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

maxAUC (mg/L) is preferred for fetal skeletal malformations 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) MOE calculated with BMDL for 5% increase in fetal skeletal malformations -- dermal 

 developmental studiy (Becci et al., 1982)--Preferred metric: max AUC24

(2) MOE calculated with BMDL internal dose values for 5% reduction in fetal BW--

 Inhalation developmental study (Saillenfait et al. 2003)--Preferred metric: average AUC

(1) ↓ (2) ↓ (1) ↓ (2) ↓

dermal air conc.

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

(mg-hr/L)

avg AUC 

(mg-hr/L)

peak 

(Cmax, 

mg/L))

maxAUC 

(mg-hr/L)

avg AUC 

(mg-hr/L)

peak 

(Cmax, 

mg/L)

MOE for 

max AUC 

(1)

MOE for 

avg AUC 

(2)

MOE 

for max 

AUC (1)

MOE for 

avg AUC 

(2)

74 0 32.12 22.69 3.56 32.07 22.66 3.50 7.4 10.8 7.4 10.9

225 0 99.86 70.54 11.03 99.69 70.43 10.89 2.4 3.5 2.4 3.5

74 13 32.44 22.92 3.60 32.40 22.89 3.56 7.3 10.7 7.3 10.7

225 39 100.82 71.21 11.19 100.65 71.11 11.07 2.4 3.5 2.4 3.5

0 13 2.44 1.72 0.26 2.47 1.75 0.26 97.3 142.9 95.8 140.8

0 39 7.33 5.18 0.78 7.44 5.25 0.79 32.3 47.5 31.9 46.8

74 13 33.94 23.98 3.75 33.94 23.98 3.72 7.0 10.3 7.0 10.3

225 39 105.53 74.54 11.69 105.48 74.52 11.57 2.2 3.3 2.2 3.3

Benchmark Dose Metric and Endpoints 

Combined dermal, inhalation, and vapor-throughskin exposures / Worker with exposed hands and no 

face mask 

Exposure Scenario 

0 months pregnancy 8 months pregnancy

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) / (NOTE: if skin absorption turned off, 

values reduced ~ 40%)

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) 

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) 

High or low values of 

dermal exposure rate or 

inhalation concentration 

were evaluated, as specified 

below

Exposure Levels

Benchmark MOE=30 

Note: MOEs highlighted in red text show 

risks, MOE< 

benchmark MOE

0 months pregnancy8 months pregnancy

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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 (mghr/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 (2) Average AUC BMDL for comparison

BMCL05 Cmax (mg/L) 30.7 (Evaluated but not used, since it's not the preferred metric for the fetal BW endpoint)

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

Becci et al. (1982) dermal data for vertebrae/incomplete ossification

BMCL05 max AUC24 (mg/L) 237 (1) max AUC24 BMDL for comparison

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