ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 

FOR 

TRIMETHYL PHOSPHITE 

CAS Reg. No. 121-45-9 

PROPOSED 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

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1 

2 ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) 

3 FOR 

4 TRIMETHYL PHOSPHITE 

5 CAS Reg. No. 121-45-9 

6 

7 

8 

9 PROPOSED

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TRIMETHYL PHOSPHITE Proposed: October, 2009 

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1 

2 

3 PREFACE 

4 

5 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 

6 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous 

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

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

9 chemicals. 

10 

11 AEGLs represent threshold exposure limits for the general public and are applicable to 

12 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels C AEGL-1, 

13 AEGL-2 and AEGL-3 C are developed for each of five exposure periods (10 and 30 minutes, 1 

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

15 The three AEGLs are defined as follows: 

16 

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

18 cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general 

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

20 certain asymptomatic, non-sensory effects. However, the effects are not disabling and are 

21 transient and reversible upon cessation of exposure. 

22 

23 AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above 

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

25 experience irreversible or other serious, long-lasting adverse health effects or an impaired ability 

26 to escape. 

27 

28 AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above 

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

30 experience life-threatening health effects or death. 

31 

32 Airborne concentrations below the AEGL-1 represent exposure levels that could produce 

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

34 irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations 

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

36 of effects described for each corresponding AEGL. Although the AEGL values represent 

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

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

39 individuals, subject to unique or idiosyncratic responses, could experience the effects described 

40 at concentrations below the corresponding AEGL 

41 

42 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

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1 TABLE OF CONTENTS 

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

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

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

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

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

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

8 2.2.1. Odor Threshold/Odor Awareness........................................................................................8

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

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

11 2.4. Genotoxicity....................................................................................................................................9

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

13 2.6. Summary.........................................................................................................................................9

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

15 3.1. Acute Lethality...............................................................................................................................9

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

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

18 3.4. Genotoxicity..................................................................................................................................11

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

20 3.6. Summary.......................................................................................................................................12

21 4. SPECIAL CONSIDERATIONS .....................................................................................................12

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

46 9. REFERENCES.................................................................................................................................17

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

48 APPENDIX B: DERIVATION SUMMARY FOR TRIMETHYL PHOSPHITE AEGLS...............22

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

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1 LIST OF TABLES 

2 

3 Table 1. Summary of AEGL Values for Trimethyl Phosphite ................................................ 7 

4 Table 2. Chemical and physical properties for trimethyl phosphite...................................... 8 

5 Table 3. Time to death in mice and rats exposed to 6450 ppm TPM for 6 hours ................ 10 

6 Table 4. AEGL-1 values for trimethyl phosphite.................................................................... 14 

7 Table 5. AEGL-2 values for trimethyl phosphite.................................................................... 14 

8 Table 6. AEGL-3 values for trimethyl phosphite.................................................................... 15 

9 Table 7. Summary of AEGL values ......................................................................................... 16 

10 Table 8. Extant standards and guidelines for trimethyl phosphite....................................... 16

11 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

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1 EXECUTIVE SUMMARY 

2 

3 Trimethyl phosphite (TMP) is a colorless liquid 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 production of textiles, as an intermediate in the production of 

6 flame-retardant polymers for polyurethane foams, and as a catalyst (HSDB, 2009). 

7 

8 The no-effect-level for clinical signs in rats (10 ppm) exposed to TMP 6 hr/day, 5 days/week 

9 for 4 weeks (Biodynamics, 1979) was used as the point-of-departure for AEGL-1 values. An 

10 intraspecies uncertainty factor of 3 was applied because the point-of-departure is from a repeated 

11 exposure study and the endpoint is not likely the result of a single exposure. An interspecies 

12 uncertainty factor of 1 was applied. Although an interspecies UF of 3 might normally be 

13 applied, use of a total uncertainty factor of 10 yields AEGL-1 values that are not compatible with 

14 human occupational exposure data (AEGL-1 values derived with a total UF of 10 are 3.3, 2.3, 

15 1.8, 1.1, and 0.60 ppm for 10-min, 30-min, 1-hr, 4-hr, and 8-hr, respectively). No effects were 

16 noted in workers repeatedly exposed up to 15 ppm (ACGIH, 1991). The concentration-exposure 

17 time relationship for many irritant and systemically-acting vapors and gases may be described by 

Cn 18 x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al., 1986). To obtain 

19 conservative and protective AEGL values in the absence of an empirically derived chemical20 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 Cn 21 x t = k 

22 equation (NRC, 2001). Extrapolation was used to derive the 10-minute value because the 6-hour 

23 point-of-departure is from a repeated exposure study. 

24 

25 The lens opacities in rats exposed to 101 ppm TMP 6 hours/day, 5 days/week for 4 weeks 

26 (Biodynamics, 1979) were used as the point-of-departure for AEGL-2 values. This endpoint was 

27 still present in some animals at 2-weeks post-exposure. An intraspecies uncertainty factor of 3 

28 was applied because the point-of-departure is from a repeated exposure study and the endpoint is 

29 not likely the result of a single exposure. The lens opacities observed in rats repeatedly exposed 

30 to 101 ppm TMP were noted after 2 weeks and continued to increase in frequency and severity 

31 after 4 weeks exposure, suggesting a cumulative effect. An interspecies uncertainty factor of 1 

32 was applied. Although an interspecies UF of 3 might normally be applied, use of a total 

33 uncertainty factor of 10 yields AEGL-2 values that are not compatible with human occupational 

34 exposure data (AEGL-2 values derived with a total UF of 10 are 33, 23, 18, 12, and 6.0 ppm for 

35 10-min, 30-min, 1-hr, 4-hr, and 8-hr, respectively). No effects were noted in workers repeatedly 

36 exposed up to 15 ppm (ACGIH, 1991). Time scaling is as described above for AEGL-1. 

37 

38 Up to 50% lethality was observed in mice exposed to 6450 ppm TMP for approximately 3 

39 hours (Hazleton, 1962). In the absence of other appropriate data for deriving AEGL-3 values, 

40 this exposure concentration was divided by 3 to estimate a threshold for lethality (Rusch et al., 

41 2009) (point-of-departure 2150 ppm). Inter- and intraspecies uncertainty factors of 3 each (total 

42 10) were applied because TMP is highly irritating, and much of the toxicity resulting from an 

43 acute exposure is likely caused by a direct chemical effect on the tissue; this type of portal-of44 entry effect is not expected to vary greatly between species or among individuals. Temporal 

45 scaling was performed using n=3 when extrapolating to shorter time points and n = 1 when 

extrapolating to longer time points using the Cn 46 x t = k equation (NRC, 2001). 

47 

48 The calculated values are listed in Table 1 below. 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

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1 

2 

Table 1. Summary of AEGL Values for Trimethyl Phosphite

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

AEGLB1 

(Nondisabling) 

11 ppm 

(56 mg/m3

) 

7.6 ppm 

(39 mg/m3) 

6.1 ppm 

(31 mg/m3)

3.8 ppm 

(19 mg/m3) 

2.5 ppm 

(13 mg/m3) 

NOEL for clinical signs 

in rats (Biodynamics, 

1979) 

AEGLB2 

(Disabling) 

110 ppm 

(560 mg/m3

) 

77 ppm 

(390 mg/m3)

61 ppm 

(310 mg/m3)

38 ppm 

(190 mg/m3) 

25 ppm 

(128 mg/m3) 

Lens opacities in rats 

(Biodynamics, 1979) 

AEGLB3 

(Lethal) 

560 ppm 

(2900 mg/m3

) 

390 ppm 

(2000 

mg/m3

) 

310 ppm 

(1600 

mg/m3) 

160 ppm 

(820 mg/m3

) 

81 ppm 

(410 mg/m3) 

Estimated 3-hr lethality 

threshold in mice 

(Hazleton, 1962) 

3 

4 

5 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

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1 

2 1. INTRODUCTION 

3 

4 Trimethyl phosphite (TMP) is a colorless liquid with an irritating, pungent, oily, pyridine5 like odor. Its primary use is as an intermediate in the manufacture of pesticides. It is also used 

6 as a fireproofing agent in the production of textiles, as an intermediate in the production of 

7 flame-retardant polymers for polyurethane foams, and as a catalyst (HSDB, 2009). It is 

8 produced by reaction of phosphorus trichloride and methyl alcohol in the presence of a tertiary 

9 amine. Trimethyl phosphite is manufactured primarily overseas and is imported into the US for 

10 domestic use; manufacture is in closed systems (HPV, 2005). No current quantitative 

11 manufacturing information was located. Chemical and physical properties are presented in Table 

12 2. 

13 

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 C3H9O3P HSDB, 2009 

Molecular weight 124.08 HSDB, 2009 

CAS Reg. No. 121-45-9 HSDB, 2009 

Physical state Colorless 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/m3

1 mg/m3

 = 0.20 ppm 

15 

16 2. HUMAN TOXICITY DATA 

17 2.1. Acute Lethality 

18 

19 No information concerning acute lethality was located. 

20 

21 2.2. Nonlethal Toxicity 

22 2.2.1. Odor Threshold/Odor Awareness 

23 

24 An odor threshold of 0.0001 ppm was reported from a laboratory test panel. No further 

25 information was available (Mobil Oil, 1979). 

26 

27 ACGIH (1991) reported that in an occupational setting, the odor of TMP was not generally 

28 considered objectionable until concentrations approached 20 ppm. No further information was 

29 available. 

30 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

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1 2.2.2. Case Reports 

2 

3 ACGIH (1991) reported that analyses of air in a TMP manufacturing plant from 1969 to 

4 1971 showed an average concentration of up to 8 ppm. ACGIH (1991) also reported that 

5 average workplace exposures in another TMP plant in 1979 usually ranged from 0.3 to 4 ppm, 

6 with occupational exposures up to 15 ppm. Monitoring of 179 employees in these plants showed 

7 no ocular effects or other adverse effects associated with occupational exposure to TMP. No 

8 further details were provided. 

9 

10 

11 2.3. Developmental/Reproductive Toxicity 

12 

13 No human developmental/reproductive data were located. 

14 

15 2.4. Genotoxicity 

16 

17 No human data were located. 

18 

19 2.5. Carcinogenicity 

20 

21 No human data were located. 

22 

23 2.6. Summary 

24 

25 Human data are limited to odor threshold and occupational monitoring data, both of which 

26 are available only from secondary sources. An odor threshold of 0.0001 ppm was reported, and 

27 odor was not considered objectionable until concentrations approached 20 ppm. No effects were 

28 reported from occupational exposure concentrations ranging from 0.3 to 15 ppm. 

29 

30 3. ANIMAL TOXICITY DATA 

31 3.1. Acute Lethality 

32 

33 Groups of ten male Swiss albino mice, ten male Wistar rats, and ten male English short-hair 

34 guinea pigs were exposed to a “mean theoretical concentration” of 6450 ppm TMP for 6 hours, 

35 followed by a 24-hour observation period (Hazleton, 1962). Concentrations were calculated 

36 from air flow and net loss of test material. Exposures were conducted in a 500 liter stainless 

37 steel chamber with one or two fritted-disc glass bubblers at the inlet containing the TMP. A 

38 glass trap was placed between the vapor generator and chamber to collect liquid. Air flow was 

39 18 L/minute with one bubbler and 35 L/min with two bubblers. Animals were observed 

40 continually during exposure for signs of toxicity and mortality. At the end of the 24-hour 

41 observation period, surviving animals were sacrificed and necropsies were performed; necropsies 

42 were also performed on animals that died during exposure. Both clinical signs and lethality data 

43 suggest that mice are more sensitive than rats, and rats may be more sensitive than guinea pigs. 

44 Clinical signs included an initial increase in activity, followed by progressive depression. At 30 

45 minutes, all mice were prostrate and rats and guinea pigs were depressed. Lacrimation and 

46 ptosis were observed in most animals, and after 3-hours, mice exhibited increasing 

47 exophthalmos. Signs remained unchanged until the death of the animal or cessation of exposure 

48 after 6 hours. No guinea pigs died during exposure; whereas ten mice and six rats died during 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

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1 exposure; times to death for mice and rats dying during exposure are summarized in Table 3. 

2 Additionally, one rat died the day after exposure. Animals dying during exposure showed a 

3 foamy fluid in the stomachs and lungs and liver congestion. Four rats also exhibited congestion 

4 of the spleen and two rats had adrenal congestion. Mice all had distention of the large intestine. 

5 Guinea pigs sacrificed at study termination had lung and liver congestion and gaseous distention 

6 of the gastrointestinal tract. Necropsies of surviving rats showed only lung congestion with 

7 hemorrhage and kidney congestion. 

8 

9 

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 - 

 

LT50 (hrs: mins) ( 95%CI) 3:08 (2:51-3:27) 4:03 (3:27-4:47) 

10 Hazleton, 1962

11 

12 A nominal 1-hr rat LC50 of 35,885 ppm was reported by Mobil Oil (1979); no further details 

13 were provided. 

14 

15 A nominal 4-hr rat LC50 of > 10,000 ppm has also been reported (Levin and Gabriel, 1973). 

16 Animals showed a high degree of irritation, discomfort, and respiratory distress. No further 

17 details were provided. 

18 

19 

20 

21 3.2. Repeated-Exposure Studies 

22 

23 Groups of Sprague-Dawley rats were repeatedly exposed to 0 (20 rats/sex), 105 (20 rats/sex), 

24 or 600 ppm (36 rats/sex) TMP (Biodynamics, 1978). Control and 105 ppm group animals were 

25 exposed 6 hours/day, 5 days/week for four weeks. Animals in the 600 ppm group were exposed 

26 6 hours/day, 5 days/week for three weeks and received three 6-hour exposures during the fourth 

27 week. Animals were exposed in one cubic meter stainless steel and glass dynamic chambers, 

28 with an airflow of 132 L/min. The test atmosphere was generated by passing a nitrogen stream 

29 through a bubbler containing the TMP, varying the amount of nitrogen to volatilize the 

30 appropriate amount of test material. Test atmospheres were sampled four times per exposure for 

31 infrared analysis. Additionally, periodic samples were taken from the chambers each exposure 

32 day and analyzed via gas chromatography. The purpose of the study was to determine if 

33 lenticular cataracts would develop from TMP exposure. No treatment-related mortality was 

34 reported in the control or 105 ppm groups; however, 30/36 males and 19/36 females in the 600 

35 ppm group died during the study. One male and one female in the 600 ppm group were 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

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1 sacrificed in extremis. Deaths occurred between days 15 and 31 of the study. All rats in both 

2 treatment groups showed concentration-related signs of irritation during the 4-week exposure. 

3 Additionally, animals exposed to 600 ppm exhibited decreased activity, poor condition, 

4 excessive salivation, and ocular abnormalities. Ophthalmoscopic examinations revealed grooved 

5 lens opacities in 7 of 30 rats exposed to 105 ppm; these lesions were reversible within 8 weeks 

6 post exposure. At 600 ppm, almost all rats developed mature (severe), irreversible cataracts. 

7 Body weight in the 105 ppm group was comparable to controls throughout the study. Body 

8 weight in the 600 ppm group was significantly decreased from week 1 through 5; body weights 

9 then increased and became comparable with controls, thereafter. No treatment-related necropsy 

10 findings were noted in rats in the 105 ppm group. However, there was an increase in absolute 

11 and relative lung weights in the 600 ppm group, and gross necropsy revealed lung congestion 

12 and discoloration. 

13 

14 In another study, Biodynamics (1979) groups of twenty male and twenty female 

15 Sprague-Dawley rats were exposed to 0, 10, 51, or 101 ppm TMP 6 hours/day, 5 days/week for 

16 up to four weeks. Five rats/sex were sacrificed after two and four weeks exposure, and after two 

17 and eight weeks post-exposure. Exposure methods are similar to those described above 

18 (Biodynamics, 1978). No treatment-related deaths occurred at any concentration, and no clinical 

19 signs were observed during the exposure period. Body and lung weights for all treatment groups 

20 were similar to those of controls. No lens effects were noted at 10 ppm. Ocular surface 

21 irregularities were noted at the end of 4 weeks in rats exposed to 51 or 101 ppm, with females 

22 affected more than males. Two weeks after exposure, lens opacities were noted only in females 

23 in the 51 ppm group (2/10), and 101 ppm group (6/10). 

24 

25 Albino rats were administered 100, 300, or 600 ppm TMP 6 hours/day, 5 days/week for four 

26 weeks (Mobil Oil, 1979). There were no treatment-related deaths at 100 ppm. Approximately 

27 10% mortality occurred in the 300 ppm group, and mortality exceeded 70% in the 600 ppm 

28 group over the 4 week exposure period. No respiratory effects were noted at 100 or 300 ppm; 

29 however, gross histological evidence of lung inflammation was noted at 600 ppm. Clinical signs 

30 of ocular irritation were noted in all treatment groups. A few rats exposed to 100 ppm had mild 

31 and reversible striate opacities of the lenses; however, these lesions were similar to those 

32 occurring spontaneously in untreated rats. Mild cataracts were noted at 300 ppm, and severe 

33 cataracts were reported at 600 ppm. No other experimental details were available. 

34 

35 Groups of five rats were exposed to 0 (5 males) or 500 ppm (nominal concentration; 4 males, 

36 1 female) TMP 7.5 hours/day, 5 days/week for 8 weeks (Levin and Gabriel, 1973). 

37 Histopathological changes in the lungs were noted; however, a later review of this study deemed 

38 the results unreliable because the effects were likely related to chronic lung disease in the 

39 laboratory rats (HPV, 2005). 

40 

41 3.3. Developmental/Reproductive Toxicity 

42 

43 No inhalation data were located. 

44 

45 3.4. Genotoxicity 

46 

47 Trimethyl phosphite was negative for bacterial mutagenicity in a series of S. typhimurium

48 Ames tests both with and without activation. Trimethyl phosphite was positive both with and 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

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1 without metabolic activation in the mouse lymphoma assay and was also positive in a battery of 

2 Drosophila melanogaster mutagenicity assays. It gave both positive and negative results in 

3 DNA damage and repair assays in vitro in E. coli and S. typhimurium strains, both with and 

4 without exogenous metabolic activation and was negative for cell transformation in C3H/T101⁄2 

5 cells in vitro (HSDB, 2009; HPV, 2005). 

6 

7 3.5. Chronic Toxicity/Carcinogenicity 

8 

9 No data were located. 

10 

11 3.6. Summary 

12 

13 Limited acute inhalation data suggest that trimethyl phosphite is of low acute toxicity with 

14 regard to lethality. Clinical signs from both acute and repeated-exposure studies suggest that 

15 TMP is an irritant; effects included lacrimation, exophthalmos, respiratory distress, ocular 

16 opacities, cataracts, and pulmonary congestion. Cumulative effects were also noted; lens 

17 opacities observed in rats repeatedly exposed to approximately 100 ppm TMP were noted after 2 

18 weeks and continued to increase in frequency and severity after 4 weeks exposure. Genotoxicity 

19 testing yielded both positive and negative results. No data on developmental/ reproductive 

20 toxicity or chronic toxicity/carcinogenicity were located. 

21 

22 4. SPECIAL CONSIDERATIONS 

23 4.1. Metabolism and Disposition 

24 

25 Little information was located concerning the metabolism and disposition of trimethyl 

26 phosphite. However, trimethyl phosphite may be hydrolyzed in the moist respiratory tract to 

27 dimethyl phosphite and methanol (ACGIH, 1991). 

28 

29 4.2. Mechanism of Toxicity 

30 

31 TMP is an acute irritant to the skin, eyes, and upper respiratory tract (ACGIH, 1991). 

32 Clinical signs noted in rat inhalation studies include lacrimation, exophthalmos, respiratory 

33 distress, ocular opacities, cataracts, and pulmonary congestion. Cumulative effects were also 

34 noted. Lens opacities observed in rats repeatedly exposed to approximately 100 ppm TMP were 

35 noted after 2 weeks and continued to increase in frequency and severity after 4 weeks exposure 

36 (Biodynamics, 1979).

37 

38 

39 4.3. Structure Activity Relationships 

40 

41 TMP is structurally similar to organophosphate insecticides that inhibit cholinesterase 

42 activity. However, a study of cholinesterase inhibition following intravenous administration of 

43 TMP in rats, rabbits, and dogs and in vitro studies of cholinesterase inhibition potential showed 

44 that TMP does not inhibit cholinesterase activity (HPV, 2005). Repeated-exposure inhalation 

45 studies in rats (Biodymanics, 1978, 1979; Mobil Oil, 1979; Levin and Gabriel, 1973) did not 

46 indicate systemic or cumulative toxic effects suggesting cholinesterase inhibition. 

47 

48 4.4. Other Relevant Information 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

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1 

2 

3 4.4.1. Species Variability 

4 

5 Data are not sufficient for determining species sensitivity. 

6 

7 4.4.2. Susceptible Populations 

8 

9 No information was available on populations especially sensitive to TMP toxicity. 

10 

11 4.4.3. Concentration-Exposure Duration Relationship 

12 

13 The concentration exposure time relationship for many irritant and systemically acting 

vapors and gases may be described by Cn 14 x t = k, where the exponent ranges from 0.8 to 3.5 (ten 

15 Berge et al. 1986). In lieu of a definitive data set allowing empirical derivation of the exponent 

16 n, temporal scaling was performed, using n = 3 when extrapolating to shorter time points and n = 

1 when extrapolating to longer time points using the Cn 17 x t = k equation (NRC, 2001). 

18 

19 4.4.4. Concurrent Exposure Issues 

20 

21 No concurrent exposure issues were identified. 

22 

23 5. DATA ANALYSIS FOR AEGL-1 

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

25 

26 No human data relevant to development of AEGL-1 values were identified. 

27 

28 5.2. Summary of Animal Data Relevant to AEGL-1 

29 

30 No clinical signs during exposure or ocular effects at study termination were noted in rats 

31 exposed to 10 ppm TMP 6 hr/day, 5 days/week for 4 weeks (Biodymanics, 1979). Two weeks 

32 after exposure, lens opacities were noted only in females in the 51 ppm group (next highest 

33 concentration tested) (2/10), and 101 ppm group (6/10). Corneal surface irregularities were 

34 noted at the end of 4 weeks in rats exposed to 51 or 101 ppm, with both males and females 

35 affected. 

36 

37 

38 5.3. Derivation of AEGL-1 

39 

40 The no-effect-level for clinical signs in rats (10 ppm) exposed to TMP 6 hr/day, 5 days/week for 

41 4 weeks (Biodynamics, 1979) will be used as the point-of-departure for AEGL-1 values. An 

42 intraspecies uncertainty factor of 3 will be applied because the point-of-departure is from a 

43 repeated exposure study and the endpoint is not likely the result of a single exposure. An 

44 interspecies uncertainty factor of 1 will be applied. Although an interspecies UF of 3 might 

45 normally be applied, use of a total uncertainty factor of 10 yields AEGL-1 values that are not 

46 compatible with human occupational exposure data (AEGL-1 values derived with a total UF of 

47 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 

48 effects were noted in workers repeatedly exposed up to 15 ppm (ACGIH, 1991). The 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

14

1 concentration-exposure time relationship for many irritant and systemically-acting vapors and 

gases may be described by Cn 2 x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et 

3 al., 1986). To obtain conservative and protective AEGL values in the absence of an empirically 

4 derived chemical-specific scaling exponent, temporal scaling may be performed using n=3 when 

5 extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the 

Cn 6 x t = k equation (NRC, 2001). Extrapolation will be used to derive the 10-minute value 

7 because the 6-hr point-of-departure is from a repeated exposure study. The AEGL-1 values are 

8 presented in Table 4, and calculations are presented in Appendix A.

9 

Table 4. AEGL-1 values for trimethyl phosphite 

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

11 ppm 

(56 mg/m3) 

7.6 ppm 

(39 mg/m3) 

6.1 ppm 

(31 mg/m3) 

3.8 ppm 

(19 mg/m3) 

2.5 ppm 

(13 mg/m3) 

10 

11 6. DATA ANALYSIS FOR AEGL-2 

12 6.1. Summary of Human Data Relevant to AEGL-2 

13 

14 No human data relevant to development of AEGL-2 values were identified. 

15 

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

17 

18 Lens surface irregularities were noted after 2 and of 4 wk in rats exposed to 101 ppm TMP 6 

19 hr/day, 5 days/week. Two weeks after exposure, lens opacities were still noted in some animals. 

20 

21 6.3. Derivation of AEGL-2 

22 

23 The lens opacities in rats exposed to 101 ppm TMP 6 hr/day, 5 days/week for 4 weeks 

24 (Biodynamics, 1979) will be used as the point-of-departure for AEGL-2 values. An intraspecies 

25 uncertainty factor of 3 will be applied because the point-of-departure is from a repeated exposure 

26 study and the endpoint is not likely the result of a single exposure. The lens opacities observed 

27 in rats repeatedly exposed to 101 ppm TMP were noted after 2 weeks and continued to increase 

28 in frequency and severity after 4 weeks exposure, suggesting a cumulative effect. An 

29 interspecies uncertainty factor of 1 will be applied. Although an interspecies UF of 3 might 

30 normally be applied, use of a total uncertainty factor of 10 yields AEGL-2 values that are not 

31 compatible with human occupational exposure data (AEGL-2 values derived with a total UF of 

32 10 are 33, 23, 18, 12, and 6.0 ppm for 10-min, 30-min, 1-hr, 4-hr, and 8-hr, respectively). No 

33 effects were noted in workers repeatedly exposed up to 15 ppm (ACGIH, 1991). The 

34 concentration-exposure time relationship for many irritant and systemically-acting vapors and 

gases may be described by Cn 35 x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et 

36 al., 1986). To obtain conservative and protective AEGL values in the absence of an empirically 

37 derived chemical-specific scaling exponent, temporal scaling may be performed using n=3 when 

38 extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the 

Cn 39 x t = k equation (NRC, 2001). Extrapolation will be used to derive the 10-minute value 

40 because the 6-hr point-of-departure is from a repeated exposure study. AEGL-2 values are 

41 presented in Table 5, and calculations are presented in Appendix A.

42 

Table 5. AEGL-2 values for trimethyl phosphite 

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

15

110 ppm 

(560 mg/m3) 

77 ppm 

(390 mg/m3) 

61 ppm 

(310 mg/m3) 

38 ppm 

(190 mg/m3) 

25 ppm 

(128 mg/m3) 

1 

2 7. DATA ANALYSIS FOR AEGL-3 

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

4 

5 No human data relevant to development of AEGL-3 values were identified. 

6 

7 7.2. Summary of Animal Data Relevant to AEGL-3 

8 

9 A 1-hr rat LC50 of 35, 885 ppm (nominal) was reported by Mobil Oil (1979), and a 4-hr rat 

10 LC50 of >10,000 ppm (nominal) was reported by Levin and Gabriel (1973). In a time-to-death 

11 study, up to 50% mortality was reported in mice exposed to 6450 ppm (nominal) TMP for 

12 approximately 3 hours (Hazleton, 1962); mortality was 2/10 at 2 hr 55 min, 4/10 at 2 hr 58 min, 

13 and 5/10 at 3 hr 1 min. 

14 

15 7.3. Derivation of AEGL-3 

16 

17 Up to 50% lethality was observed in mice exposed to 6450 ppm TMP for approximately 3 

18 hours (Hazleton, 1962). In the absence of other appropriate data for deriving AEGL-3 values, 

19 this exposure concentration will be divided by 3 to estimate a threshold for lethality (Rusch et al., 

20 2009) (point-of-departure 2150 ppm). Inter- and intraspecies uncertainty factors of 3 each (total 

21 10) will be applied because TMP is highly irritating, and much of the toxicity resulting from an 

22 acute exposure is likely caused by a direct chemical effect on the tissue; this type of portal-of23 entry effect is not expected to vary greatly between species or among individuals. The 

24 concentration-exposure time relationship for many irritant and systemically-acting vapors and 

gases may be described by Cn 25 x t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et 

26 al., 1986). To obtain conservative and protective AEGL values in the absence of an empirically 

27 derived chemical-specific scaling exponent, temporal scaling may be performed using n=3 when 

28 extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the 

Cn 29 x t = k equation (NRC, 2001). AEGL-3 values are presented in Table 6, and calculations are 

30 presented in Appendix A. 

31 

Table 6. AEGL-3 values for trimethyl phosphite 

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

560 ppm 

(2900 mg/m3) 

390 ppm 

(2000 mg/m3) 

310 ppm 

(1600 mg/m3) 

160 ppm 

(820 mg/m3) 

81 ppm 

(410 mg/m3) 

32 

33 The AEGL-3 values are supported by the 4-hr rat LC50 of >10,000 ppm (Levin and Gabriel, 

34 1973). Dividing 10,000 ppm by three yields an estimated 4-hr lethality threshold of 3000 ppm; 

35 applying a total uncertainty factor of 10, yields a 4-hr AEGL-3 value of 300 ppm. Also, no 

36 deaths were noted in rats exposed to approximately 100 ppm TMP 6 hr/day, 5 days/week for 4 

37 weeks (Biodymanics, 1978, 1979; Mobil Oil, 1979). These data suggest that the AEGL-3 values 

38 are protective. 

39 

40 8. SUMMARY OF AEGLS 

41 8.1. AEGL Values and Toxicity Endpoints 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

16

1 

2 AEGL values are summarized in Table 7. AEGL-1 values are based on a no-effect-level for 

3 clinical signs in rats repeatedly exposed to TMP. AEGL-2 values are based on lens opacities in 

4 rats repeatedly exposed to TMP, and AEGL-3 values are based on an estimated lethality 

5 threshold in mice. 

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/m3

) 

7.6 ppm 

(39 mg/m3) 

6.1 ppm 

(31 mg/m3) 

3.8 ppm 

(19 mg/m3) 

2.5 ppm 

(13 mg/m3) 

AEGL-2 

(Disabling) 

110 ppm 

(560 mg/m3

) 

77 ppm 

(390 mg/m3) 

61 ppm 

(310 mg/m3) 

38 ppm 

(190 mg/m3) 

25 ppm 

(128 mg/m3) 

AEGL-3 

(Lethal) 

560 ppm 

(2900 mg/m3

) 

390 ppm 

(2000 mg/m3) 

310 ppm 

(1600 mg/m3) 

160 ppm 

(820 mg/m3) 

81 ppm 

(410 mg/m3) 

7 

8 8.2. Comparison with Other Standards and Guidelines 

9 

10 AEGL values for trimethyl phosphite are compared to other guidelines and standards for this 

11 compound are listed in Table 8. 

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/m3

) 

7.6 ppm 

(39 mg/m3) 

6.1 ppm 

(31 mg/m3) 

3.8 ppm 

(19 mg/m3) 

2.5 ppm 

(13 mg/m3) 

AEGL-2 110 ppm 

(560 mg/m3

) 

77 ppm 

(390 mg/m3) 

61 ppm 

(310 mg/m3) 

38 ppm 

(190 mg/m3) 

25 ppm 

(128 mg/m3) 

AEGL-3 560 ppm 

(2900 mg/m3

) 

390 ppm 

(2000 mg/m3) 

310 ppm 

(1600 mg/m3) 

160 ppm 

(820 mg/m3) 

81 ppm 

(410 mg/m3) 

 

TLV-TWA 

(ACGIH)a 2 ppm 

MAC-Peak 

Category (The 

Netherlands)b

 2 ppm 

13 a 14 ACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value - Time Weighted 

15 Average) (ACGIH 2008) is the time-weighted average concentration for a normal 8-hour workday and a 40-hour work 

16 week, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect. Basis is ocular nd 

17 skin irritation. 

18 b 19 MAC (Maximaal Aanvaaarde Concentratie [Maximal Accepted Concentration - Peak Category]) (SDU Uitgevers 

20 [under the auspices of the Ministry of Social Affairs and Employment], The Hague, The Netherlands 2000) is defined 

21 analogous to the ACGIH-Ceiling 

22 

23 8.3. Data Adequacy and Research 

24 

25 There are no quantitative human data, and animal data are limited. Acute animal inhalation 

26 data are limited to studies with nominal concentrations. Repeated-exposure analytical data are 

27 available. Additional acute inhalation toxicity studies would be helpful. 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

17

1 

2 9. REFERENCES 

3 

4 ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Documentation 

5 of the Threshold Limit Values and Biological Exposure Indices: Trimethyl Phosphite. Sixth ed., 

6 ACGIH, Cincinnati, OH. 

7 

8 ACGIH (American Conference of Governmental Industrial Hygienists). 2008. Threshold limit 

9 values (TLVs) for chemical and physical agents and biological exposure indices (BEIs). 

10 ACGIH, Cincinnati, OH. 

11 

12 Biodynamics, 1978. Initial Submission: A repeated (4-week) inhalation study of MCTR-180-78 

13 in the rat with cover letter dated 082892. Project No. 78-7229. OTS0538473. 

14 

15 Biodynamics, 1979. A repeated (4-week) inhalation study of MCTR-74-79 in the rat. Project 

16 No. 79-7279. OTS 88-7900291. 

17 

18 Hazleton, 1962. Initial Submission: Letter submitting acute inhalation exposure in mice, rat, 

19 and guinea pigs, on hexachloro-2-cyclopentanone (final report) with attachments. Hazelton 

20 Laboratories, Inc. Falls Church, VA. November 1, 1962. OTS0537047. 

21 

22 HPV, 2005. High Production Volume (HPV) Chemical Challenge Program. Test Plan for 

23 Trimethyl phosphite. Submitted to US EPA by the Trimethyl Phosphite Consortium. December, 

24 2005. 

25 

26 HSDB (Hazardous Substances Data Bank). 2009. Trimethyl Phosphite. [Online] Available. 

27 http://toxnet.nlm.nih.gov/ [02/09/2009]. TOXNET, Toxicology Data Network. US. Natl. Library 

28 of Medicine. 

29 

30 Levin, L. and Gabriel, K.L. 1973. The vapor toxicity of trimethyl phosphite. Am. Ind. Hyg. 

31 Assoc. J. 34:286-291. 

32 

33 Mobil Oil. 1979. Initial Submission: The toxicologic profile of trimethyl phosphite (TMP) with 

34 cover letter dated 082892. July 1, 1979. OTS0583484. 

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 Rusch, G.M., Bast, C.B. and Cavender, F.L. 2009. Establishing a Point of Departure for Risk 

42 Assessment Using Acute Inhalation Toxicology Data. Regulatory Toxicology and 

43 Pharmacology. 54: 247-255. 

44 

45 SDU Uitgevers 2000. MAC Ministry of Social Affairs and Employment. Nationale MAC 

46 (Maximum Allowable Concentration) List, 2000. The Hague, The Netherlands. 

47 

48 ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

18

1 relationship of irritant and systemically acting vapours and gases. J. Hazard. Materials: 13: 

2 301-309. 

3 

4 

5 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

19

1 

2 APPENDIX A: Derivation of AEGL Values

3 

4 Derivation of AEGL-1

5 

6 Key Study: Biodynamics, 1979. A repeated (4-week) inhalation study of MCTR-74-

7 79 in the rat. Project No. 79-7279. OTS 88-7900291. 

8 

9 Toxicity endpoint: NOEL for clinical signs in rats exposed to 10 ppm TMP 6 hr/day, 5 

10 days/week for 4 weeks. Ocular effects were noted at the next highest 

11 concentration tested (51 ppm). 

12 

13 Uncertainty factors: Intraspecies: 3, the point-of-departure is from a repeated exposure study 

14 and the endpoint is not likely the result of a single exposure 

15 

16 Interspecies: 1, A UF of 3 might normally be applied. However use of a 

17 total uncertainty factor of 10 yields AEGL-1 values that are not 

18 compatible with human worker exposure data (no effects with 

19 occupational exposures up to 15 ppm). 

20 

21 Modifying factor: NA 

22 

Time scaling: C3 23 x t = k (10- min, 30-min, 1-hr, 4-hr) 

10 ppm 3 x 6 hr = 6000 ppm3 24 -hr 

25 

C1 26 x t = k (8-hr) 

27 10 ppm x 6 hr = 60 ppm-hr 

28 

10-minute AEGL-1: C3 x 0.167 hr = 6000 ppm3 29 ·hr 

 C3 30 = 35928 ppm 

31 C = 32.9 ÷ 3 = 11 ppm 

32 

30-minute AEGL-1: C3 x 0.5 hr = 6000 ppm3 33 ·hr 

 C3 34 = 12,000 ppm 

35 C = 22.8 ÷ 3 = 7.6 ppm 

36 

1-hour AEGL-1: C3

 x 1 hr = 6000 ppm3 37 ·hr 

 C3 38 = 6000 ppm 

39 C = 18.2 ÷ 3 = 6.1 ppm 

40 

4-hour AEGL-1: C3

 x 4 hr = 6000 ppm3 41 ·hr 

 C3 42 = 1500 ppm 

43 C = 11.4 ÷ 3 = 3.8 ppm 

44 

45 

8-hour AEGL-1: C1 46 x 8 hr = 60 ppm·hr 

 C1 47 = 7.5 ppm 

48 C = 7.5 ÷ 3= 2.5 ppm 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

20

1 Derivation of AEGL-2 

2 

3 Key Study: Biodynamics, 1979. A repeated (4-week) inhalation study of MCTR-74-

4 79 in the rat. Project No. 79-7279. OTS 88-7900291. 

5 

6 Toxicity endpoint: Lens opacities in rats exposed to 101 ppm TMP 6 hr/day, 5 days/week for 

7 4 weeks. Ocular effects were still noted 2-weeks post-exposure. 

8 

9 Uncertainty factors: Intraspecies: 3, The point-of-departure is from a repeated exposure study 

10 and the endpoint is not likely the result of a single exposure. The lens 

11 opacities observed in rats repeatedly exposed to 101 ppm TMP were noted 

12 after 2 weeks and continued to increase in frequency and severity after 4 

13 weeks exposure, suggesting a cumulative effect. 

14 

15 Interspecies: 1, A UF of 3 might normally be applied. However use of a 

16 total uncertainty factor of 10 yields AEGL-2 values that are not 

17 compatible with human worker exposure data (no effects with 

18 occupational exposures up to 15 ppm). 

19 

20 Modifying factor: NA 

21 

Time scaling: C3 22 x t = k (10- min, 30-min, 1-hr, 4-hr) 

101 ppm 3 x 6 hr = 6,181,806 ppm3 23 -hr 

24 

C1 25 x t = k (8-hr) 

26 101 ppm x 6 hr = 606 ppm-hr 

27 

10-minute AEGL-2: C3 x 0.167 hr = 6,181,806 ppm3 28 ·hr 

 C3 29 = 37016802 ppm 

30 C = 333 ÷ 3 = 110 ppm 

31 

30-minute AEGL-2: C3

 x 0.5 hr = 6,181,806 ppm3 32 ·hr 

 C3 33 = 12363612 ppm 

34 C = 231 ÷ 3 = 77 ppm 

35 

1-hour AEGL-2: C3

 x 1 hr = 6,181,806 ppm3 36 ·hr 

 C3 37 = 6,181,806 ppm 

38 C = 183 ÷ 3 = 61 ppm 

39 

4-hour AEGL-2: C3

 x 4 hr = 6,181,806 ppm3 40 ·hr 

 C3 41 = 1545452 ppm 

42 C = 115 ÷ 3 = 38 ppm 

43 

8-hour AEGL-2: C1 44 x 8 = 606 ppm-hr 

45 C = 76 ÷ 3 = 25 

46 

47 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

21

1 

2 Derivation of AEGL-3 

3 

4 Key Study: Hazleton, 1962. Initial Submission: Letter submitting acute inhalation 

5 exposure in mice, rat, and guinea pigs, on hexachloro-2-cyclopentanone 

6 (final report) with attachments. Hazelton Laboratories, Inc. Falls Church, 

7 VA. November 1, 1962. OTS0537047. 

8 

9 Toxicity endpoint: 3-hr estimated lethality threshold in mice (2150 ppm) 

10 

11 Uncertainty factors: Interspecies: 3, TMP is highly irritating, and much of the acute toxicity is 

12 likely caused by a direct chemical effect on the tissues; this type of portal13 of-entry effect is not expected to vary greatly between species. 

14 

15 Intraspecies: 3, TMP is highly irritating, and much of the acute toxicity is 

16 likely caused by a direct chemical effect on the tissues; this type of portal17 of-entry effect is not expected to vary greatly among individuals. 

18 

19 Modifying factor: NA 

20 

Time scaling: C3 21 x t = k (10- min, 30-min, 1-hr) 

2150 ppm 3 x 3 hr = 2.98 x 1010 ppm3 22 -hr 

23 

C1 24 x t = k (4-hr, 8-hr) 

25 2150 ppm x 3 hr = 6450 ppm-hr 

26 

10-minute AEGL-3: C3 x 0.167 hr = 2.98 x 1010 ppm3 27 -hr 

 C3 = 1.78 x 1011 28 ppm 

29 C = 5630 ÷ 10 = 560 ppm 

30 

30-minute AEGL-3: C3

 x 0.5 hr = 2.98 x 1010 ppm3 31 -hr 

 C3 = 5.96 x 1010 32 ppm 

33 C = 3906 ÷ 10 = 390 ppm 

34 

1-hour AEGL-3: C3

 x 1 hr = 2.98 x 1010 ppm3 35 -hr 

 C3 = 2.98 x 1010 36 ppm 

37 C = 3100 ÷ 10 = 310 ppm 

38 

4-hour AEGL-3: C1 39 x 4 hr = 6450 ppm·hr 

40 C = 1613 ppm ÷ 10 = 160 ppm 

41 

8-hour AEGL-3: C1 42 x 8 hr = 6450 ppm·hr 

43 C = 806 ppm ÷ 10 = 81 ppm 

44 

45 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

22

1 APPENDIX B: Derivation Summary for Trimethyl Phosphite AEGLs 

2 

3 

4 AEGL-1 VALUES 

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

11 ppm 

(56 mg/m3

) 

7.6 ppm 

(39 mg/m3) 

6.1 ppm 

(31 mg/m3) 

3.8 ppm 

(19 mg/m3) 

2.5 ppm 

(13 mg/m3) 

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 exposure 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 repeated 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: Cn 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 Cn

 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 use of a NOEL from a repeated-exposure study. 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

23

1 

2 AEGL-2 VALUES 

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

110 ppm 

(560 mg/m3) 

77 ppm 

(390 mg/m3) 

61 ppm 

(310 mg/m3) 

38 ppm 

(190 mg/m3) 

25 ppm 

(128 mg/m3) 

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 exposure 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 repeated 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 after 4 weeks exposure, suggesting a cumulative effect. 

Modifying Factor: NA 

Animal to Human Dosimetric Adjustment: NA 

Time Scaling: Cn 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 Cn

 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 use of a repeated-exposure study. 

3 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

24

1 

2 

3 AEGL-3 VALUES 

4 

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

560 ppm 

(2900 mg/m3

) 

390 ppm 

(2000 mg/m3) 

310 ppm 

(1600 mg/m3) 

160 ppm 

(820 mg/m3) 

81 ppm 

(410 mg/m3) 

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: Mice/Swiss albino/10 males; 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 threshold 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 toxicity 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: cn 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 LC50 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. 

 

5 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

25

1 

2 APPENDIX C: Category Plot for Trimethyl Phosphite 

3 

4 

5 

1 

10 

100 

1000 

10000 

100000 

ppm

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

6 
TRIMETHYL PHOSPHITE Proposed: October, 2009 

26

1 Category Plot Data 

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