## TCE Occupational Scenarios
**Assumptions:** Workers exposed to NMP-based paint strippers for 8 h/day, 5/d week, with a 30 min break after the first 4 h of exposure Skin exposed to vapor: 6700-840=5860 cm^2 (even when inhalation exposure is off, skin absorption can occur), except first six rows Skin exposed to liquid/spray: 840 cm^2m except when dermal=0, when this area is assumed to be protected/accluded (0.01 cm^2 used to avoid divide-by-zero) Maternal blood AUC or Cmax of parent compound used as a surrogate for fetal dose metric

**Preferred dose metrics:** Average AUC24 (mg-hr/L) is preferred for the fetal bodyweight endpoint assuming that a sustained internal dose of parent compound is needed to induce changes in fetal body weights Cmax (mg/L) is preferred for fetal skeletal anomalies assuming that a single dose effect is need to induce these effects

**Preferred benchmark MOE:** Margin of Exposures (MOEs) were compared to a benchmark MOE of 30 to determine whether risks were present for the different exposure scenarios. The benchmark MOE of 30 consists of 3X was used for interspecies variability. The PBPK model was used for interspecies extrapolation. 10X was used to account for human variability. The PBPK model did not account for human toxicokinetic variability. The data used in the human PBPK model was based on healthy humans. In addition, CYP2E1 is partly involved in the metabolism of NMP in humans. There are large variations in CYP2E1 activity in humans (Ligocka et al., 2003) which supported the retention of the 10X. See Ligocka et al., 2003 at http://www.ncbi.nlm.nih.gov/pubmed/12734639.

1

## TCE Occupational Scenarios

**dermal air conc.** 

rate (mg/h) mg/m^3 avg AUC

(mg-hr/L) peak

(Cmax, mg/L)) avg AUC

(mg-hr/L) peak

(C max, mg/L) MOE for avg AUC MOE for

Cmax MOE for avg

AUC MOE for

Cmax

Dermal exposure only/ Worker with exposed hands handling NMP-based paint stripper (liquid or spray product) but wearing a face mask /No vapor absorption through skin (minimal skin area exposed other than hands) / Lower dermal rate NOAEL for maternal and fetal toxicity--Dermal developmental toxicity study (Becci et al. 1982)--Preferred metric: AUC 74 0 22.69 3.54 22.66 3.50 

## 61.0 180.9 

## 61.1 183.1

Dermal exposure only/ Worker with exposed hands but wearing a face mask /No vapor absorption through skin (minimal skin area exposed other than hands) / Higher dermal rate NOAEL for maternal and fetal toxicity--Dermal developmental toxicity study (Becci et al. 1982)--Preferred metric: AUC 225 0 70.54 11.03 70.43 10.89 

## 19.6 58.1 

## 19.7 58.9

Dermal exposure only/ Worker with exposed hands handling NMP-based paint stripper (liquid or spray product) but wearing a face mask /No vapor absorption through skin (minimal skin area exposed other than hands) / Lower dermal rate BMDL internal dose values for 5% reduction in fetal BW

-- Inhalation developmental study (Saillenfait et al. 2003)-- Preferred metric: AUC 74 0 22.69 3.54 22.66 3.50 

## 10.8 8.7 

## 10.9 8.8

Dermal exposure only/ Worker with exposed hands but wearing a face mask /No vapor absorption through skin (minimal skin area exposed other than hands) / Higher dermal rate BMDL internal dose values for 5% reduction in fetal BW

-- Inhalation developmental study (Saillenfait et al. 2003)-- Preferred metric: AUC 225 0 70.54 11.03 70.43 10.89 

## 3.5 2.8 

## 3.5 2.8

Dermal exposure only/ Worker with exposed hands handling NMP-based paint stripper (liquid or spray product) but wearing a face mask /No vapor absorption through skin (minimal skin area exposed other than hands) / Lower dermal rate BMDL internal dose values for 5% increase in fetal skeletal anomalies --Pooled internal doses from inhalation and dermal studies (Saillenfait et al. 2003 and Becci et al., 1982)-- Preferred metric: Cmax 74 0 22.69 3.54 22.66 3.50 Not calculated 

## 7.6 Not calculated 

## 7.7

Dermal exposure only/ Worker with exposed hands but wearing a face mask /No vapor absorption through skin (minimal skin area exposed other than hands) / Higher dermal rate BMDL internal dose values for 5% increase in fetal skeletal anomalies --Pooled internal doses from inhalation and dermal studies (Saillenfait et al. 2003 and Becci et al., 1982)-- Preferred metric: Cmax 225 0 70.54 11.03 70.43 10.89 Not calculated 

## 2.4 Not calculated 

## 2.5 **Benchmark MOE=30** Note: Preferred metrics are those highlighted in red text . Underlined MOEs show risks, MOE<

benchmark MOE **0 months pregnancy 8 months pregnancy**  **Exposure Scenario Benchmark Dose Metric and**  **Endpoints 8 months pregnancy**  **0 months pregnancy**

2**dermal air conc.** 

rate (mg/h) mg/m^3 avg AUC

(mg-hr/L) peak

(Cmax, mg/L)) avg AUC

(mg-hr/L) peak

(C max, mg/L) MOE for avg AUC MOE for

Cmax MOE for avg

AUC MOE for

Cmax

Dermal exposure only/ Worker with exposed hands in contact with liquid form but wearing a face mask / Vapor absorption through other areas of exposed skin (i.e., arms, face) / Lower

dermal rate, lower NMP air concentration NOAEL for maternal and fetal toxicity--Dermal developmental toxicity study (Becci et al. 1982)--Preferred metric: AUC 74 13 22.92 3.60 22.89 3.56 

## 60.4 178.2 

## 60.5 180.0

Dermal exposure only/ Worker with exposed hands in contact with liquid form but wearing a face mask / Vapor absorption through other areas of exposed skin (i.e., arms, face) / Higher dermal rate, higher NMP air concentration NOAEL for maternal and fetal toxicity--Dermal developmental toxicity study (Becci et al. 1982)--Preferred metric: AUC 225 39 71.21 11.19 71.11 11.07 

## 19.4 57.3 

## 19.5 57.9

Dermal exposure only/ Worker with exposed hands in contact with liquid form but wearing a face mask / Vapor absorption through other areas of exposed skin (i.e., arms, face) / Lower

dermal rate, lower NMP air concentration BMDL internal dose values for 5% reduction in fetal BW

-- Inhalation developmental study (Saillenfait et al. 2003)-- Preferred metric: AUC 74 13 22.92 3.60 22.89 3.56 

## 10.7 8.5 

## 10.7 8.6

Dermal exposure only/ Worker with exposed hands in contact with liquid form but wearing a face mask / Vapor absorption through other areas of exposed skin (i.e., arms, face) / Higher dermal rate, higher NMP air concentration BMDL internal dose values for 5% reduction in fetal BW

-- Inhalation developmental study (Saillenfait et al. 2003)-- Preferred metric: AUC 225 39 71.21 11.19 71.11 11.07 

## 3.5 2.7 

## 3.5 2.8

Dermal exposure only/ Worker with exposed hands in contact with liquid form but wearing a face mask / Vapor absorption through other areas of exposed skin (i.e., arms, face) / Lower

dermal rate, lower NMP air concentration BMDL internal dose values for 5% increase in fetal skeletal anomalies --Pooled internal doses from inhalation and dermal studies (Saillenfait et al. 2003 and Becci et al., 1982)-- Preferred metric: Cmax 74 13 22.92 3.60 22.89 3.56 Not calculated 

## 7.5 Not calculated 

## 7.6

Dermal exposure only/ Worker with exposed hands in contact with liquid form but wearing a face mask / Vapor absorption through other areas of exposed skin (i.e., arms, face) / Higher dermal rate, higher NMP air concentration BMDL internal dose values for 5% increase in fetal skeletal anomalies --Pooled internal doses from inhalation and dermal studies (Saillenfait et al. 2003 and Becci et al., 1982)-- Preferred metric: Cmax 225 39 71.21 11.19 71.11 11.07 Not calculated 

## 2.4 Not calculated 

## 2.4 **0 months pregnancy 8 months pregnancy**  **Exposure Scenario** NOTE: Preferred scenarios are those highlighted in red text

. **Benchmark Dose Metric 0 months pregnancy**  **8 months pregnancy**

3**dermal air conc.** 

rate (mg/h) mg/m^3 avg AUC

(mg-hr/L) peak

(Cmax, mg/L)) avg AUC

(mg-hr/L) peak

(C max, mg/L) MOE for avg AUC MOE for

Cmax MOE for avg

AUC MOE for

Cmax

Inhalation exposure only/ Worker wearing gloves but no face mask / Inhalation with skin absorption of NMP vapor through other areas of exposed skin (i.e., arms, face) / Lower NMP air concentration (NOTE: if skin absorption turned off, values

reduced ~ 40%) BMDL internal dose values for 5% reduction in fetal BW

-- Inhalation developmental study(Saillenfait et al. 2003)-- Preferred metric: AUC 0 13 1.72 0.26 1.75 0.26 

## 142.9 117.9 

## 140.8 116.6

Inhalation exposure only / Worker wearing gloves but no face mask / Inhalation with skin absorption of vapor through other areas of exposed skin (i.e., arms, face) / Higher NMP air concentration (NOTE: if skin absorption turned off, values

reduced ~ 40%) BMDL internal dose values for 5% reduction in fetal BW

-- Inhalation developmental study (Saillenfait et al. 2003)-- Preferred metric: AUC 0 39 5.18 0.78 5.25 0.79 

## 47.5 39.2 

## 46.8 38.8

Inhalation exposure only/ Worker wearing gloves but no face mask / Inhalation with skin absorption of NMP vapor through other areas of exposed skin (i.e., arms, face) / Lower NMP air concentration (NOTE: if skin absorption turned off, values

reduced ~ 40%) BMDL internal dose values for 5% increase in fetal skeletal anomalies --Pooled internal doses from inhalation and dermal studies (Saillenfait et al. 2003 and Becci et al., 1982)-- Preferred metric: Cmax 0 13 1.72 0.26 1.75 0.26 Not calculated 

## 103.7 Not calculated 

## 102.5

Inhalation exposure only/ Worker wearing gloves but no face mask / Inhalation with skin absorption of vapor through other areas of exposed skin (i.e., arms, face) / Higher NMP air concentration (NOTE: if skin absorption turned off, values

reduced ~ 40%) BMDL internal dose values for 5% increase in fetal skeletal anomalies --Pooled internal doses from inhalation and dermal studies (Saillenfait et al. 2003 and Becci et al., 1982)-- Preferred metric: Cmax 0 39 5.18 0.78 5.25 0.79 Not calculated 

## 34.5 Not calculated 

## 34.1 **0 months pregnancy 8 months pregnancy**  **Exposure Scenario** NOTE: Preferred scenarios are those highlighted in red text

. **Benchmark Dose Metric 0 months pregnancy**  **8 months pregnancy**

4**dermal air conc.** 

rate (mg/h) mg/m^3 avg AUC

(mg-hr/L) peak

(Cmax, mg/L)) avg AUC

(mg-hr/L) peak

(C max, mg/L) MOE for avg AUC MOE for

Cmax MOE for avg

AUC MOE for

Cmax

Combined dermal, inhalation, and vapor-through-skin exposures/ Worker with exposed hands and no face mask / Lower dermal rate, lower NMP air concentration NOAEL for maternal and fetal toxicity--Dermal developmental toxicity study (Becci et al. 1982)--Preferred metric: AUC 74 13 23.98 3.75 23.98 3.72 

## 57.8 170.7 

## 57.8 172.2

Combined dermal, inhalation, and vapor-through-skin exposures/ Worker with exposed hands and no face mask / Higher dermal rate, higher NMP air concentration NOAEL for maternal and fetal toxicity--Dermal developmental toxicity study (Becci et al. 1982)--Preferred metric: AUC 225 39 74.54 11.69 74.52 11.57 

## 18.6 54.8 

## 18.6 55.4

Combined dermal, inhalation, and vapor-through-skin exposures/ Worker with exposed hands and no face mask / Lower dermal rate, lower NMP air concentration BMDL internal dose values for 5% reduction in fetal BW

-- Inhalation developmental study (Saillenfait et al. 2003)-- Preferred metric: AUC 74 13 23.98 3.75 23.98 3.72 

## 10.3 8.2 

## 10.3 8.2

Combined dermal, inhalation, and vapor-through-skin exposures/ Worker with exposed hands and no face mask / Higher dermal rate, higher NMP air concentration BMDL internal dose values for 5% reduction in fetal BW

-- Inhalation developmental study (Saillenfait et al. 2003)-- Preferred metric: AUC 225 39 74.54 11.69 74.52 11.57 

## 3.3 2.6 

## 3.3 2.7

Combined dermal, inhalation, and vapor-through-skin exposures/ Worker with exposed hands and no face mask / Lower dermal rate, lower NMP air concentration BMDL internal dose values for 5% increase in fetal skeletal anomalies --Pooled internal doses from inhalation and dermal studies (Saillenfait et al. 2003 and Becci et al., 1982)-- Preferred metric: Cmax 74 13 23.98 3.75 23.98 3.72 Not calculated 

## 7.2 Not calculated 

## 7.3

Combined dermal, inhalation, and vapor-through-skin exposures/ Worker with exposed hands and no face mask / Higher dermal rate, higher NMP air concentration BMDL internal dose values for 5% increase in fetal skeletal anomalies --Pooled internal doses from inhalation and dermal studies (Saillenfait et al. 2003 and Becci et al., 1982)-- Preferred metric: Cmax 225 39 74.54 11.69 74.52 11.57 Not calculated 

## 2.3 Not calculated 

## 2.3 **0 months pregnancy 8 months pregnancy**  **Exposure Scenario** NOTE: Preferred scenarios are those highlighted in red text

. **Benchmark Dose Metric 0 months pregnancy**  **8 months pregnancy**

5

# BENCHMARK DOSE METRICS **Rat internal metrics for GD 6-20 inhalation exposures reported in Saillenfait et al. (2003)**

External air conc (mg/m3) Average AUC24 (mg-hr/L) Cmax (mg/L) Fetal BW

(g) ±Std Dev
0 0 0 5.67±0.37 122 94 12 5.62±0.36 243 191 24 5.47±0.25 487 397 50 5.39±0.45* *Significant difference from the control (air), P<0.05
**BMDL values calculated with internal doses (Values used for MOE estimates)**
BMCL05 average AUC 24-hr (mg-hr/L) **246** BMCL05 Cmax (mg/L) **30.7** 

### Rat internal metrics for GD 6-15 dermal exposures, but averaged over GD 6-21 reported in Becci et al. (1982) mg/kg-d Average AUC 24-hr (mg-hr/L) Cmax (mg/L) 0 0 0 75 359 202 **237 1385**  **641** 237 mg/kg-day is the NOAEL for maternal and fetal toxicity (increased resorption, fewer 750 6000 2050 live fetuses, reduced body weight, skeletal abnormalities)



### Combined Becci et al. (1982) dermal and Saillenfait et al. (2003) inhalation data for vertebrae/incomplete ossification

BMCL05 Cmax (mg/L) **27**

6