
47
4.4. Other Relevant Information 48TRIMETHYL PHOSPHITE Proposed: October, 2009

13 1

2 4.4.1. Species Variability 3
4 Data are not sufficient for determining species sensitivity. 5

6 4.4.2. Susceptible Populations 7
8 No information was available on populations especially sensitive to TMP toxicity. 9
10 4.4.3. Concentration-Exposure Duration Relationship 11
12 The concentration exposure time relationship for many irritant and systemically acting 13 vapors and gases may be described by C n x t = k, where the exponent ranges from 0.8 to 3.5 (ten 14 Berge et al. 1986). In lieu of a definitive data set allowing empirical derivation of the exponent 15 n, temporal scaling was performed, using n = 3 wh en extrapolating to sh orter time points and n = 16 1 when extrapolating to l onger time points using the C n x t = k equation (NRC, 2001). 17
18 4.4.4. Concurrent Exposure Issues 19
20 No concurrent exposure issues were identified. 21

22
5. DATA ANALYSIS FOR AEGL-1 23 5.1. Summary of Human Data Relevant to AEGL-1 24
25 No human data relevant to developm ent of AEGL-1 values were identified. 26
27 5.2. Summary of Animal Data Relevant to AEGL-1 28
29 No clinical signs during exposur e or ocular effects at study te rmination were noted in rats 30 exposed to 10 ppm TMP 6 hr/day, 5 days/week for 4 weeks (Biodymanics, 1979). Two weeks 31 after exposure, lens opacities were noted only in females in the 51 ppm group (next highest 32 concentration tested) (2/10), a nd 101 ppm group (6/10). Corneal surface irregula rities were 33 noted at the end of 4 weeks in rats exposed to 51 or 101 ppm, with both males and females 34
affected. 35
36
37
5.3. Derivation of AEGL-1 38
39 The no-effect-level for clinical signs in rats ( 10 ppm) exposed to TMP 6 hr/day, 5 days/week for 40 4 weeks (Biodynamics, 1979) will be used as the point-of-departure for AEGL-1 values. An 41 intraspecies uncertainty factor of 3 will be applied because the point-of-departure is from a 42 repeated exposure study and the endpoint is no t likely the result of a single exposure. An 43 interspecies uncertainty factor of 1 will be ap plied. Although an inters pecies UF of 3 might 44 normally be applied, use of a total uncertainty fa ctor of 10 yields AEGL-1 values that are not 45 compatible with human occupational exposure data (AEGL-1 values derived with a total UF of 46 10 are 3.3, 2.3, 1.8, 1.1, and 0.60 ppm for 10-min, 30-min, 1-hr, 4-hr, and 8-hr, respectively). No 47 effects were noted in workers repeatedly exposed up to 15 ppm (ACGIH, 1991). The 48TRIMETHYL PHOSPHITE Proposed: October, 2009

14 concentration-exposure time relationship for many irritant and systemi cally-acting vapors and 1 gases may be described by C n x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et 2 al., 1986). To obtain conservative and protective AEGL values in the absence of an empirically 3 derived chemical-specific scaling exponent, tempor al scaling may be performed using n=3 when 4 extrapolating to shorter time points and n = 1 wh en extrapolating to longer time points using the 5
C n x t = k equation (NRC, 2001). Extrapolation will be used to derive the 10-minute value 6 because the 6-hr point-of-departure is from a re peated exposure study. The AEGL-1 values are 7 presented in Table 4, and calculati ons are presented in Appendix A. 8
9

Table 4. AEGL-1 values for trimethyl phosphite

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

11 ppm (56 mg/m 3 ) 7.6 ppm (39 mg/m 3 ) 6.1 ppm (31 mg/m 3 ) 3.8 ppm (19 mg/m 3 ) 2.5 ppm (13 mg/m 3 )

10
6. DATA ANALYSIS FOR AEGL-2 11 6.1. Summary of Human Data Relevant to AEGL-2 12
13 No human data relevant to developm ent of AEGL-2 values were identified. 14
15 6.2. Summary of Animal Data Relevant to AEGL-2 16
17 Lens surface irregularities were noted after 2 and of 4 wk in rats exposed to 101 ppm TMP 6 18 hr/day, 5 days/week. Two weeks after exposure, le ns opacities were still noted in some animals. 19
20
6.3. Derivation of AEGL-2 21

22 The lens opacities in rats exposed to 1 01 ppm TMP 6 hr/day, 5 days/week for 4 weeks 23 (Biodynamics, 1979) will be used as the point-of-de parture for AEGL-2 values. An intraspecies 24 uncertainty factor of 3 will be applied because the point-of-departure is from a repeated exposure 25 study and the endpoint is not likely the result of a single exposure. The lens opacities observed 26 in rats repeatedly exposed to 101 ppm TMP were noted after 2 weeks and continued to increase 27 in frequency and severity after 4 weeks e xposure, suggesting a cumulative effect. An 28 interspecies uncertainty factor of 1 will be ap plied. Although an inters pecies UF of 3 might 29 normally be applied, use of a total uncertainty fa ctor of 10 yields AEGL-2 values that are not 30 compatible with human occupational exposure data (AEGL-2 values derived with a total UF of 31 10 are 33, 23, 18, 12, and 6.0 ppm for 10-min, 30-min, 1-hr, 4-hr, and 8-hr, respectively). No 32 effects were noted in workers repeatedly exposed up to 15 ppm (ACGIH, 1991). The 33 concentration-exposure time relationship for many irritant and systemi cally-acting vapors and 34 gases may be described by C n x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et 35 al., 1986). To obtain conservative and protective AEGL values in the absence of an empirically 36 derived chemical-specific scaling exponent, tempor al scaling may be performed using n=3 when 37 extrapolating to shorter time points and n = 1 wh en extrapolating to longer time points using the 38
C n x t = k equation (NRC, 2001). Extrapolation will be used to derive the 10-minute value 39 because the 6-hr point-of-departure is from a re peated exposure study. AEGL-2 values are 40 presented in Table 5, and calculati ons are presented in Appendix A. 41

42

Table 5. AEGL-2 values for trimethyl phosphite

10-minute 30-minute 1-hour 4-hour 8-hourTRIMETHYL PHOSPHITE Proposed: October, 2009

15 110 ppm (560 mg/m 3 ) 77 ppm (390 mg/m 3 ) 61 ppm (310 mg/m 3 ) 38 ppm (190 mg/m 3 ) 25 ppm (128 mg/m 3 )

1
7. DATA ANALYSIS FOR AEGL-3 2 7.1. Summary of Human Data Relevant to AEGL-3 3
4 No human data relevant to developmen t of AEGL-3 values were identified. 5

6 7.2. Summary of Animal Data Relevant to AEGL-3 7
8
A 1-hr rat LC 50 of 35, 885 ppm (nominal) was reported by Mobil Oil (1979), and a 4-hr rat 9
LC 50 of >10,000 ppm (nominal) was reported by Levi n and Gabriel (1973). In a time-to-death 10 study, up to 50% mortality was reported in mi ce exposed to 6450 ppm (nominal) TMP for 11 approximately 3 hours (Hazleton, 1962); mortality was 2/10 at 2 hr 55 min, 4/10 at 2 hr 58 min, 12
and 5/10 at 3 hr 1 min. 13

14
7.3. Derivation of AEGL-3 15
16 Up to 50% lethality was observed in mice exposed to 6450 ppm TMP for approximately 3 17 hours (Hazleton, 1962). In the absence of other a ppropriate data for deriving AEGL-3 values, 18 this exposure concentration will be divided by 3 to estimate a threshold for lethality (Rusch et al., 19 2009) (point-of-departure 2150 ppm). Inter- and intr aspecies uncertainty factors of 3 each (total 20 10) will be applied because TMP is highly irritating, and much of the toxicity resulting from an 21 acute exposure is likely caused by a direct chemical effect on the tissue; this type of portal-of22 entry effect is not expected to vary grea tly between species or among individuals. The 23 concentration-exposure time relationship for many irritant and systemi cally-acting vapors and 24 gases may be described by C n x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et 25 al., 1986). To obtain conservative and protective AEGL values in the absence of an empirically 26 derived chemical-specific scaling exponent, tempor al scaling may be performed using n=3 when 27 extrapolating to shorter time points and n = 1 wh en extrapolating to longer time points using the 28
C n x t = k equation (NRC, 2001). AEGL-3 values are presented in Table 6, and calculations are 29 presented in Appendix A. 30
31

Table 6. AEGL-3 values for trimethyl phosphite

10-minute 30-minute 1-hour 4-hour 8-hour
560 ppm (2900 mg/m 3 ) 390 ppm (2000 mg/m 3 ) 310 ppm (1600 mg/m 3 ) 160 ppm (820 mg/m 3 ) 81 ppm (410 mg/m 3 )

32 The AEGL-3 values are supported by the 4-hr rat LC 50 of >10,000 ppm (Levin and Gabriel, 33 1973). Dividing 10,000 ppm by three yields an estimat ed 4-hr lethality th reshold of 3000 ppm; 34 applying a total uncertainty factor of 10, yields a 4-hr AEGL-3 value of 300 ppm. Also, no 35
deaths were noted in rats e xposed to approximately 100 ppm TMP 6 hr/day, 5 days/week for 4 36 weeks (Biodymanics, 1978, 1979; Mob il Oil, 1979). These data suggest that the AEGL-3 values 37 are protective. 38
39
8. SUMMARY OF AEGLS 40 8.1. AEGL Values and Toxicity Endpoints 41TRIMETHYL PHOSPHITE Proposed: October, 2009

16 1
AEGL values are summarized in Table 7. AEGL -1 values are based on a no-effect-level for 2 clinical signs in rats re peatedly exposed to TMP. AEGL-2 va lues are based on lens opacities in 3 rats repeatedly exposed to TMP, and AEGL-3 values are based on an estimated lethality 4
threshold in mice. 5

6
Table 7. Summary of AEGL values Exposure Duration Classification 10-minute 30-minute 1-hour 4-hour 8-hour

AEGL-1 (Nondisabling) 11 ppm (56 mg/m 3 ) 7.6 ppm (39 mg/m 3 ) 6.1 ppm (31 mg/m 3 ) 3.8 ppm (19 mg/m 3 ) 2.5 ppm (13 mg/m 3 )

AEGL-2 (Disabling) 110 ppm (560 mg/m 3 ) 77 ppm (390 mg/m 3 ) 61 ppm (310 mg/m 3 ) 38 ppm (190 mg/m 3 ) 25 ppm (128 mg/m 3 )

AEGL-3 (Lethal) 560 ppm (2900 mg/m 3 ) 390 ppm (2000 mg/m 3 ) 310 ppm (1600 mg/m 3 ) 160 ppm (820 mg/m 3 ) 81 ppm (410 mg/m 3 )

7 8.2. Comparison with Other St andards and Guidelines 8
9 AEGL values for trimethyl phosphite are compared to other guidelines and standards for this 10 compound are listed in Table 8. 11

12

Table 8. Extant standards and guidelines for trimethyl phosphate
Exposure Duration Guideline 10 minute 30 minute 1 hour 4 hour 8 hour

AEGL-1 11 ppm (56 mg/m 3 ) 7.6 ppm (39 mg/m 3 ) 6.1 ppm (31 mg/m 3 ) 3.8 ppm (19 mg/m 3 ) 2.5 ppm (13 mg/m 3 )

AEGL-2 110 ppm (560 mg/m 3 ) 77 ppm (390 mg/m 3 ) 61 ppm (310 mg/m 3 ) 38 ppm (190 mg/m 3 ) 25 ppm (128 mg/m 3 )

AEGL-3 560 ppm (2900 mg/m 3 ) 390 ppm (2000 mg/m 3 ) 310 ppm (1600 mg/m 3 ) 160 ppm (820 mg/m 3 ) 81 ppm (410 mg/m 3 )

TLV-TWA (ACGIH) a 2 ppm

MAC-Peak Category (The Netherlands) b 2 ppm

13

a ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Th reshold Limit Value - Time Weighted 14 Average) (ACGIH 2008) is the time-weighted average con centration for a normal 8-hour workday and a 40-hour work 15
week, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect. Basis is ocular nd 16

skin irritation. 17 18

b MAC (Maximaal Aanvaaarde Concentratie [Maximal Accepted Concentration - Peak Category]) (SDU Uitgevers 19 [under the auspices of the Ministry of Social Affairs and Employ ment], The Hague, The Netherlands 2000) is defined 20 analogous to the ACGIH-Ceiling 21
22 8.3. Data Adequacy and Research 23
24 There are no quantitative human data, and animal data are limited. Acute animal inhalation 25
data are limited to studies with nominal concen trations. Repeated-exposur e analytical data are 26
available. Additional acute inhalati on toxicity studies would be helpful. 27TRIMETHYL PHOSPHITE Proposed: October, 2009

17 1
9. REFERENCES 2
3 ACGIH (American Conference of Governmental I ndustrial Hygienists). 1991. Documentation 4 of the Threshold Limit Values and Biological E xposure Indices: Trimethyl Phosphite. Sixth ed., 5 ACGIH, Cincinnati, OH. 6

7 ACGIH (American Conference of Governmental I ndustrial Hygienists). 2008. Threshold limit 8 values (TLVs) for chemical and physical agen ts and biological expos ure indices (BEIs). 9 ACGIH, Cincinnati, OH. 10

11 Biodynamics, 1978. Initial Submission: A repeat ed (4-week) inhalati on study of MCTR-180-78 12
in the rat with cover letter date d 082892. Project No. 78-7229. OTS0538473. 13

14 Biodynamics, 1979. A repeated (4-week) inhalation study of MCTR-74-79 in the rat. Project 15
No. 79-7279. OTS 88-7900291. 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 HPV, 2005. High Production Volume (HPV) Chemi cal Challenge Program. Test Plan for 22 Trimethyl phosphite. Submitted to US EPA by the Trimethyl Phosphite Consortium. December, 23
2005. 24
25 HSDB (Hazardous Substances Data Bank). 2009. Tr imethyl Phosphite. [Online] Available. 26 http://toxnet.nlm.nih.gov/ [02/09/ 2009]. TOXNET, Toxicology Data Network. US. Natl. Library 27
of Medicine. 28
29 Levin, L. and Gabriel, K.L. 1973. The vapor toxicity of trimethyl phosphite. Am. Ind. Hyg. 30
Assoc. J. 34:286-291. 31
32
Mobil Oil. 1979. Initial Submission: The toxico logic profile of trimet hyl phosphite (TMP) with 33 cover letter dated 082892. July 1, 1979. OTS0583484. 34
35 NRC (National Research Council). 2001. Standing operating procedures for developing acute 36 exposure guideline levels for hazardous chemicals. Committee on Toxicology, Board on 37 Toxicology and Environmental Health Hazards , Commission on Life Sciences, National 38 Research Council. National Academy Press, Washington, DC. 39
40 Rusch, G.M., Bast, C.B. and Cavender, F.L. 2009. Establishing a Point of Departure for Risk 41 Assessment Using Acute Inhalation Toxico logy Data. Regulatory Toxicology and 42 Pharmacology. 54: 247-255. 43

44 SDU Uitgevers 2000. MAC Ministry of Social Affairs and Em ployment. Nationale MAC 45 (Maximum Allowable Concentration) Li st, 2000. The Hague, The Netherlands. 46
47 ten Berge, W.F., A. Zwart, and L.M. Appelman . 1986. Concentration-time mortality response 48TRIMETHYL PHOSPHITE Proposed: October, 2009

18 relationship of irritant and sy stemically acting vapours and gase s. J. Hazard. Materials: 13: 1
301-309. 2
3

4
5TRIMETHYL PHOSPHITE Proposed: October, 2009

19 1
APPENDIX A: Derivation of AEGL Values 2
3
Derivation of AEGL-1 4
5 Key Study: Biodynamics, 1979. A repeated (4-week) inhalation study of MCTR-74- 6 79 in the rat. Project No. 79-7279. OTS 88-7900291. 7
8 Toxicity endpoint: NOEL for clinical signs in rats exposed to 10 ppm TMP 6 hr/day, 5 9 days/week for 4 weeks. Ocular eff ects were noted at the next highest 10 concentration tested (51 ppm). 11

12 Uncertainty factors: Intraspeci es: 3, the point-of-departure is from a repeated exposure study 13 and the endpoint is not likely the result of a single exposure 14
15 Interspecies: 1, A UF of 3 might norma lly be applied. However use of a 16 total uncertainty factor of 10 yiel ds AEGL-1 values that are not 17 compatible with human worker e xposure data (no effects with 18 occupational exposures up to 15 ppm). 19
20 Modifying factor: NA 21

22 Time scaling: C 3 x t = k (10- min, 30-min, 1-hr, 4-hr) 23 10 ppm 3 x 6 hr = 6000 ppm 3 -hr 24
25
C 1 x t = k (8-hr) 26 10 ppm x 6 hr = 60 ppm-hr 27
28
10-minute AEGL-1: C 3 x 0.167 hr = 6000 ppm 3 ·hr 29
C 3 = 35928 ppm 30 C = 32.9 ÷ 3 = 11 ppm 31
32
30-minute AEGL-1: C 3 x 0.5 hr = 6000 ppm 3 ·hr 33
C 3 = 12,000 ppm 34 C = 22.8 ÷ 3 = 7.6 ppm 35
36
1-hour AEGL-1: C 3 x 1 hr = 6000 ppm 3 ·hr 37
C 3 = 6000 ppm 38 C = 18.2 ÷ 3 = 6.1 ppm 39
40
4-hour AEGL-1: C 3 x 4 hr = 6000 ppm 3 ·hr 41
C 3 = 1500 ppm 42 C = 11.4 ÷ 3 = 3.8 ppm 43

44
45
8-hour AEGL-1: C 1 x 8 hr = 60 ppm·hr 46
C 1 = 7.5 ppm 47 C = 7.5 ÷ 3= 2.5 ppm 48TRIMETHYL PHOSPHITE Proposed: October, 2009

20 Derivation of AEGL-2 1
2 Key Study: Biodynamics, 1979. A repeated (4-week) inhalation study of MCTR-74- 3 79 in the rat. Project No. 79-7279. OTS 88-7900291. 4
5 Toxicity endpoint: Lens opaciti es in rats exposed to 101 pp m TMP 6 hr/day, 5 days/week for 6
4 weeks. Ocular effects were still noted 2-weeks post-exposure. 7
8 Uncertainty factors: Intraspecies: 3, The point-o f-departure is from a repeated exposure study 9 and the endpoint is not likely the resu lt of a single exposure. The lens 10 opacities observed in rats repeatedly exposed to 101 ppm TMP were noted 11
after 2 weeks and continued to increase in frequency and severity after 4 12 weeks exposure, suggesting a cumulative effect. 13

14 Interspecies: 1, A UF of 3 might norma lly be applied. However use of a 15 total uncertainty factor of 10 yiel ds AEGL-2 values that are not 16 compatible with human worker e xposure data (no effects with 17 occupational exposures up to 15 ppm). 18
19 Modifying factor: NA 20

21 Time scaling: C 3 x t = k (10- min, 30-min, 1-hr, 4-hr) 22 101 ppm 3 x 6 hr = 6,181,806 ppm 3 -hr 23

24
C 1 x t = k (8-hr) 25 101 ppm x 6 hr = 606 ppm-hr 26
27
10-minute AEGL-2: C 3 x 0.167 hr = 6,181,806 ppm 3 ·hr 28
C 3 = 37016802 ppm 29 C = 333 ÷ 3 = 110 ppm 30
31
30-minute AEGL-2: C 3 x 0.5 hr = 6,181,806 ppm 3 ·hr 32
C 3 = 12363612 ppm 33 C = 231 ÷ 3 = 77 ppm 34
35
1-hour AEGL-2: C 3 x 1 hr = 6,181,806 ppm 3 ·hr 36
C 3 = 6,181,806 ppm 37 C = 183 ÷ 3 = 61 ppm 38
39
4-hour AEGL-2: C 3 x 4 hr = 6,181,806 ppm 3 ·hr 40
C 3 = 1545452 ppm 41 C = 115 ÷ 3 = 38 ppm 42
43
8-hour AEGL-2: C 1 x 8 = 606 ppm-hr 44
C = 76 ÷ 3 = 25 45
46
47TRIMETHYL PHOSPHITE Proposed: October, 2009

21 1
Derivation of AEGL-3 2
3 Key Study: Hazleton, 1962. Initial Submi ssion: Letter submitting acute inhalation 4 exposure in mice, rat, and guinea pi gs, on hexachloro-2-cyclopentanone 5 (final report) with attachments. Haze lton Laboratories, In c. Falls Church, 6 VA. November 1, 1962. OTS0537047. 7
8 Toxicity endpoint: 3-hr estimated lethality threshold in mice (2150 ppm) 9
10 Uncertainty factors: Interspecies: 3, TMP is highl y irritating, and much of the acute toxicity is 11 likely caused by a direct chemical effecton the tissues; this type of portal12 of-entry effect is not expected to vary greatly between species. 13

14 Intraspecies: 3, TMP is highly irritating, and much of the acute toxicity is 15 likely caused by a direct chemical effecton the tissues; this type of portal16 of-entry effect is not expected to vary greatly among individuals. 17
18 Modifying factor: NA 19
20 Time scaling: C 3 x t = k (10- min, 30-min, 1-hr) 21 2150 ppm 3 x 3 hr = 2.98 x 10 10 ppm 3 -hr 22
23
C 1 x t = k (4-hr, 8-hr) 24 2150 ppm x 3 hr = 6450 ppm-hr 25
26
10-minute AEGL-3: C 3 x 0.167 hr = 2.98 x 10 10 ppm 3 -hr 27
C 3 = 1.78 x 10 11 ppm 28 C = 5630 ÷ 10 = 560 ppm 29
30
30-minute AEGL-3: C 3 x 0.5 hr = 2.98 x 10 10 ppm 3 -hr 31
C 3 = 5.96 x 10 10 ppm 32 C = 3906 ÷ 10 = 390 ppm 33
34
1-hour AEGL-3: C 3 x 1 hr = 2.98 x 10 10 ppm 3 -hr 35
C 3 = 2.98 x 10 10 ppm 36 C = 3100 ÷ 10 = 310 ppm 37
38
4-hour AEGL-3: C 1 x 4 hr = 6450 ppm·hr 39 C = 1613 ppm ÷ 10 = 160 ppm 40

41
8-hour AEGL-3: C 1 x 8 hr = 6450 ppm·hr 42 C = 806 ppm ÷ 10 = 81 ppm 43

44
45TRIMETHYL PHOSPHITE Proposed: October, 2009

22 APPENDIX B: Derivation Summary for Trimethyl Phosphite AEGLs 1
2
3
AEGL-1 VALUES 4

10-minute 30-minute 1-hour 4-hour 8-hour 11 ppm (56 mg/m 3 ) 7.6 ppm (39 mg/m 3 ) 6.1 ppm (31 mg/m 3 ) 3.8 ppm (19 mg/m 3 ) 2.5 ppm (13 mg/m 3 )
Key Reference: Biodynamics, 1979. A repeated (4-week) inhalation study of MCTR-74-79 in the rat. Project No.
79-7279. OTS 88-7900291. Test Species/Strain/Number: Rat/Sprague-Dawley/20/sex/group Exposure Route/Concentrations/Durations: Inhalation/0, 10, 51, 101 ppm/ 6 hr/day, 5 days/week, up to 4 weeks

Effects: 10 ppm: No effects 51 ppm: Lens irregularities and opacities (2/10 females still affected at two weeks post-exposure) 101 ppm: Lens irregularities and opacities (6/10 females still affected at two weeks post-exposure) Endpoint/Concentration/Rationale: NOEL for clinical signs/ 10 ppm/ Ocular effects seen at next highest
concentration tested Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 1 Although an interspecies UF of 3 might normally be applied, use of a total uncertainty factor of 10 yields AEGL-1 values that are not compatible with human occupational ex posure data (AEGL-1 values derived with a total UF of 10 are 3.3, 2.3, 1.8, 1.1, and 0.60 ppm for 10-min, 30-min, 1-hr, 4-hr, and 8-hr, respectively). No effects were noted in workers repeatedly exposed up to 15 ppm (ACGIH, 1991). Intraspecies: 3 The point-of-departure is from a rep eated exposure study and the endpoint is not likely the result of a single

exposure. 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). Extrapolation was used to derive the 10-minute value because the 6-hr point-of-departure is from a repeated exposure study. Data Adequacy: Poor data set necessitated us e of a NOEL from a repeated-exposure study.TRIMETHYL PHOSPHITE Proposed: October, 2009

23 1
AEGL-2 VALUES 2

10-minute 30-minute 1-hour 4-hour 8-hour 110 ppm (560 mg/m 3 ) 77 ppm (390 mg/m 3 ) 61 ppm (310 mg/m 3 ) 38 ppm (190 mg/m 3 ) 25 ppm (128 mg/m 3 )
Key Reference: Biodynamics, 1979. A repeated (4-week) inhalation study of MCTR-74-79 in the rat. Project No.
79-7279. OTS 88-7900291. Test Species/Strain/Number: Rat/Sprague-Dawley/20/sex/group Exposure Route/Concentrations/Durations: Inhalation/0, 10, 51, 101 ppm/ 6 hr/day, 5 days/week, up to 4 weeks

Effects: 10 ppm: No effects 51 ppm: Lens irregularities and opacities (2/10 females still affected at two weeks post-exposure) 101 ppm: Lens irregularities and opacities (6/10 females still affected at two weeks post-exposure) Endpoint/Concentration/Rationale: Lens opacities/ 101 ppm/ lens effects still present 2-weeks post-exposure Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 1 Although an interspecies UF of 3 might normally be applied, use of a total uncertainty factor of 10 yields AEGL-2 values that are not compatible with human occupational ex posure data (AEGL-2 values derived with a total UF of 10 are 33, 23, 18, 12, and 6.0 ppm for 10-min, 30-min, 1-hr, 4-hr, and 8-hr, respectively). No effects were noted in workers repeatedly exposed up to 15 ppm (ACGIH, 1991). Intraspecies: 3 The point-of-departure is from a rep eated exposure study and the endpoint is not likely the result of a single exposure. The lens opacities observed in rats repeatedly exposed to 101 ppm TMP were noted after 2 weeks and continued to increase in frequency and severity af ter 4 weeks exposure, suggesting a cumulative effect. 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). Extrapolation was used to derive the 10-minute value because the 6-hr point-of-departure is from a repeated exposure study. Data Adequacy: Poor data set necessita ted use of a repeated-exposure study.

3TRIMETHYL PHOSPHITE Proposed: October, 2009

24 1

2
AEGL-3 VALUES 3
4

10-minute 30-minute 1-hour 4-hour 8-hour 560 ppm (2900 mg/m 3 ) 390 ppm (2000 mg/m 3 ) 310 ppm (1600 mg/m 3 ) 160 ppm (820 mg/m 3 ) 81 ppm (410 mg/m 3 )
Key Reference: Hazleton, 1962. Initial Submission: Lette r 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: Mice/Swiss albino/10 male s; Rats/Wistar/10 males; Guinea pigs/English short
hair/10 males Exposure Route/Concentrations/Durations: Inhalation/6450 ppm/up to 6-hr (time to death study)

Effects: Clinical signs : Initial increased activity, followed by progressive depression; lacrimation; ptosis;exophthalmos

Mortality: Guinea pigs: No mortality

Mice and Rats:

Time to death (hrs:min) Cumulative Mortality
Mice Rats
2:55 2/10 -
2:58 4/10 -
3:01 5/10 -
3:02 - 2/10
3:05 6/10 -
3:11 - 3/10
4:03 8/10 5/10
4:07 9/10 -
4:20 - 6/10
4:44 10/10 -

Endpoint/Concentration/Rationale: Estimated lethality th reshold in mice/ One-third the concentration: time exposure causing up to 50% lethality in mice (6450 ppm ÷ 3 = 2150 ppm) Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 TMP is highly irritating, and much of the acute toxic ity is likely caused by a direct chemical effect 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: none Time Scaling: c n x t = k, where the exponent, n=3 when extrapolating to shorter time points (30, 60 min, 1-hr) and n = 1 when extrapolating to longer time (4- and 8-hr). (NRC, 2001) Data Adequacy: Sparse data set. AEGL -3 values are supported by the 4-hr rat LC 50 of >10,000 ppm (Levin and Gabriel, 1973). Dividing 10,000 ppm by three yields an estimated 4-hr lethality threshold of 3000 ppm; applying a total uncertainty factor of 10, yields a 4-hr AEGL-3 value of 300 ppm. Also, no deaths were noted in rats exposed to approximately 100 ppm TMP 6 hr/day, 5 days/week for 4 weeks (Biodymanics, 1978, 1979; Mobil Oil, 1979). These data suggest that the AEGL-3 values are protective.

5TRIMETHYL PHOSPHITE Proposed: October, 2009

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

4 5

1 10 100 1000 10000 100000ppm

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 Trimethyl Phosphite

AEGL-3

AEGL-1 AEGL-2

6TRIMETHYL PHOSPHITE Proposed: October, 2009

26 Category Plot Data 1 2 3 Source Species Sex # Exposures ppm MinutesCategoryComments

NAC/AEGL-1 11 10 AEGL
NAC/AEGL-1 7.6 30 AEGL
NAC/AEGL-1 6.1 60 AEGL
NAC/AEGL-1 3.8 240 AEGL
NAC/AEGL-1 2.5 480 AEGL

NAC/AEGL-2 110 10 AEGL
NAC/AEGL-2 77 30 AEGL
NAC/AEGL-2 61 60 AEGL
NAC/AEGL-2 38 240 AEGL
NAC/AEGL-2 25 480 AEGL

NAC/AEGL-3 560 10 AEGL
NAC/AEGL-3 390 30 AEGL
NAC/AEGL-3 310 60 AEGL
NAC/AEGL-3 160 240 AEGL
NAC/AEGL-3 81 480 AEGL

rat 1 6450 181 2 Clinical signs, depression, lacrimation; no mortality rat 1 6450 243 pl 5/10 mortality rat 1 6450 260 pl 6/10 mortality mouse 1 6450 175 pl 2/10 mortality mouse 1 6450 284 3 10/10 mortality gp 1 6450 360 2 Clinical signs, depression, lacrimation rat 1 35885 60 pl LC50 rat 1 10000 240 pl LC50 rat 20 105 360 2 Lens opacity rat 20 600 360 pl Corneal opacity, partial mortality
rat 20 10 360 0 No effects rat 20 51 360 2 Lens opacity rat 20 101 360 2 Lens opacity rat 20 100 360 2 Lens opacity rat 20 300 360 pl partial mortality rat 20 600 360 pl partial mortality human 15 480 0 No effect in worker exposures 4