### JANUARY 201 2 

# Appendix B: Benchmark Dose Modeling Results for the Derivation of Reference Values for 

# 1,2,4

- and 1,3,5

- TrimethylbenzeneDRAFT

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# DISCLAIMER

This document is an Interagency Science Consultation draft

. This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It has not been formally disseminated by the EPA. It does not represent and should not be construed to represent any Ag ency determination or policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.DRAFT

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# CONTENTS

DISCLAIMER

................................ ................................ ................................ ................................ ............. 2

CONTENTS

................................ ................................ ................................ ................................ ................. 3

LIST OF TABLES AND FIGURES

................................ ................................ ................................ .......... 4 B.1. BMDS Modeling Methodology

................................ ................................ ................................ ........... 6 B.2. BMDS Modeling Results

................................ ................................ ................................ ..................... 8

B.3. References

................................ ................................ ................................ ................................ .......... 25DRAFT

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# LIST OF TABLES AND FIGURES

Table B

- 1. Benchmark dose modeling results (constant variance) for increased latency to pawlick in male Wistar rats exposed to 1,2,4

- TMB. (Korsak and Rydzyński, 1996)

................................ ......... 8 Figure B

- 1. Exponential 4 model fit for increased latency to pawlick in male Wistar rats (BMR = 1 SD, constant variance) exposed to 1,2,4

- TMB. (Korsak and Rydzyński, 1996)

................................ .... 8

Table B

- 2. Benchmark dose modelin g results (constant variance) for increased macrophages in BAL fluid in male Wistar rats exposed to 1,2,4

- TMB. (Korsak et al., 1997)

................................ ......... 9

Table B

- 3. Benchmark dose modeling results (modeled variance) for increased macrophages in BAL fluid in male Wistar rats exposed to 1,2,4

- TMB. (Korsak et al., 1997)

................................ ........ 9

Table B

- 4. Benchmark dose modeling results (constant variance) for increased RBC in male Wistar rats exposed to 1,2,4

- TMB. (Korsak et al., 2000)

................................ ................................ ...... 10 Figure B

- 2. Exponential 4 model fit for increased RBC in male Wistar rats (BMR = 1 SD, constant variance) exposed to 1,2,4

- TMB. (Korsak et al., 2000)

................................ ................................ .......... 10

Table B

- 5. Benchmark dose modeling results (constant variance) for decreased reticulocytes in female Wistar rats exposed to 1,2,4

- TMB. (Korsak et al., 2000)

................................ .......................... 11

Table B

- 6. Benchmark dose modeling results (modeled variance) for decreased reticulocytes in female Wistar rats exposed to 1,2, 4

- TMB. (Korsak et al., 2000)

................................ .......................... 11

Table B

- 7. Benchmark dose modeling results (constant variance) for decreased clotting time in femal e Wistar rats exposed to 1,2,4

- TMB. (Korsak et al., 2000)

................................ .......................... 12

Table B

- 8. Benchmark dose modeling results (modeled variance) for dec reased clotting time in female Wistar rats exposed to 1,2,4

- TMB. (Korsak et al., 2000)

................................ ......................... 12

Table B

- 9. Benchmark dose modeling resu lts for decreased rotorod performance in male Wistar rats exposed to 1,2,4

- TMB. (Korsak and Rydzyński, 1996)

................................ ................................ .. 13 Figure B

- 3. Log

- log istic model fit for decreased rotorod performance in male Wistar rats (BMR = 10% extra risk) exposed to 1,2,4

- TMB. (Korsak and Rydzyński, 1996)

................................ .............. 13

Table B

- 10. Benchmark dose modeling results (constant variance) for decreased fetal weight in male Sprague

- Dawley rats exposed to 1,2,4

- TMB. (Saillenfait et al., 2005)

................................ ........ 14

Table B

- 11. Benchmark dose modeling results (constant variance) for decreased fetal weight in male Sprague

- Dawley rats exposed to 1,2,4

- TMB. (Saillenfait et al., 2005)

................................ ........ 14 Figure B

- 4. Linear model fit for decreased fetal weight in male Sprague

- Dawley rats (BMR = 1 SD, constant variance) exposed to 1,2,4

- TMB. (Saille nfait et al., 2005)

................................ ...................... 15 Figure B

- 5. Linear model fit for decreased fetal weight in male Sprague

- Dawley rats (BMR = 5% RD, constant variance) exposed to 1,2,4

- TMB. (Saillenfait et al., 2005)

................................ .............. 15

Table B

- 12. Benchmark dose modeling results (constant variance) for d ecreased fetal weight in female Sprague

- Dawley rats exposed to 1,2,4

- TMB. (Saillenfait et al., 2005)

................................ ..... 16

Table B

- 13. Benchmark dose modeling results (constant variance) for decreased fetal weight in female Sprague

- Dawley rats exposed to 1,2,4

- TMB. (Saillenfait et al., 2005)

................................ ..... 16DRAFT

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### Figure B

- 6. Linear model fit for decreased fetal weight in female Sprague

- Dawley rats (BMR = 1 SD, constant variance) exposed to 1,2,4

- TMB. (Saillenfait et al., 2005)

................................ ............... 17 Figure B

- 7. Linear model fit for decreased fetal weight in female Sprague

- Dawley rats (BMR = 5% RD, constant variance) exposed to 1,2,4

- TMB. (Saillenfait et al., 2005)

................................ .............. 17

Table B

- 14. Benchmark dose modeling results (constant variance) for decreased maternal weight gain in female Sprague

- Dawley rats exposed to 1,2,4

- T MB. (Saillenfait et al., 2005)

........................ 18 Figure B

- 8. Power model fit for decreased maternal weight gain in female Sprague

- Dawley rats (BMR = 1 SD, constant variance) exposed to 1,2,4

- TMB. (Saillenfait et al., 2005)

............................. 18

Table B

- 15. Benchmark dose modeling results (consta nt variance) for decreased fetal weight in male Sprague

- Dawley rats exposed to 1,3,5

- TMB. (Saillenfait et al., 2005)

................................ ........ 19

Table B

- 16. Benchmark dose modeling results (modeled variance) for decreased fetal weight in male Sprague

- Dawley rats exposed to 1,3,5

- TMB. (Saillenfait et al., 2005)

................................ ........ 19

Table B

- 17. Benchmark dose modeling results (modeled variance) for decreased fetal weight in male Sprague

- Dawley rats exposed to 1,3,5

- TMB. (Saillenfait et al., 2005)

................................ ........ 20 Figure B

- 9. Exponential 2 model fit for decreased fetal weight in male Sprague

- Dawley rats (BMR = 1 SD, constant variance) exposed to 1,3,5

- TMB. (Saillenfait et al., 2005)

................................ ......... 20 Figure B

- 10. Exponential 2 model fit for decreased fetal weight in male Sprague

- Dawley rats (BMR = 5% relative deviance) exposed to 1,3,5

- TMB. (Saillenfait et al., 2005)

................................ . 21

Table B

- 18. Benchmark dose modeling results (constant variance) for decreased fetal weight in female Sprague

- Dawley rats exposed to 1,3,5

- TMB. (Saillenfait et al., 2005)

................................ ..... 21

Table B

- 19. Benchmark dose modeling results (modeled varian ce) for decreased fetal weight in female Sprague

- Dawley rats exposed to 1,3,5

- TMB. (Saillenfait et al., 2005)

................................ ..... 22

Table B

- 20. Bench mark dose modeling results (modeled variance) for decreased fetal weight in female Sprague

- Dawley rats exposed to 1,3,5

- TMB. (Saillenfait et al., 2005)

................................ ..... 22

Table B

- 21. Benchmark dose modeling results (constant variance) for decreased maternal weight gain in female Sprague

- Dawley rats (exposed to 1,3,5

- TMB. (Saillenfait et al., 2005)

....................... 23

Table B

- 22. Benchmark dose modeling results for decreased maternal weight gain in female Sprague

- Dawley rats (BMR = 1 SD, modeled variance) exposed to 1,3,5

- TMB. (Saillenfait et al., 2005)

................................ ................................ ................................ ................................ ........................... 23 Figure B

- 11. Power model fit for decreased maternal weight gain in female Sprague

- Dawley rats (BMR = 1 SD, modele d variance) exposed to 1,3,5

- TMB. (Saillenfait et al., 2005)

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# B **.1. BMDS Modeling Methodology**

This appendix provides technical detail on dose

- response evaluation and determination of points of departure (POD) for relevant neurological, respiratory, hematological, and developmental toxicity endpoints for 1,2,4

- TMB and 1,3,5

- TMB. The modeling was conducted in accordance with the draft
Benchmark Dose Techn ical Guidance Document ( U.S. EPA, 2000 ) using Benchmark Dose Software ( 2009 ) Version 2.1.2 (BMDS). The doses used in modeli ng the individual endpoints, and reported as BMDs and BMDLs, are in mg/m3.

For dichotomous endpoints, BMDS dichotomous models were fit to the data. Model parameters were estimated using the maximum likelihood method. For the sole dichotomous endpoint, de creased rotorod performance (measured as percent failure) a BMR of 10% extra risk was chosen as the response level. No data are available that identify the response level that is biologically significant for this endpoint. In cases such as this, a BMR of 10% extra risk is recommended according to EPA Technical Guidance ( U.S. EPA, 2000 )

, under the assumption that it represents a minimal biologically significant response. Following the draft Benchmark Dose Technical Guidance Document ( U.S. EPA, 2000 ) , each mod el was tested for global goodness

- of

- fit using a chi

- square goodness

- of

- fit test (χ2 p

- value < 0.10 indicated inadequate fit). Other factors were used to assess the model fit, such as adequacy of fit in the low

- dose region and near the BMR (scaled residua ls < |2|) 

### and graphical fit.

For continuous endpoints, BMDS continuous models were fit to the data. Model parameters were estimated using the maximum likelihood method. For the continuous endpoints (latency to pawlick, increased BAL macrophages, decreased RBC, increased WBC, decreas ed reticulocytes, decreased clotting time, decreased fetal weight, and decreased maternal weight change), a BMR equal to a change in the meal response equivalent to 1 standard deviation of the estimated mean was chosen as the response level.
A BMR equal t o a change in the meal response equivalent to 1 standard deviation is recommended as the response level for endpoints for which no data exist as to what level of response to consider adverse ( U.S. EPA, 2000 ) . In addition to this a BMR of 5% relative deviance was also used as a response level for the decreased fetal weight endpoints. As a decrease of 10% body weight is often used as a biologically significantly response level for adult animals, a 5% decrease in body weight was determined as biologically significant for prenat al rats. Model fit was assessed following the draft Benchmark Dose
Technical Guidance Document ( U.S. EPA, 2000 ) as follows. For each model:

The homogeneity of the variances (the “constant variance” case) was tested using a likelihood ratio test (BMDS Test 2). If Test 2 was not rejected (χ2 p

- value ≥ 0.10), the model was fitted to the data under
the constant variance case.

If Test 2 was reje cted (χ2 p

- value < 0.10), the variance was tested as a power function of the mean (the “modeled variance” case) using a likelihood ratio test (BMDS Test 3). If Test 3 was not rejected (χ2

p

- value ≥ 0.10), the model was fitted to the data under the modeled variance case.DRAFT

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### For fitting models in either the constant variance or modeled variance case, models were tested for adequacy of fit to the means using a likelihood ratio test (BMDS Test 4, with χ2 p

- value < 0.10 indicating inadequate fit). Other factors were used to assess the model fit, such as adequacy of fit in the low

- dose region and near the BMR (scaled residuals < |2|) 

### and graphical fit.

For each endpoint, the best

- fit model was selected from among the models exhibiting adequate fit.
For each mo del, the BMDL was calculated using the profile likelihood method, where the BMDL refers to the 95% lower confidence limit on the BMD. If the BMDL estimates were “sufficiently close,” that is, differed by at most 3

- fold, the model selected was the one that yielded the lowest AIC value. If more than one model had the lowest AIC, BMDL values from these models were averaged to obtain a POD. If the BMDL estimates were not sufficiently close, the lowest BMDL was selected as the POD.

Below are tables summariz ing the modeling results for the following modeled endpoints: latency to pawlick (as a measure of decreased pain sensitivity and thus CNS effects, male rats), increased BAL macrophages (male rats), decreased RBC (male rats), decreased reticulocytes (female rats), decreased clotting time (female rats), decreased rotorod performance (male rats), decreased fetal weight (male and female rats), and decreased maternal weight gain (female rats).

The following parameter restrictions were applied. For the log

- log istic and dichotomous Hill models, restrict slope ≥ 1; for the multistage models, restrict beta’s ≥ 0; for the Weibull and dichotomous power models, restrict power ≥ 1; for the polynomial models, restrict beta’s ≥ 0; for the Hill and continuous power model s, restrict power ≥ 1.

Comprehensive modeling results for all endpoints are provided on EPA’s Health Effects Research Online (HERO) database ( U.S. EPA, 2011 )

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# B **.2. BMDS Modeling Results**

Table B

- 1. Benchmark dose modeling results (constant variance) for increased latency to pawlick in male Wistar rats exposed to 1,2,4

- TMB. ( Korsak and Rydzyński, 1996 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC Exponential 2 Exponential 3 0.01148 184.2916 673.534 530.785

Only Exponential model 4 provided an adequate fit and therefore was selected 

### Exponential 4 0.3756 178.142 161.328 83.9538 

### Exponential 5 N/A 179.3571 210.915 92.5214


### Hill NA 179.357065 194.987 90.2031


### Linear Polynomial 2° Polynomial 3° Power 0.02926 182.419864 534.778 395.907

a Constant variance case presented (Test 2 p

- value = 0.07651), although this p

- value is less than 0.10, the result indicates a marginal fit at the 95% confidence level. For that reason, the constant variance model is determined to adequately describe the observed variance. Selected model in bold; scaled residuals for selected model for concentrations 0, 123, 492, and 1230 mg/m 3 were 0.3396,

- 0.6151, 0.5003, and

- 0.1816, respectively



### Figure B

- 1. Exponential 4 model fit for increased latency to pawlick in male Wistar rats (BMR = 1 SD, constant variance) exposed to 1,2,4

- TMB. ( Korsak and Rydzyński, 1996 ) 10 15 20 25 30 35

0 200 400 600 800 1000 1200Mean Response

dose Exponential Model 4 with 0.95 Confidence Level

12:26 05/11 2011 BMD BMDL ExponentialDRAFT

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### Table B

- 2. Benchmark dose modeling results (constant variance) for increased macrophages in BAL fluid in male Wistar rats exposed to 1,2,4

- T MB. ( Korsak et al., 1997 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Sel ection p - value AIC

Exponential 2 Exponential 3 < 0.0001 35.31797 1102.28 700.595

No model selected 

### Exponential 4 < 0.0001 1.670182 19.9808 12.0886 

### Exponential 5 N/A 3.39269 51.2844 12.4452


### Hill NA 3.39269 99.57 12.7896



### Linear Polynomial 2° Polynomial 3° Power <.0001 34.391868 910.65 542.067

a Constant variance case presented (Test 2 p

- value < 0.001), this p

- value indicates that a constant variance model does not adequately describe the observed variances. BMDS recommends using a non

- homogenous variance model.



### Table B

- 3. Benchmark dose modeling results (modeled variance) for increased macrophages in BAL fluid in male Wistar rats exposed to 1,2,4

- TMB. ( Korsak et al., 1997 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC
Exponential 2 < 0.0001 27.50191 357476 8755.97

No model selected 

### Exponential 3 < 0.0001 27.51253 143324 2676.29 

### Exponential 4 0.007731

- 22.95564 0.63732 2.0E

- 03 

### Exponential 5 N/A

- 20.96099 8.44473 6.5E

- 03


### Hill NA

- 20.960993 66.3984

-- 

### Linear <.0001 27.505758

- 9999

-- 

### Polynomial 2° <.0001 29.506992

- 9999

-- 

### Polynomial 3° <.0001 29.495219 13362.4

-- 

### Power <.0001 27.515776 147269 1358.77

a Modeled variance case presented (Test 3 p

- value < 0.001), this p

- value indicates that the modeled variance does not adequately describe the observed variances. Therefore, this endpoint cannot be modeled in BMDS and the NOAEL/LOAEL approach is recommended. In addition, the majority of models either failed to converge, or did converge but on inadequate fits to the means.DRAFT

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### Table B

- 4. Benchmark dose modeling results (constant variance) for increased RBC in male Wistar rats exposed to 1,2,4

- TMB. ( Korsak et al., 2000 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC

Exponential 2 Exponential 3 0.5999 76.43277 711.931 462.026

Of the models that provided an adequate fit and valid BMDL estimate, the Exponential 4 model was selected based on the lowest BMDL (BMDLs differed by more than 3

- fold). 

### Exponential 4 0.5509 77.7664 473.209 174.057 

### Exponential 5 N/A 79.41075 481.769 186.184


### Hill NA 79.410749 479.415

--


### Linear Polynomial 2° Polynomial 3° Power 0.5285 76.686149 770.334 528.519

a Constant variance case presented (Test 2 p

- value = 0.4329), selected model in bold; scaled residuals for selected model for doses 0, 123, 492, and 1230 mg/m 3 were

- 0.2734, 0.4609,

- 0.2508, 0.06325, respectively.



### Figure B

- 2. Exponential 4 model fit for increased RBC in male Wistar rats (BMR = 1 SD, constant variance) exposed to 1,2,4

- TMB. ( Korsak et al., 2000 ) 7 8 9 10 11

0 200 400 600 800 1000 1200Mean Response

dose Exponential Model 4 with 0.95 Confidence Level

13:22 05/11 2011 BMD BMDL ExponentialDRAFT

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### Tabl e B

- 5. Benchmark dose modeling results (constant variance) for decreased reticulocytes in female Wistar rats exposed to 1,2,4

- TMB. ( Korsak et al., 2000 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC
Exponential 2 0.1363 89.48175 884.846 297.802

No model selected. 

### Exponential 3 0.0009374 98.44341 7.86E+06 1810.44 

### Exponential 4 0.279 88.66811 100.174 0.55191 

### Exponential 5 0.279 88.66811 100.174 0.23142


### Hill 0.33 88.444923 113.052 1.72E

- 12



### Linear Polynomial 2° Polynomial 3° Power 0.09332 90.239573 1170.28 704.361

a Constant variance case presented (Test 2 p

- value < 0.0001), this p

- value indicates that a constant variance model does not adequately describe the observed variances. BMDS recommends using a non

- homogenous variance model.



### Table B

- 6. Benchmark dose modeling results (modeled variance) for decreased reticulocytes in female Wistar rats exposed to 1,2,4

- TMB. ( Korsak et al., 2000 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC
Exponential 2 0.2684 69.81474 2358.64 879.155

No model selected 

### Exponential 3 < 0.0001 100.4434 1.89E+07 108315 

### Exponential 4 Exponential 5 0.583 69.48553 Not Computed 0



### Hill 0.7315 69.301892

-- -- 

### Linear Polynomial 2° Polynomial 3° Power 0.09136 71.969947 1853.54 1130.45

a Modeled variance case presented (Test 3 p

- value = 0.253), however, for adequately fitting models, the estimated BMDs are either not calculated or are larger than the highest exposure concentration. Therefore, this endpoint cannot be modeled in BMDS and the NOAEL/LOAEL approach is recommended.DRAFT

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### Table B

- 7. Benchmark dose modeling results (constant variance) for decreased clotting time in female Wistar rats exposed to 1,2,4

- TMB. ( Korsak et al., 2000 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC

Exponential 2 Exponential 3 0.009612 205.5042 1528.43 715.376

No model selected. 

### Exponential 4 0.3014 199.2826 106.35 0.708206 

### Exponential 5 N/A 201.2538 115.896 0.645003


### Hill NA 201.253789 120.705 0.00149623



### Linear Polynomial 2° Polynomial 3° Power 0.008122 205.841099 1644.88 860.549

a Constant variance case presented (BMDS Test 2 p

- value = 0.0.02286), this p

- value indicates that a constant variance model does not adequately describe the observed variances. BMDS recommends using a non

homogenous variance model..



### Table B

- 8. Benchmark dose modeling results (modeled variance) for decreased clotting time in female Wistar rats exposed to 1,2,4

- TMB. ( Korsak et al., 2000 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC

Exponential 2 Exponential 3 0.0005418 206.9293 2039.67 746.39

No model selected. 

### Exponential 4 0.09221 196.7234 280.816 0.628271 

### Exponential 5 N/A 198.7223 177.377 0.530841


### Hill NA 198.722332 161.869 1.16E

- 07



### Linear Polynomial 2° Polynomial 3° Power 0.0004693 207.21649 2116.49 901.197

a Modeled variance case presented (Test 3 p

- value = 0.2001), However, the goodness

- of

- fit p

- value indicates poor model fit for all models except the Exponential 5 and Hill models, which return biologically, unreasonably low BMDL estimates. Therefore, this endpoint cannot be modeled in BMDS and the NOAEL/LOAEL approach is recommendedDRAFT

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### Table B

- 9. Benchmark dose modeling results for decreased rotorod performance in male Wistar rats exposed to 1,2,4

- TMB. ( Korsak and Rydzyński, 1996 )

Model a 

### Goodness

- of

- fit BMD 10% 

### BMDL 10% 

### Basis for Model Selection p - value AIC Logistic 0.6024 35.5306 528.905 341.987

Of the models that provided an adequate fit and valid BMDL estimate, the log

- logistic model was selected based on the lowest BMDL (BMDLs differed by more than 3

- fold). 

### Log

- logistic 0.9743 32.1664 193.575 93.947 

### Log

- probit 0.5825 35.4276 426.494 232.739


### Probit 0.6248 35.4027 489.595 317.868 

### Dichotomous Hill 0.9352 34.1023 160.508

--



### Gamma Weibull Linear Multistage 2° Multistage 3° 0.9338 32.3299 228.574 129.306

a Decreased rotorod performance was measured as increased percentage of failures per rat, selected model in bold; scaled residuals for selected model for concentrations 0, 123, 492, and 1230 mg/m 3 were 0.000, 0.434,

- 0.154,

- 0.089, respectively



### Figure B

- 3. Log

- logistic model fit for decreased rotorod performance in male Wistar rats (BMR = 10% extra risk) exposed to 1,2,4

- TMB. ( Korsak and Rydzyński, 1996 ) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7

0 200 400 600 800 1000 1200Fraction Affected

dose Log-Logistic Model with 0.95 Confidence Level

14:41 05/11 2011 BMDL BMD Log-LogisticDRAFT

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### Table B

- 10. Benchmark dose modeling results (constant variance) for decreased fetal weight in male Sprague

- Dawley rats exposed to 1,2,4

- TMB. ( Saillenfait et al., 2005 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC
Exponential 2 0.5553

- 84.19486 2827 2157.12

Of the models that provided an adequate fit and valid BMDL estimate, the linear model was selected based on the lowest AIC (BMDLs differed by less than 3

- fold). 

### Exponential 3 0.8206

- 83.88273 3477.3 2376.65 

### Exponential 4 0.5553

- 84.19486 2827 2070.08 

### Exponential 5 0.8206

- 83.88273 3477.3 2375.04


### Hill 0.5424

- 81.906855 3477.45 2393.95


### Linear 0.6048

- 84.431422 2862.3 2219.05 

### Polynomial 2° 0.869

- 83.997275 3429.49 2409.2 

### Polynomial 3° 0.9457

- 84.166344 3476.36 2439


### Power 0.8309

- 83.907452 3477.46 2394.53

a Constant variance case presented (Test 2 p

- value = 0.1008), selected model in bold; scaled residuals for selected model for concentrations 0, 492, 1476, 2952, and 4428 mg/m 3 were

- 0.333,

- 0.327, 0.478, 0.935,

- 0.175, respectively



### Table B

- 11. Benchmark dose modeling results (constant variance) for decreased fetal weight in male Sprague

- Dawley rats exposed to 1,2,4

- TMB. ( Saillenfait et al., 2005 )

Model a 

### Goodness

- of

- fit BMD 5% 

### BMDL 5% 

### Basis for Model Selection p - value AIC
Exponential 2 0.5553

- 84.19486 2025.51 1589.6

Of the models that provided an adequate fit and valid BMDL estimate, the linear model was selected based on the lowest AIC (BMDLs differed by less than 3

- fold). 

### Exponential 3 0.8206

- 83.88273 2900.94 1735.12 

### Exponential 4 0.5553

- 84.19486 2025.51 1439.31 

### Exponential 5 0.8206

- 83.88273 2900.93 1708.52


### Hill 0.5424

- 81.906855 2897.13 1768.21


### Linear 0.6048

- 84.431422 2072.97 1652.29 

### Polynomial 2° 0.869

- 83.997275 2830.76 1778.84 

### Polynomial 3° 0.9457

- 84.166344 2876.68 1798.47


### Power 0.8309

- 83.907452 2025.51 1589.6

a Constant variance case presented (Test 2 p

- value = 0.1008), selected model in bold; scaled residuals for selected model for concentrations 0, 492, 1476, 2952, and 4428 mg/m 3 were

- 0.333,

- 0.327, 0.478, 0.935,

- 0.175, respectivelyDRAFT

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### Figure B

- 4. Linear model fit for decreased fetal weight in male Sprague

- Dawley rats (BMR = 1 SD, constant variance) exposed to 1,2,4

- TMB. ( Saillenfait et al., 2005 )

Figure B

- 5. Linear model fit for decreased fetal weight in male Sprague

- Dawley rats (BMR = 5% RD, constant variance) exposed to 1,2,4

- TMB. ( Saillenfait et al., 2005 ) 5 5.2 5.4 5.6 5.8

6

0 500 1000 1500 2000 2500 3000 3500 4000 4500Mean Response

dose Linear Model with 0.95 Confidence Level

13:40 05/13 2011 BMD BMDL Linear

5 5.2 5.4 5.6 5.8

6

0 500 1000 1500 2000 2500 3000 3500 4000 4500Mean Response

dose Linear Model with 0.95 Confidence Level

12:35 08/22 2011 BMD BMDL LinearDRAFT

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### Table B

- 12. Benchmark dose modeling results (constant variance) for decre ased fetal weight in female Sprague

- Dawley rats exposed to 1,2,4

- TMB. ( Saillenfait et al., 2005 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC
Exponential 2 0.4859

- 101.5432 2674.19 2061.81

Of the models that provided an adequate fit and valid BMDL estimate, the linear model was selected based on the lowest AIC (BMDLs differed by less than 3

- fold). 

### Exponential 3 0.6334

- 101.0717 3353.03 2237.72 

### Exponential 4 0.4859

- 101.5432 2674.19 1965.3 

### Exponential 5 0.6334

- 101.0717 3353.03 2228.46


### Hill 0.3519

- 99.118484 3351.17 2265.93


### Linear 0.5336

- 101.79365 2715.13 2125.87 

### Polynomial 2° 0.7025

- 101.27877 3290.33 2289.13 

### Polynomial 3° 0.8151

- 101.57624 3355.31 2336.97



### Power 0.6487

- 101.11942 3351.29 2266.61

a Constant variance case presented (Test 2 p

- value = 0.3936), selected model in bold; scaled residuals for selected model for concentrations 0, 492, 1476, 2952, and 4428 mg/m 3 were

- 0.305,

- 0.196, 0.134, 1.19,

- 0.78, respectively



### Table B

- 13. Benchmark dose modeling results (constant variance) for decreased fetal weight in female Sprague

- Dawley rats exposed to 1,2,4

- TMB. ( Saillenfait et al., 2005 )

Model a 

### Goodness

- of

- fit BMD 5% 

### BMDL 5% 

### Basis for Model Selection p - value AIC
Exponential 2 0.4859

- 101.5432 1967.39 1561.2

Of the models that provided an adequate fit and valid BMDL estimate, the linear model was selected based on the lowest AIC (BMDLs differed by less than 3

- fold). 

### Exponential 3 0.6334

- 101.0717 2820.97 1680.31 

### Exponential 4 0.4859

- 101.5432 1967.39 1409.34 

### Exponential 5 0.6334

- 101.0717 2820.97 1640.53


### Hill 0.3519

- 99.118484 2815.13 1719.81


### Linear 0.5336

- 101.79365 2017.28 1625.17 

### Polynomial 2° 0.7025

- 101.27877 2734.8 1735.86 

### Polynomial 3° 0.8151

- 101.57624 2800.31 1767.94



### Power 0.6487

- 101.11942 1967.39 1561.2

a Constant variance case presented (Test 2 p

- value = 0.3936), selected model in bold; scaled residuals for selected model for concentrations 0, 492, 1476, 2952, and 4428 mg/m 3 were

- 0.305,

- 0.196, 0.134, 1.19,

- 0.78, respectivelyDRAFT

- DO NOT CITE OR QUOTE 17 

### Figure B

- 6. Linear model fit for decreased fetal weight in female Sprague

- Dawley rats (BMR = 1 SD, constant variance) exposed to 1,2,4

- TMB. ( Saillenfait et al., 2005 )

Figure B

- 7. Linear model fit for decreased fetal weight in female Sprague

- Dawley rats (BMR = 5% RD, constant variance) exposed to 1,2,4

- TMB. ( Saillenfait et al., 2005 ) 4.8

5 5.2 5.4 5.6 5.8

0 500 1000 1500 2000 2500 3000 3500 4000 4500Mean Response

dose Linear Model with 0.95 Confidence Level

13:38 05/13 2011 BMD BMDL Linear

4.8

5 5.2 5.4 5.6 5.8

0 500 1000 1500 2000 2500 3000 3500 4000 4500Mean Response

dose Linear Model with 0.95 Confidence Level

12:38 08/22 2011 BMD BMDL LinearDRAFT

- DO NOT CITE OR QUOTE 18 

### Table B

- 14. Benchmark dose modeling results (constant variance) for decreased maternal weight gain in female Sprague

- Dawley rats exposed to 1,2,4

- TMB. ( Saillenfait et al., 2005 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC
Exponential 2 < 0.0001 1025.385 3.71403 Bad Completion

Of the models that provided an adequate fit and valid BMDL estimate, the power model was selected based on the lowest AIC (BMDLs differed by less than 3

- fold). 

### Exponential 3 0.7424 717.3861 2863.64 2278.75 

### Exponential 4 < 0.0001 773.2296 Not Computed 0 

### Exponential 5 0.4402 719.3861 2863.64 2278.75


### Hill 0.5915 719.078339 2818.27 2186.37


### Linear 0.1279 720.47615 2024.57 1661.86 

### Polynomial 2° Polynomial 3° 0.7264 717.429644 2919.7 2162.54



### Power 0.758 717.344387 2852.91 2157.58

a Constant variance case presented (Test 2 p

- value = 0.4284), selected model in bold; scaled residuals for selected model for concentrations 0, 492, 1476, 2952, and 4428 mg/m 3 were

- 0.471, 0.424, 0.257,

- 0.28, 0.0873, respectively



### Figure B

- 8. Power model fit for decreased maternal weight gain in female Sprague

- Dawley rats (BMR = 1 SD, constant variance) exposed to 1,2,4

- TMB. ( Saillenfait et al., 2005 ) -10

0 10 20 30 40

0 500 1000 1500 2000 2500 3000 3500 4000 4500Mean Response

dose Power Model with 0.95 Confidence Level

11:00 08/22 2011 BMD BMDL PowerDRAFT

- DO NOT CITE OR QUOTE 19 

### Table B

- 15. Benchmark dose modeling result s (constant variance) for decreased fetal weight in male Sprague

- Dawley rats exposed to 1,3,5

- TMB. ( Saillenfait et al., 2005 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC

Exponential 2 Exponential 3 0.6903

- 66.93107 3411.32 2570.9

No model selected. 

### Exponential 4 0.7118

- 65.71648 2592.36 1337.87 

### Exponential 5 0.4105

- 63.71902 2590.61 1338.28


### Hill 0.4242

- 63.757684 2560.86 1271.48



### Linear Polynomial 2° Polynomial 3° Power 0.6458

- 66.736286 3529.42 2706.9

a Constant variance case presented (Test 2 p

- value = 0.0.002368), this p

- value indicates that a constant variance model does not adequately describe the observed variances. BMDS recommends using a non

- homogenous variance model..



### Table B

- 16. Benchmark dose modeling results (modeled variance) for decreased fetal weight in male Sprague

- Dawley rats exposed to 1,3,5

- TMB. ( Saillenfait et al., 2005 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC

Exponential 2 Exponential 3 0.5138

- 73.25245 2531.75 1783.99

Of the models that provided an adequate fit and valid BMDL estimate, the Exponential 2 model was selected based on the lowest AIC (BMDLs differed by less than 3

- fold). 

### Exponential 4 0.432

- 71.867 2031.49 1121.11 

### Exponential 5 0.3996

- 70.83596 2040.36 1237.36


### Hill 0.4432

- 65.685821 2397.45 1293.3



### Linear Polynomial 2° Polynomial 3° Power 0.4703

- 73.01794 2646.61 1896.45

a Modeled variance case presented (Test 3 p

- value = 0.06027, except the Hill model, for which Test 3 p

- value = 0.00544), the p

- values for all models except the Hill indicate a marginal fit at the 95% confidence level, and therefore are determined to adequately fit the observed variance, selected model in bold; scaled residuals for selected model for concen trations 0, 492, 1476, 2952, 5904 were 0.2058, 0.5536,

- 1.062,

- 0.08453, 0.4459, respectively.DRAFT

- DO NOT CITE OR QUOTE 20 

### Table B

- 17. Benchmark dose modeling results (modeled variance) for decreased fetal weight in male Sprague

- Dawley rats exposed to 1,3,5

- TMB. ( Saillenfait et al., 2005 )

Model a 

### Goodne ss - of

- fit BMD 5% 

### BMDL 5% 

### Basis for Model Selection p - value AIC

Exponential 2 Exponential 3 0.5138

- 73.25245 2192.55 1648.74

Of the models that provided an adequate fit and valid BMDL estimate, the Exponential 2 model was selected based on the lowest AIC (BMDLs differed by less than 3

- fold). 

### Exponential 4 0.432

- 71.867 1771.91 1021.62 

### Exponential 5 0.3996

- 70.83596 1869.62 1136.96


### Hill 0.4432

- 65.685821 1647.57 787.02



### Linear Polynomial 2° Polynomial 3° Power 0.4703

- 73.01794 2288.25 1748.25

a Modeled variance case presented (Test 3 p

- value = 0.06027, except the Hill model, for which Test 3 p

- value = 0.00544), the p

- values for all models except the Hill indicate a marginal fit at the 95% confidence level, and therefore are determined to adequat ely fit the observed variance, selected model in bold; scaled residuals for selected model for concentrations 0, 492, 1476, 2952, 5904 were 0.2058, 0.5536,

- 1.062,

- 0.08453, 0.4459, respectively.



### Figure B

- 9. Exponential 2 model fit for decreased fetal weight in male Sprague

- Dawley rats (BMR = 1 SD, constant variance) exposed to 1,3,5

- TMB. ( Saillenfait et al., 2005 ) 4.8

5 5.2 5.4 5.6 5.8

6

0 1000 2000 3000 4000 5000 6000Mean Response

dose Exponential Model 2 with 0.95 Confidence Level

13:56 05/26 2011 BMD BMDL ExponentialDRAFT

- DO NOT CITE OR QUOTE 21 

### Figure B

- 10. Exponential 2 model fit for decreased fetal weight in male Sprague

- Dawley rats (BMR = 5% relative deviance) exposed to 1,3,5

- TMB. ( Saillenfait et al., 2005 )

Table B

- 18. Benchmark dose modeling results (constant variance) for decreased fetal weight in female Sprague

- Dawley rats exposed to 1,3,5

- TMB. ( Saillenfait et al., 2005 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC

Exponential 2 Exponential 3 0.918

- 61.99283 3594.03 2678.44

No model selected. 

### Exponential 4 Exponential 5 0.7778

- 59.99422 3559.25 1907.53



### Hill 0.7781

- 59.994856 3555.35 1857.43



### Linear Polynomial 2° Polynomial 3° Power 0.9141

- 61.975069 3690.97 2805.32

a Constant variance case presented (Test 2 p

- value < 0.0001), ), this p

- value indicates that a constant variance model does not adequately describe the observed variances. BMDS recommends using a non

- homogenous variance model.. 4.8

5 5.2 5.4 5.6 5.8

6

0 1000 2000 3000 4000 5000 6000Mean Response

dose Exponential Model 2 with 0.95 Confidence Level

12:44 08/22 2011 BMD BMDL ExponentialDRAFT

- DO NOT CITE OR QUOTE 22 

### Table B

- 19. Benchmark dose modeling results (modeled variance) for decreased fetal weight in female Sprague

- Dawley rats exposed to 1,3,5

- TMB. ( Saillenfait et al., 2005 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC

Exponential 2 Exponential 3 0.01844

- 67.43659 2704.89 1834.83

No model selected. 

### Exponential 4 0.05143

- 69.51702 1473.6 794.208 

### Exponential 5 0.5334

- 73.06401 1474.45 1069.05


### Hill 0.4907

- 59.535986 3144.94 1608.56



### Linear Polynomial 2° Polynomial 3° Power 0.01408

- 66.953226 2855.53 1978.81

a Modeled variance case presented (Test 3 p

- value = 0.01301), this p

- value indicates that the modeled variance does not adequately describe the observed variances. Therefore, this endpoint cannot be modeled in BMDS and the NOAEL/LOAEL approach is recommend ed.



### Table B

- 20. Benchmark dose modeling results (modeled variance) for decreased fetal weight in female Sprague

- Dawley rats exposed to 1,3,5

- TMB. ( Saillenfait et al., 2005 )

Model a 

### Goodness

- of

- fit BMD 5% 

### BMDL 5% 

### Basis for Model Selection p - value AIC

Exponential 2 Exponential 3 0.01844

- 67.43659 2247.71 1636.48

No model selected. 

### Exponential 4 0.05143

- 69.51702 1440.58 847.218 

### Exponential 5 0.5334

- 73.06401 1477.62 1125.13


### Hill 0.4907

- 59.535986 1998.41 924.583



### Linear Polynomial 2° Polynomial 3° Power 0.01408

- 66.953226 2351.35 1743.09

a Modeled variance case presented (Test 3 p

- value = 0.01301), this p

- value indicates that the modeled variance does not adequately describe the observed variances. Therefore, this endpoint cannot be modeled in BMDS and the NOAEL/LOAEL approach is recommended.DRAFT

- DO NOT CITE OR QUOTE 23 

### Table B

- 21. Benchmark dose modeling results (constant variance) for decreased maternal weight gain in female Sprague

- Dawley rats (exposed to 1,3,5

- TMB. ( Saillenfait et al., 2005 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC
Exponential 2 < 0.0001 805.8321 3.37E

- 51 Bad Completion

No model selected. 

### Exponential 3 < 0.0001 807.8353 6.32685 Bad Completion 

### Exponential 4 < 0.0001 701.8275 Not Computed 0 

### Exponential 5 0.002667 649.3909 2053.87 1397.91


### Hill 0.5307 639.930755 2027.62 1351.61



### Linear Polynomial 2° Polynomial 3° 0.6794 637.049906 1991.84 1663.47



### Power 0.4696 639.049217 2004.05 1663.5

a Constant variance case presented (Test 2 p

- value = 0.003114), this p

- value indicates that a constant variance model does not adequately describe the observed variances. BMDS recommends using a non

- homogenous variance model..



### Table B

- 22. Benchmark dose modeling results for decreased maternal weight gain in female Sprague

- Dawley rats (BMR = 1 SD, modeled variance) exposed to 1,3,5

- TMB. ( Saillenfait et al., 2005 )

Model a 

### Goodness

- of

- fit BMD 1SD 

### BMDL 1SD 

### Basis for Model Selection p - value AIC

Exponential 2 Exponential 3 < 0.0001 921.089 Not Computed 0

Only the power model provided an adequate fit and calculated a BMD and BMDL, and therefore was selected 

### Exponential 4 < 0.0001 698.0766 3.76E

- 46 3.76E

- 46 

### Exponential 5 < 0.0001 650.8941 1482.95 602.205


### Hill <.0001 639.699605 1638.95 1240.48


### Linear 0.0002979 645.50167 2775.12 2352.39 

### Polynomial 2° 0.2155 631.751385 1558.76

-- 

### Polynomial 3° 0.07689 633.811629 1580.02

-- 

### Power 0.1907 631.31265 1818.08 1302.68

a Modeled variance case presented (Test 3 p

- value = 0.2221), selected model in bold; scaled residuals for selected model for concentrations 0, 492, 1476, 2952, 5904 were 0.2058, 0.5536,

- 1.062,

- 0.08453, 0.4459, respectively.DRAFT

- DO NOT CITE OR QUOTE 24 

### Figure B

- 11. Power model fit for decreased maternal weight gain in female Sprague

Dawley rats (BMR = 1 SD, modeled variance) exposed to 1,3,5

- TMB. ( Saillenfait et al., 2005 ) -20 -10

0 10 20 30 40

0 1000 2000 3000 4000 5000 6000Mean Response

dose Power Model with 0.95 Confidence Level

13:49 05/26 2011 BMD BMDL PowerDRAFT

- DO NOT CITE OR QUOTE 25 

# B **.3. References**

Korsak, Z; Rydzyński, K. (1996). Neurotoxic effects of acute and subchronic inhalation exposure to trimethylbenzene isomers (pseudocumene, mesitylene, hemimellitene) in rats. Int J Occup Med Environ Health 9:
341

- 349.

Korsak, Z; Rydzyński, K; Jajte, J. (1997). Respiratory irritative effects of trimethylbenzenes: An experimental animal study. Int J Occup Med Environ Health 1 0: 303

- 311.

Korsak, Z; Stetkiewicz, J; Majcherek, W; Stetkiewicz, I; Jajte, J; Rydzyński, K. (2000). Sub

- chronic inhalation toxicity of 1,2,4

- trimethylbenzen e (pseudocumene) in rats. Int J Occup Med Environ Health 13: 155

- 164.

Saillenfait, AM; Gallissot, F; Sabate, JP; Morel, G. (2005). Developmental toxicity of two trimethylbenzene isomers, mesitylene and pseudocumene, in rats following inhalation exposure. Food Chem Toxicol 43: 1055

- 1063. http://dx.doi.org/10.1016/j.fct.2005.02.008.

U.S. EPA. (U.S. Environmental Protection Agency). (2000). Benchmark dose technical guidance document [external review draft]. (EPA/630/R

- 00/001). Washington, DC: U.S. Environmental Protection Agency, Risk Assessment Forum. http://www.epa.g ov/raf/publications/benchmark

- dose

- doc

- draft.htm.

U.S. EPA. (U.S. Environmental Protection Agency). (2009). Benchmark dose software (BMDS) Retrieved
December 19, 2009, from http://www.epa.gov/NCEA/bmds

U.S. EPA. (U.S. Environmental Protection Agency). (2011). Results of the BMD analyses for 1,2,4

- TMB and 1,3,5

- TMB [BMDS]. Research Triangle Park, NC.