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NMP Occupational Scenarios

Assumptions: 

All scenarios are combined dermal, inhalation and vapor-through-skin exposures

Workers exposed to NMP-based paint strippers for 1 h, 4 h or 8 h/day, with a 30 min break after the first 4 h of exposure

Chronic exposures were assumed to be 5/d week and acute exposures were 1 day

Skin exposed to vapor or liquid/spray was 445, 668 or 890 cm2 (even when inhalation exposure is off, skin absorption can occur)

Bystanders were exposed to vapor the same as users and had 1 mm2 of surface area exposed to represent a stray droplet of liquid

Maternal blood AUC or Cmax of parent compound used as a surrogate for fetal dose metric 

Workers may be exposed repeatedly or in a single event. Thus, chronic and acute risks were evaluated.

Preferred dose metrics:

The fetal bodyweight endpoint is the most sensitive for repeated exposures 

Average AUC24 (mg-hr/L) is the preferred metric assuming a sustained internal dose of parent compound is needed to induce changes in fetal body weights 

The endpoint of fetal resorptions and fetal mortality are biologically relevant to actue exposures 

Cmax (mg/L) is preferred for acute effects 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. 
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NMP Occupational Scenarios

air conc.

Respirator 

APF

Gloves % 

Effective

ness

mg/m3 avg AUC 

(mg-hr/L)

peak 

(Cmax, 

mg/L))

avg AUC 

(mghr/L)

peak (C 

max, mg/L)

MOE for 

avg AUC

MOE for 

Cmax

MOE for avg 

AUC

MOE for 

Cmax

0 0 4.24 1.81 4.23 1.60 97.0 119.3 97.1 134.7

10 0 4.09 1.75 4.08 1.55 100.4 123.2 100.7 139.2

0 90 0.60 0.25 0.61 0.23 680.1 847.6 676.4 949.1

10 90 0.46 0.20 0.46 0.18 892.4 1090.9 893.2 1230.5

bystander 0 NA 0.20 0.08 0.21 0.08 2008.6 2615.1 1968.6 2875.4

0 0 75.55 17.05 75.09 16.11 5.4 12.7 5.5 13.4

10 0 69.63 15.80 69.08 14.91 5.9 13.7 5.9 14.5

0 90 12.95 2.98 13.07 2.88 31.7 72.4 31.5 75.0

10 90 8.10 1.90 8.10 1.81 50.7 114.0 50.8 119.3

bystander 0 NA 6.73 1.53 6.87 1.50 61.1 141.1 59.9 144.1

0 0 4085.28 412.09 3969.28 390.60 0.1 0.5 0.1 0.6

10 0 4021.20 406.56 3905.60 385.18 0.1 0.5 0.1 0.6

0 90 146.65 21.68 145.84 20.95 2.8 10.0 2.8 10.3

10 90 133.88 19.87 132.87 19.17 3.1 10.9 3.1 11.3

bystander 0 NA 13.35 1.95 13.62 1.96 30.8 110.7 30.2 110.5

0 0 4.04 1.73 4.03 1.53 101.7 124.7 102.0 141.0

10 0 4.04 1.73 4.02 1.53 101.8 124.8 102.1 141.1

0 90 0.41 0.17 0.40 0.15 1013.6 1236.7 1015.1 1395.8

10 90 0.40 0.17 0.40 0.15 1024.5 1248.9 1026.4 1410.1

bystander 0 NA 0.006 0.003 0.006 0.002 66048.7 85919.5 64746.5 94507.4

0 0 67.64 15.37 67.11 14.50 6.1 14.1 6.1 14.9

10 0 67.46 15.33 66.92 14.47 6.1 14.1 6.1 14.9

0 90 6.27 1.47 6.26 1.40 65.5 146.8 65.6 153.9

10 90 6.13 1.44 6.11 1.37 67.1 150.2 67.3 157.5

bystander 0 NA 0.21 0.05 0.21 0.05 1981.3 4563.7 1941.8 4657.2

0 0 4003.88 405.06 3888.80 383.74 0.1 0.5 0.1 0.6

10 0 3999.38 404.67 3884.33 383.36 0.1 0.5 0.1 0.6

0 90 129.79 19.27 128.82 18.60 3.2 11.2 3.2 11.6

10 90 128.91 19.15 127.93 18.47 3.2 11.3 3.2 11.7

bystander 0 NA 0.94 0.14 0.96 0.14 438.4 1575.4 429.7 1571.3

Exposure Scenario 

1) Miscellaneous stripping (assumed mostly indoor)

-- low end of range parameter characterization

-- 0.25 weight fraction, 445 cm2 skin surface area, 1 hr/day contact

2) Miscellaneous stripping (assumed mostly indoor)

-- mid range parameter characterization

-- 0.625 weight fraction, 668 cm2 skin surface area, 4 hr/day contact

PPE

Benchmark MOE=30

Underlined MOEs show risks, 

MOE < benchmark MOE

0 months pregnancy 8 months pregnancy

8

65

0 months pregnancy 8 months pregnancy

2.02

4.52

5) Graffiti removal (assumed mostly outdoor but may include 

confined spaces)

-- mid range parameter characterization

-- 0.625 weight fraction, 668 cm2 skin surface area, 4 hr/day contact

6) Graffiti removal (assumed mostly outdoor but may include 

confined spaces)

-- high end of range parameter characterization

-- 1.0 weight fraction, 890 cm2 skin surface area, two 4 hr/day 

contacts

64

0.24

3) Miscellaneous stripping (assumed mostly indoor)

-- high end of range parameter characterization

-- 1.0 weight fraction, 890 cm2 skin surface area, two 4 hr/day 

contacts

4) Graffiti removal (assumed mostly outdoor but may include 

confined spaces)

-- low end of range parameter characterization

-- 0.25 weight fraction, 445 cm2 skin surface area, 1 hr/day contact
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BENCHMARK DOSE METRICS

Rat internal metrics for chronic exposures based on GD 6-20 inhalation exposures reported in Saillenfait et al. (2003) 

BMDL values calculated with internal doses (Values used for MOE estimates)

BMCL05 average AUC (mg-hr/L) for fetal body weight decrease 411

Rat internal metrics for resorptions after combined inhalation or oral exposures reported in Saillenfait et al. (2002 & 2003) 

BMDL values calculated with internal doses (Values used for MOE estimates)

BMCL01 Cmax (mg/L) for fetal mortality 216