PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
v>EPA
United States
Environmental Protection Agency
Office of Chemical Safety and
Pollution Prevention
Draft Risk Evaluation for
N-Methylpyrrolidone
(2-Pyrrolidinone, 1-Methyl-)
CASRN: 872-50-4
Benchmark Dose Modeling Supplemental File
October 2019
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Table of Contents
1 INTRODUCTION 4
2 BENCHMARK DOSE MODELING OF FETAL AND PUP BODY WEIGHT CHANGES 5
2.1 Results for Saillenfait et al., 2003 7
2.2 Results for Saillenfait et al., 2002 10
2.3 Results for Saillenfait et al., 2002 and 2003 combined 13
2.4 Results for DuPont, 1990 16
2.5 Results for Becci et al., 1982 19
3 BENCHMARK DOSE MODELING OF EFFECTS FOR RESORPTIONS AND FETAL
MORTALITY 21
3.1 Results for Saillenfait et al., 2002 and 2003 combined using Cnmx 22
3.2 Results for Saillenfait et al., 2002 and 2003 combined using AUC 25
3.3 Results for Sitarek et al., 2012 28
4 BENCHMARK DOSE MODELING OF MALE FERTILITY, FEMALE FECUNDITY,
LITTER SIZE AND PUP DEATH IN EXXON, 1991 29
4.1 Overall BMD Modeling Approach for Exxon 1991 Data 29
4.2 PBPK Analysis for Exxon 1991 Data 30
4.3 Summary of BMD Modeling for Exxon, 1991 Data 33
4.4 Results of BMD Modeling of P2 Male and Female Fertility Indices (Exxon, 1991) 34
4.4.1 P2/F2A Male Fertility (Males Unsuccessful/Males Used; Exxon Appendix AF) 36
4.4.2 P2/F2B Male Fertility (Males Unsuccessful/Males Used; Exxon Appendix AG) 40
4.4.3 P2/F2A Female Fecundity (Females Unsuccessful/Females Mated; Exxon Appendix AF). 44
4.4.4 P2/F2B Female Fecundity (Females Unsuccessful/Females Mated; Exxon Appendix AG) 48
4.5 Results of BMD Modeling of P2 Litter (Exxon, 1991) 52
4.5.1 P2/F2A Litter Size - 50 g Rat (Exxon Appendix AJ, "Total Pups Born") 54
4.5.2 P2/F2B Litter Size - 50 g Rat (Exxon Appendix AK, "Total Pups Born") 58
4.5.3 P2/F2A Litter Size - GD 6-21 Rat (Exxon Appendix AJ, "Total Pups Born") 62
4.5.4 P2/F2B Litter Size - GD 6-21 Rat (Exxon Appendix AK, "Total Pups Born") 66
4.6 Results of BMD Modeling of P2 Pup Death (Exxon, 1991) 70
4.6.1 P2/F2A Pups Dead at Day 0 (Stillborn Day 0/Total Pups Born; Exxon 1991 Appendix AJ)71
4.6.2 P2/F2B Pups Dead at Day 0 (Stillborn Day 0/Total Pups Born; Exxon 1991 Appendix AK)
78
4.6.3 P2/F2A Pups Dead by Day 4 (Dead by Day 4/Total Pups Born; Exxon Appendix AJ) 80
4.6.4 P2/F2B Pups Dead by Day 4 (Dead by Day 4/Total Pups Born; Exxon Appendix AK) 82
5 REFERENCES 84
Page 2 of 84
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List of Figures
Figure 2-1 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body
Weight in Rats Exposed to NMP via Inhalation (Saillenfait et al., 2003) 8
Figure 2-2 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body
Weight in Rats Exposed to NMP via Gavage (Saillenfait et al., 2002) 11
Figure 2-3 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body
Weight in Rats Exposed to NMP via Gavage or Inhalation (Saillenfait et al. (2003; 2002))
14
Figure 2-4 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body
Weight in Rats Exposed to NMP via Inhalation (DuPont, 1990) 17
Figure 2-5 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body
Weight in Rats Exposed to NMP Dermally (Becci et al., 1982) 19
Figure 3-1 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Resorptions in Rat
Exposed to NMP via Gavage or Inhalation (Saillenfait et al. (2003; 2002)) 23
Figure 3-2 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Resorptions in Rat
Exposed to NMP via Gavage or Inhalation (Saillenfait et al. (2003; 2002)) 26
List of Tables
Table 2-2-1 Fetal Body Weight Data Selected for Dose-Response Modeling for NMP 5
Table 2-2-2 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Inhalation Using
Daily Average AUC as the Dose Metric (Saillenfait et al., 2003) 7
Table 2-2-3 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Gavage Using Daily
Average AUC as the Dose Metric (Saillenfait et al., 2002) 10
Table 2-2-4 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Gavage or
Inhalation using Daily Average AUC as the Dose Metric (Saillenfait et al. (2003; 2002))
13
Table 2-2-5 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Inhalation using
Daily Average AUC as the Dose Metric (DuPont, 1990) 16
Table 2-2-6 Model Predictions for Fetal Body Weights in Rats Exposed to NMP Dermally Using Daily
Average AUC as the Dose Metric (Becci et al., 1982) 19
Table 3-3-1 Skeletal Malformations, Resorptions and Fetal Mortality Data Selected for Dose-Response
Modeling for NMP 21
Table 3-3-2 Model Predictions for Resorptions in Rats Exposed to NMP via Gavage or Inhalation Using
Cmax as the Dose Metric (Saillenfait et al. (2003; 2002)) 22
Table 3-3-3 Model Predictions for Resorptions in Rats Exposed to NMP via Gavage or Inhalation Using
AUC as the Dose Metric (Saillenfait et al. (2003; 2002)) 25
Table 3-3-4 Model Predictions for Fetal Mortality in Rats Exposed to NMP by Gavage Using Cmax as the
Dose Metric (Sitarek et al., 2012) 28
Table 4-1 PBPK-predicted average blood concentrations (Cavg, mg/L) in juvenile rats 31
Table 4-2 PBPK-predicted average blood concentrations (Cavg, mg/L) during gestation for P2/F2A ...31
Table 4-3 PBPK-predicted average blood concentrations (Cavg, mg/L) during gestation for P2/F2B ... 32
Table 4-4 BMD Modeling Summary for Exxon (1991) 33
Table 4-5 Model Predictions for Reduced Male Fertility in P2/F2A Male Rats (Exxon, 1991) 36
Table 4-6 Model Predictions for Reduced Male Fertility in P2/F2B Male Rats (Exxon, 1991) 40
Table 4-7 Model Predictions for Reduced Fecundity in P2/F2A Female Rats (Exxon, 1991) 44
Table 4-8 Model Predictions for Reduced Fecundity in P2/F2B Female Rats (Exxon, 1991) 48
Table 4-9 Model Predictions for Litter Size in P2/F2A Rats Based on Post-weaning Exposure (Exxon,
1991) 54
Page 3 of 84
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Table 4-10 Model Predictions for Litter Size in P2/F2B Rats Based on Post-weaning Exposure (Exxon,
1991) 58
Table 4-11 Model Predictions for Litter Size in P2/F2A Rats Based on Gestational Exposure (Exxon,
1991) 62
Table 4-12 Model Predictions for Litter Size in P2/F2B Rats Based on Gestational Exposure (Exxon,
1991) 66
Table 4-13 Model Predictions for Pup Death at Day 0 in P2/F2A Rats (Exxon, 1991) 72
Table 4-14 Model Predictions for Pup Death at Day 0 in P2/F2B Rats (Exxon, 1991) 78
Table 4-15 Model Predictions for Pup Death at Day 4 in P2/F2A Rats (Exxon, 1991) 81
Table 4-16 Model Predictions for Pup Death at Day 4 in P2/F2B Rats (Exxon, 1991) 83
1 INTRODUCTION
This supplemental file describes benchmark dose (BMD) modeling approaches and results for all
endpoints considered in the derivation of points of departure (PODs) for NMP. Reduced male fertility,
reduced female fecundity, and reduced fetal/pup body weights were all identified as sensitive
reproductive and developmental endpoints associated with repeated dose exposures and were evaluated
as the potential basis for chronic PODs. Resorptions and fetal mortality were identified as sensitive
developmental endpoints that are relevant for single dose exposures and were evaluated as the potential
basis for acute PODs.
BMD modeling for fetal and pup body weight changes (Section 2) and resorption/fetal death (Section 3)
was performed using USEPA's BMD Software package version 2.5 (BMDS 2.5), in a manner con si stent
with EPA Benchmark 1 ' These benchmark modeling results were previously
presented in EPA's risk assessment of NMP ( ).
Subsequent BMD modeling for reduced male fertility, female fecundity, reduced litter size, and pup
death (Section 4) described in a 2-generation reproductive study in rats (Exxon. 1991) was performed
using USEPA's BMD Software package version 3.1.1 (BMDS 3.1.1) or 2.7 (BMDS 2.7)1 in a manner
consistent with Benchmark Dose Technic 3! '"jridance. Litter size and pup death were not the most
sensitive reproductive and developmental endpoints in this study, but were evaluated for comparison
with developmental effects in other studies and as supporting evidence for the reduced fertility observed
in this study.
A peer-reviewed rat PBPK model for NMP (Poet et at.. 2010) modified by EPA was used to calculate
BMDs for each endpoint in terms of internal doses (blood concentrations) in exposed rats. PODs based
on internal doses in rats can be compared to blood concentrations in people predicted by human PBPK
models for each condition of use. Internal dose metrics calculated with the rat PBPK model are in units
of either AUC (hr mg/L) for chronic exposures or peak blood concentration (Cmax, mg/L) for acute
exposures.
1 While EPA's preferred nested dichotomous model (NLogistic) is available inbothBMDS 2.7 and 3.1.1 and, in this case,
provided the best fit to the pup death endpoint, BMDS 2.7 was used to provide an evaluation of this endpoint that includes
two alternative nested dichotomous models that are not currently available in BMDS 3.1.1.
Page 4 of 84
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2 Benchmark Dose Modeling of Fetal and Pup Body Weight Changes
BMD modeling for fetal and pup body weight changes and resorption/fetal death was performed using
USEPA's BMD Software package version 2.5 (BMDS 2.5), in a manner consistent with EPA
Benchmark Dose Technical Guidance. These benchmark modeling results were previously presented in
EPA's (2.015) risk assessment of NMP.
Continuous models were used to fit dose-response data for mean fetal/pup body weights. A BMR of 5%
RD from control mean was applied in modeling pup body weight changes under the assumption that it
represents a minimal biologically significant response. In adults, a 10% decrease in body weight in
animals is generally recognized as a biologically significant response associated with identifying a
maximum tolerated dose. During development, however, identification of a smaller (5%) decrease in
body weight is consistent with the assumptions that development represents a susceptible lifestage and
that the developing animal is more adversely affected by a decrease in body weight than the adult. In
humans, reduced birth weight is associated with numerous adverse health outcomes, including increased
risk of infant mortality as well as heart disease and type 11 diabetes in adults 0^-! fi,'„ 2007; Reyes and
Manalich. 2005). The selection of a 5% BMR is additionally supported by data from (kavlock et al..
1995) which found that a BMR of 5% RD for fetal weight reduction was statistically similar to several
other BMR measurements as well as to statistically-dervived NOAEL values. For these reasons, a BMR
of 5% RD was selected for decreased pup weight. A BMR of 1 standard deviation is also shown for
comparison.
Daily AUC for NMP in blood, averaged over the exposure period until the day of measurement (e.g.
GD6-20 for Becci et al. (i* -) or GD5-21 for Saillenfait et al. (2u )), was used as an appropriate dose
measure for this endpoint. The doses and response data used for the modeling are presented in Table
2-2-1.
Table 2-2-1 Fetal Body Weight Data Selected for Dose-Response Modeling for NMP
Reference
Dose
AUC (hrmg/L)
Number of
litters
Fetal body weight (g)
Mean ± Standard Deviation
Saillenfait ct al.
(2003)
0
24
5.671 ±0.370
158
20
5.623 ±0.358
323
19
5.469 ±0.252
668
25
5.393 ±0.446
Saillenfait et
al.(2002)
0
21
5.73 ±0.5
1 144
21
5.59 ±0.22
2503
24
5.18 ± 0.35
5674
25
4.02 ±0.21
9231
8
3.01 ±0.39
Page 5 of 84
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Reference
Dose
AUC (hr mg/L)
Number of
litters
Fetal body weight (g)
Mean ± Standard Deviation
Saillenfait et
al.(2002) and (2003)
pooled
0
45
5.698 ±0.44
158
20
5.623 ±0.358
323
19
5.469 ±0.252
668
25
5.393 ±0.446
1144
21
5.59 ±0.22
2503
24
5.18 ±0.35
5674
25
4.02 ±0.21
9231
8
3.01 ±0.39
DuPont (1990)
0
39
7.48 ±0.701
51
16
7.03 ±0.705
268
15
7.13 ±0.695
633
22
6.66 ±0.616
Becci et al. (1982)
0
24
3.45 ±0.20
561
22
3.49 ±0.24
2052
23
3.54 ±0.29
7986
22
2.83 ±0.39
The best fitting model was selected based on Akaike information criterion (AIC; lower value indicates a
better fit), chi-square goodness of fit p-value (higher value indicates a better fit), ratio of the
BMC:BMCL (lower value indicates less model uncertainty) and visual inspection. A comparison of
model fits obtained for each data set of fetal/pup body weight changes is provided in Table 2-2-2 to
Table 2-2-6. The best-fitting models, based on the criteria described above, are indicated in bold. For
each of the best fitting models in Sections 2.1 -2.5, subsequent tables and figures show the model version
number, model form, benchmark dose calculation, parameter estimates and estimated values.
Page 6 of 84
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2.1 Results for Saillenfait et al., 2003
Table 2-2-2 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Inhalation
Using Daily Average AUC as the Dose Metric (Saillenfait et al., 2003)
Model3
Goodness of fit
BMR = 5% RD
BMR =1SD
Basis for model
selection
P-
value
AIC
BMDsrd (hr
mg/L)
BMDUrd (hr
mg/L)
BMDisd (hr
mg/L)
BMDLisd (hr
mg/L)
Linear
0.952
-84.637
642
411
747
456
Of the acceptable
models based on p-
value (>0.1) and
visual fit the
BMDLs were
sufficiently close
and the Linear
model was
selected based on
lowest AIC.
Exponential
(M2)
0.948
-84.629
641
405
749
451
Exponential
(M4)
0.948
-84.629
641
284
749
381
Exponential
(M3)
0.815
-82.682
653
406
745
453
Power
0.812
-82.680
653
413
744
458
Polynomial 3°b
Polynomial 2°
0.789
-82.665
652
412
738
457
Hill
N/Ac
-80.737
649
176
889
error
Exponential
(M5)
N/Ac
-80.737
643
168
error
error
Notes:
a Modeled variance case presented (BMDS Test 2 p-value = 0.0670), selected model in bold; scaled residuals for
selected model for doses 0,158.3, 322.6 and 668.2 hr mg/L were 0.0675, 0.316, -0.654 and 0.24, respectively.
b For the Polynomial 3° model, the b3 coefficient estimates was 0 (boundary of parameters space). The models in
this row reduced to the Polynomial 2° model.
c No available degrees of freedom to calculate a goodness of fit value.
Page 7 of 84
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Linear M odei. with BM r ofO.05 ReJ. Dev. tor the BM D and 0.95 Lower Confidence Limit tor the BMDL
5.8
5.7
©
® 5.6
O
a.
od
ai
ir 5.5
c
CD
ffi
^ 5.4
5.3
5.2
0 100 200 300 400 500 600 700
dose
0926 10/21 2014
Figure 2-1 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body
Weight in Rats Exposed to NMP via Inhalation (Saillenfait el ah, 2003)
BMR = 5% Relative Deviation; Daily Average AUC as Dose Shown in hr mg/L
Linear
Linear Model. (Version: 2.19; Date: 06/25/2014)
The form of the response function is: Y[dose] = beta_0 + betal *dose
A modeled variance is fit
Benchmark Dose Computation.
BMR = 5% Relative deviation
BMD = 642.052
BMDL at the 95% confidence level = 411.487
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
lalpha
10.9507
-1.98661
rho
-7.59357
0
betaO
5.66546
5.66303
betal
-0.000441199
-0.00043693
Table of Data and Estimated Values o
Interest
Dose
N
Obs Mean
Est Mean
Obs Std Dev
Est Std Dev
Scaled Resid
0
24
5.67
5.67
0.37
0.33
0.0675
158.3
20
5.62
5.6
0.36
0.346
0.316
322.6
20
5.47
5.52
0.25
0.363
-0.654
668.2
25
5.39
5.37
0.45
0.404
0.24
Page 8 of 84
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Likelihoods of Interest
Model
Log(likelihood)
# Param's
AIC
A1
45.950356
5
-81.900712
A2
49.530515
8
-83.061031
A3
46.368255
6
-80.736511
fitted
46.318536
4
-84.637072
R
41.618363
2
-79.236727
Tests of Interes
Test
2*log(Likelihood
Ratio)
Test df
p-valuc
Test 1
15.8243
6
0.01473
Test 2
7.16032
3
0.06696
Test 3
6.32452
2
0.04233
Test 4
0.099439
2
0.9515
Page 9 of 84
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2.2 Results for Saillenfait et al., 2002
Table 2-2-3 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Gavage Using
Daily Average AUC as the Dose Metric (S
BMR = 5% Relative Deviation (RD) and for Comparison 1 Standard Deviation (SD)
Model3
Goodness of fit
BMD5RD (hr
mg/L)
BMDL5RD
(hr mg/L)
BMDisd (hr
mg/L)
BMDLisd (hr
mg/L)
Basis for model selection
p-value
AIC
Exponential
(M5)
0.966
-109.73
1637
1184
1880
1400
Of the acceptable models
based on p-value (>0.1) and
visual fit (Exponential (M5),
Hill and Exponential (M3))
the BMDLs were
sufficiently close and the
Exponential (M5) model
was selected based on
lowest AIC.
Hill
0.962
-109.73
1660
1194
1895
1409
Exponential
(M3)
0.325
-109.49
1329
1035
1578
1245
Linear
0.0687
-106.63
938
895
1210
1036
Power
0.0479
-105.66
1114
904
1381
1070
Polynomial 4°b
Polynomial 3°c
Polynomial 2°
0.0295
-104.68
962
895
1233
1038
Exponential
(M2)
0.00183
-98.750
741
693
1028
876
Exponential
(M4)
0.00183
-98.750
741
691
1028
876
Notes:
a Modeled variance case presented (BMDS Test 2 p-value = 1.26E-04), selected model in bold; scaled residuals for selected
model for doses 0,1144, 2503, 5674 and 9231 hr mg/L were -0.1399, 0.1248, -0.02274, 0.1033 and -0.1213, respectively.
b For the Polynomial 4° model, the b4 and b3 coefficient estimates were 0 (boundary of parameters space). The models in
this row reduced to the Polynomial 2° model.
c For the Polynomial 3° model, the b3 coefficient estimates was 0 (boundary of parameters space). The models in this row
reduced to the Polynomial 2° model.
Page 10 of 84
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Exponential M odei 5. \Mtn BMP. oro.05 Rel. Dev. tor tne BM D and 0.95 Low«r Confidence Level 1br BM DL
Exponential
5.5
4.5
3.5
2.5
BMDL
jBMD
0
2000
6000
8000
Figure 2-2 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body
Weight in Rats Exposed to NMP via Gavage (Saillenfait et al., 2002)
BMR = 5% Relative Deviation; Daily Average AUC as Dose Shown in hr nig/L
Exponential Model. (Version: 1.9; Date: 01/29/2013)
The form of the response function is: Y[dose] = a * [c-(c- l) * exp(-(b * dose)Ad)]
A modeled variance is fit
Benchmark Dose Computation.
BMR = 5% Relative deviation
BMD= 1637.32
BMDL at the 95% confidence level = 1184.3
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
lnalpha
-3.80738
-2.38723
rho
1.00208
0.0548918
a
5.74092
6.0165
b
0.000143148
0.000073183
c
0.405685
0.000500291
d
1.67614
1
Page 11 of 84
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Table of Data and Estimated Values o
Interest
Dose
N
Obs Mean
Est Mean
Obs Std Dev
Est Std Dev
Scaled Resid
0
21
5.73
5.741
0.5
0.3577
-0.1399
1144
21
5.59
5.58
0.22
0.3527
0.1248
2503
24
5.18
5.182
0.35
0.3398
-0.02274
5674
25
4.02
4.014
0.21
0.299
0.1033
9231
8
3.01
3.021
0.39
0.2593
-0.1213
Likelihoods of Interest
Model
Log(likelihood)
# Param's
AIC
A1
59.67563
6
-107.3513
A2
71.17728
10
-122.3546
A3
60.86644
7
-107.7329
R
-42.05093
2
88.10186
5
60.86544
6
-109.7309
Tests of Interest
Test
2*log(Likelihood
Ratio)
Test df
p-value
Test 1
226.5
8
<0.0001
Test 2
23
4
0.0001264
Test 3
20.62
3
0.0001261
Test 7a
0.001995
1
0.9644
Page 12 of 84
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2.3 Results for Saillenfait et al., 2002 and 2003 combined
Table 2-2-4 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Gavage or
Inhalation using Daily Average AUC as the Dose Metric (Saillenfait et al. (2003; 2002))
BMR = 5% Relative Deviation (RD) and for Comparison 1 Standard Deviation (SD)
Model3
Goodness of fit
BMD5RD (hr
mg/L)
BMDL5RD
(hr mg/L)
BMDisd (hr
mg/L)
BMDLisd (hr
mg/L)
Basis for model selection
p-value
AIC
Exponential
(M2)
Exponential
(M4)b
<0.0001
-169.77
828
774
1155
1030
While none of the models
had an acceptable p-value
(>0.1) the visual fit appears
adequate and the model
with the highest p-value
and lowest AIC, the
Exponential (M5) model
was selected.
Exponential
(M3)
0.0119
-187.12
1547
1253
1911
1579
Exponential
(M5)
0.0150
-187.44
1937
1424
2283
1764
Hill
0.0138
-187.25
1962
1421
2297
1762
Power
0.00396
-184.48
1321
1039
1696
1366
Polynomial 7°c
Polynomial 5°d
Polynomial 4°e
Polynomial 3°f
0.00218
-183.08
1155
978
1532
1287
Polynomial 6°g
0.00218
-183.08
1155
978
1532
1287
Polynomial 2°h
0.00218
-183.08
1155
978
1532
1287
Linear
0.00164
-182.51
989
944
1343
1208
Notes:
a Modeled variance case presented (BMDS Test 2 p-value = 1.21E-04), selected model in bold; scaled residuals for selected
model for doses 0, 156.5, 319, 660.8, 1144, 2503, 5674 and 9231 hr mg/L were 1.671, 0.2153, -1.487, -2.354, 1.142,
0.2305, 0.03888 and -0.1112, respectively.
b For the Exponential (M4) model, the estimate of c was 0 (boundary). The models in this row reduced to the Exponential
(M2) model.
c For the Polynomial 7° model, the b7, b6, b5 and b4 coefficient estimates were 0 (boundary of parameters space). The
models in this row reduced to the Polynomial 3° model.
d For the Polynomial 5° model, the b5 and b4 coefficient estimates were 0 (boundary of parameters space). The models in
this row reduced to the Polynomial 3° model.
e For the Polynomial 4° model, the b4 coefficient estimate was 0 (boundary of parameters space). The models in this row
reduced to the Polynomial 3° model.
f The Polynomial 3° model may appear equivalent to the Polynomial 6° model, however differences exist in digits not
displayed in the table. This also applies to the Polynomial 2° model.
g The Polynomial 6° model may appear equivalent to the Polynomial 7° model, however differences exist in digits not
displayed in the table. This also applies to the Polynomial 5° model. This also applies to the Polynomial 4° model. This also
applies to the Polynomial 3° model. This also applies to the Polynomial 2° model.
h The Polynomial 2° model may appear equivalent to the Polynomial 7° model, however differences exist in digits not
displayed in the table. This also applies to the Polynomial 6° model. This also applies to the Polynomial 5° model. This also
applies to the Polynomial 4° model. This also applies to the Polynomial 3° model.
Page 13 of 84
-------
Exponential M odei 5. \Mtn BMP. of 0.05 Rel. Dev. Ibrtne BM D and 0.95 Lowr Confidence Level tor BM DL
6
5.5
¦
| ft
Exponential .
5
4.5
4
''-•N.... "
3.5
3
2.5
B M DL
BMD
0 2000 4000 6000 8000
dose
06:42 10/21 2014
Figure 2-3 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body
Weight in Rats Exposed to NMP via Gavage or Inhalation (Saillenfait et al. (2003; 2002))
BMR = 5% Relative Deviation; Daily Average AUC as Dose Shown in hr nig/L
Exponential Model. (Version: 1.9; Date: 01/29/2013)
The form of the response function is: Y[dose] = a * [c-(c-l) * exp(-(b * dose)Ad)]
A modeled variance is fit
Benchmark Dose Computation.
BMR = 5% Relative deviation
BMD = 1937.29
BMDI. at the 95% confidence level = 1423.77
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
Inalplia
-4.03673
-2.36893
rho
1.20539
0.0584431
a
5.6045
5.9829
b
0.000147759
0.0000728823
c
0.446945
0.000503101
d
1.88381
1
Page 14 of 84
-------
Table of Data and Estimated Values o
Interest
Dose
N
Obs Mean
Est Mean
Obs Std Dev
Est Std Dev
Scaled Resid
0
45
5.698
5.604
0.4353
0.3755
1.671
156.5
20
5.62
5.602
0.36
0.3754
0.2153
319
20
5.47
5.595
0.25
0.3751
-1.487
660.8
25
5.39
5.566
0.45
0.3739
-2.354
1144
21
5.59
5.497
0.22
0.3711
1.142
2503
24
5.18
5.163
0.35
0.3574
0.2305
5674
25
4.02
4.018
0.21
0.3072
0.03888
9231
8
3.01
3.02
0.39
0.2587
-0.1112
Likelihoods of Interest
Model
Log(likelihood)
# Param's
AIC
A1
104.4887
9
-190.9774
A2
119.1975
16
-206.3949
A3
105.8917
10
-191.7834
R
-48.75234
2
101.5047
5
99.71803
6
-187.4361
Tests of Interes
Test
2*lojj( Likelihood
Ratio)
Test df
p-value
Test 1
335.9
14
<0.0001
Test 2
29.42
7
0.0001214
Test 3
26.61
6
0.0001712
Test 7a
12.35
4
0.01495
Page 15 of 84
-------
2.4 Results for DuPont, 1990
Table 2-2-5 Model Predictions for Fetal Body Weights in Rats Exposed to NMP by Inhalation
using Daily Average AUC as the Dose Metric (DuPont
BMR = 5% Relative Deviation and for Comparison 1 Standard Deviation (SD)
Model3
Goodness of fit
BMD5RD (hr
mg/L)
BMDLsrd (hr
mg/L)
RMDisd (hr
mg/L)
BMDLisd
(hr mg/L)
Basis for model
selection
p-value
AIC
Exponential (M2)
Exponential (M3)b
0.140
27.266
315
223
594
411
Of the acceptable
models based on p-
value (>0.1) and visual
fit the BMDLs were
sufficiently close and the
Exponential model was
selected based on
lowest AIC.
Power0
Polynomial 3°d
Polynomial 2°e
Linear
0.138
27.288
323
234
596
421
Exponential (M4)
0.0494
29.191
260
1.16
580
2.61
Exponential (M5)
0.0494
29.191
260
1.30
580
3.07
Hill
0.0597
28.875
58.5
4.71E-04
609
1.98E-05
Notes:
a Constant variance case presented (BMDS Test 2 p-value = 0.905), selected model in bold; scaled residuals for selected
model for doses 0, 51.18, 267.9 and 633.3 hr mg/L were 0.8831, -1.718, 0.3504 and 0.0002752, respectively.
b For the Exponential (M3) model, the estimate of d was 1 (boundary). The models in this row reduced to the Exponential
(M2) model.
c For the Power model, the power parameter estimate was 1. The models in this row reduced to the Linear model.
d For the Polynomial 3° model, the b3 coefficient estimates was 0 (boundary of parameters space). The models in this
row reduced to the Polynomial 2° model. For the Polynomial 3° model, the b3 and b2 coefficient estimates were 0
(boundary of parameters space). The models in this row reduced to the Linear model.
e For the Polynomial 2° model, the b2 coefficient estimate was 0 (boundary of parameters space). The models in this row
reduced to the Linear model.
Page 16 of 84
-------
Exponential M odei 2. wrftn BMP. of 0.05 Rel. Dev. Ibrtne BM D and 0.95 Lowr Confidence Level tor BM DL
7.8
7.6
7.4
6.6
6.4
Exponential
0 100 200 3O0 400 500 600
dose
15:02 09/25 2014
Figure 2-4 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body
Weight in Rats Exposed to NMP via Inhalation (DuPont, 1990)
BMR = 5% Relative Deviation; Daily Average AUC as Dose Shown in hr mg/L
Exponential Model. (Version: 1.9; Date: 01/29/2013)
The form of the response function is: Y[dose] = a * exp(sign * b * dose)
A constant variance model is fit
Benchmark Dose Computation.
BMR = 5% Relative deviation
BMD = 314.897
BMDL at the 95% confidence level = 223.175
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
liialplia
-0.768852
-0.811648
rho(S)
n/a
0
a
7.38373
6.90878
b
0.000162889
0.000162077
c
0
0
d
1
1
Page 17 of 84
-------
Table of Data and Estimated Values o
Interest
Dose
N
Obs Mean
Est Mean
Obs Std Dev
Est Std Dev
Scaled Resid
0
39
7.48
7.384
0.701
0.6808
0.8831
51.18
16
7.03
7.322
0.705
0.6808
-1.718
267.9
15
7.13
7.068
0.695
0.6808
0.3504
633.3
22
6.66
6.66
0.616
0.6808
0.0002752
Likelihoods of Interest
Model
Log(likelihood)
# Param's
AIC
A1
-8.66418
5
27.32836
A2
-8.383601
8
32.7672
A3
-8.66418
5
27.32836
R
-18.52227
2
41.04454
2
-10.6328
3
27.26561
Tests of Interes
Test
2*log(Likelihood
Ratio)
Test df
p-value
Test 1
20.28
6
0.002471
Test 2
0.5612
3
0.9053
Test 3
0.5612
3
0.9053
Test 4
3.937
2
0.1396
Page 18 of 84
-------
2.5 Results for Becci et al., 1982
Table 2-2-6 Model Predictions for Fetal Body Weights in Rats Exposed to NMP Derniallv Using
Daily Average AUC as the Dose Metric (Becci et al., 1982)
Model3
Goodness of fit
BMDsrd (hr
mg/L)
BMDI_5rd (hr
mg/L)
BMDisd (hr
mg/L)
BMDLisd (hr
mg/L)
Basis for model selection
p-value
AIC
Polynomial 3°
0.572
-138.35
5391
4018
6015
4645
Of the acceptable models
based on p-value (>0.1) and
visual fit the BMDLs were
sufficiently close and the
Polynomial 3° modei was
selected based on lowest
AIC.
Power
0.371
-136.67
7692
3783
7864
4525
Polynomial 2°
0.307
-137.11
4326
3919
5087
4503
Linear
0.00557
-129.09
2452
1944
3331
2567
Hill
N/Ab
-134.67
7497
2302
7695
2361
Notes:
a Modeled variance case presented (BMDS Test 2 p-value = 0.0101), selected model in bold; scaled residuals for selected
model for doses 0, 588.7, 2156 and 8409 hr mg/L were -0.928, -0.111,1.08 and -0.03, respectively.
b No available degrees of freedom to calculate a goodness of fit value.
Polynomial Modul, with DMR of 0.05 Rd. Dev. for the BMD and 0.95 Lower Confidence Limit for the DMDL
fj M D
BMD
7O0O
14:21 12/10 2014
Figure 2-5 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Fetal Body
Weight in Rats Exposed to NMP Dermally (Becci et al„ 1982)
BMR = 5% Relative Deviation; Daily Average AUC as Dose Shown in hr mg/L
Polynomial Model. (Version: 2.19; Date: 06/25/2014)
The form of the response function is: Y[dose] = beta_Q + beta_l *dose + beta_2*doseA2 + ...
A modeled variance is fit
Page 19 of 84
-------
Benchmark Dose Computation.
BMR = 5% Relative deviation
BMD = 5390.85
BMDL at the 95% confidence level = 4017.68
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
lalpha
2.56784
-2.49546
rho
-4.31376
0
betaO
3.49599
3.45
betal
-1.68014E-27
0
beta_2
0
-0.000000016108
beta_3
-1.11576E-12
-2.23106E-13
Table of Data and Estimated Values o
Interest
Dose
N
Obs Mean
Est Mean
Obs Sid Dcv
Est Std Dev
Scaled Resid
0
24
3.45
3.5
0.2
0.243
-0.928
588.7
22
3.49
3.5
0.24
0.243
-0.111
2156
23
3.54
3.48
0.29
0.244
1.08
8409
22
2.83
2.83
0.39
0.382
-0.03
Likelihoods of Interest
Model
Log(likclihood)
# Param's
AIC
A1
70.088658
5
-130.177316
A2
75.754919
8
-135.509838
A3
73.734901
6
-135.469801
fitted
73.175965
4
-138.35193
R
37.76879
2
-71.537581
Tests of Interest
Test
2*log(Likclihood
Ratio)
Test df
p-value
Test 1
75.9723
6
<0.0001
Test 2
11.3325
3
0.01006
Test 3
4.04004
2
0.1327
Test 4
1.11787
2
0.5718
Page 20 of 84
-------
3 Benchmark Dose Modeling of Effects for Resorptions and Fetal
Mortality
BMD modeling for fetal and pup body weight changes and resorption/fetal death was performed using
USEPA's BMD Software package version 2.5 (BMDS 2.5), in a manner consistent with EPA
Benchmark Dose Technical Guidance. These benchmark modeling results were previously presented in
EPA's (2015) risk assessment of NMP.
Dichotomous models were used to fit fetal mortality incidence data and continuous models were used to
fit dose-response data for mean number of resorptions. A BMR of 1% was used to address the relative
severity of this endpoint (EPA. 2012). BMRs of 0.5 and 1 standard deviation are also shown for
comparison. The peak NMP in maternal blood (Cmax) was used as an appropriate dose measure for these
endpoints. The doses and response data used for the modeling are presented in Table 3-3-1.
Table 3-3-1 Skeletal Malformations, Resorptions and Fetal Mortality Data Selected for Dose-
Response Modeling for NMP
Reference arid
endpoint
Dose
Cmax (mg/L)
Dose
AUC (hr mg/L)
Number of
litters
Response
Mean ± Standard
Deviation
Saillenfait et
al.(2002) and
(2003)
Resorptions
0
0
45
3.4 ±7.13
15
156.5
20
4.3 ±4.1
30
319
20
9.9 ±22.3
62
660.8
25
7 ±9.4
120
1 144
21
8.9 ±21.2
250
2503
24
4.5 ±6.6
531
5674
25
9.4 ± 8.9
831
9231
5
91 ± 16
Sitarek et al.
(2012.)
fetal mortality
0
0
22
0.18 ±0.85
76
902
24
0±0
265
3168
20
0.13 ±0.34
669
8245
15
0.8 ± 1.1
The best fitting model was selected based on Akaike information criterion (AIC; lower value indicates a
better fit), chi-square goodness of fit p-value (higher value indicates a better fit), ratio of the
BMC:BMCL (lower value indicates less model uncertainty) and visual inspection. Comparisons of
model fits obtained for resorptions and fetal mortality are provided in Table 3-3-2 to Table 3-3-4. The
best-fitting models, based on the criteria described above, are indicated in bold. For each of the best
fitting models in Section 3.1-3.3, subsequent tables and figues show the model version number, model
form, benchmark dose calculation, parameter estimates and estimated values.
Page 21 of 84
-------
3.1 Results for Saillenfait et al., 2002 and 2003 combined using Cr
Table 3-3-2 Model Predictions for Resorptions in Rats Exposed to
Using Cmax as the Dose Metric (Saillenfait et al. (2003: 2002))
BMR =1% Relative Deviation (RD) and for Comparison 0.5 and
NMP via Gavage or Inhalation
Standard Deviation (SD)
Model3
Goodness of fit
p-value
AIC
BMDird
(mg/L)
BMDLird
(mg/L)
BMDo.ssd
(mg/L)
BMDLo.5sd
(mg/L)
BMDisd
(mg/L)
BMDLisd
(mg/L)
Basis for model
selection
Exponential
(M2)
Exponential
(M3)
Exponential
(M4)
Exponential
(M5)
Hill
Power
Polynomial 4°
Polynomial 3°
Polynomial 2°
Linear
<0.0001
1288.45
1.60
1.26
424
349
530
468
<0.0001
1263.09
247
97.9
621
510
685
602
<0.0001
1364.53
0.122
0.0122
58.2
44.5
116
89.1
While none of the
models had an
acceptable p-value
(>0.1) the visual fit
appears adequate,
the lowest AIC, the
Hill model was
selected.
<0.0001
1265.04
326
215
593
514
648
583
<0.0001
1263.03
429
216
558
514
582
548
<0.0001
1263.04
326
215
593
514
648
583
<0.0001
1276.48
128
77.6
436
419
518
504
<0.0001
1300.17
66.7
55.2
359
345
452
435
<0.0001
1336.49
19.2
3.77
247
215
349
317
<0.0001
1362.53
0.121
0.0122
58.2
44.5
116
89.1
Notes:
a Modeled variance case presented (BMDS Test 2 p-value = <0.0001), selected model in bold; scaled residuals for selected
model for doses 0,15.01, 30.34, 61.86,120, 250, 531 and 831 mg/L were -1.42, -0.619,1.41, 0.401,1.1, -0.599, 0.29 and -
0.00443, respectively.
Page 22 of 84
-------
Hill M odei. with BW R oTO.01 Rei. Dev. tor the BM D and 0.95 Lower Confidence umlt ibr the BM DL
-5-
"X"
100 200 300 400 500 600 700 800
dose
11:00 12/15 2014
Figure 3-1 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Resorptions
in Rat Exposed to NMP via Gavage or Inhalation (Saillenfait et al. (2003; 2002))
BMR= 1% Relative Deviation; Cmax as Dose Shown in mg/L
Hill Model. (Version: 2.17; Date: 01/28/2013)
The form of the response function is: Y[dose] = intercept + v*doseAn/(kAn + doseAn)
A modeled variance is fit
Benchmark Dose Computation.
BMR = 1% Relative deviation
BMD = 429.482
BMDI. at the 95% confidence level = 215.783
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
lalpha
4.75575
5.10412
rho
0.150826
0
intercept
6.00954
3.4
V
85.8437
87.6
n
18
1.9286
k
642.982
992.029
Page 23 of 84
-------
Table of Data and Estimated Values o
Interest
Dose
N
Obs Mean
Est Mean
Obs Std Dev
Est Std Dev
Scaled Resid
0
45
3.4
6.01
7.13
12.3
-1.42
15.01
20
4.3
6.01
4.1
12.3
-0.619
30.34
20
9.9
6.01
22.3
12.3
1.41
61.86
25
7
6.01
9.4
12.3
0.401
120
22
8.9
6.01
21.2
12.3
1.1
250
24
4.5
6.01
6.6
12.3
-0.599
531
25
9.4
8.67
8.9
12.7
0.29
831
25
91
91
16
15.2
-0.00443
Likelihoods of Interest
Model
Log(likelihood)
# Param's
AIC
A1
-624.644958
9
1267.289916
A2
-570.082153
16
1172.164306
A3
-595.035542
10
1210.071083
fitted
-626.515585
5
1263.03117
R
-806.807094
2
1617.614189
Tests of Interes
Test
2*lojj( Likelihood
Ratio)
Test df
p-value
Test 1
473.45
14
<0.0001
Test 2
109.126
7
<0.0001
Test 3
49.9068
6
<0.0001
Test 4
62.9601
5
<0.0001
Page 24 of 84
-------
3.2 Results for Saillenfait et al., 2002 and 2003 combined using AUC
Table 3-3-3 Model Predictions for Resorptions in Rats Exposed to NMP via Gavage or Inhalation
Using AUC as the Dose Metric (Saillenfait et al. (2003: 2002))
Model3
Goodness of fit
BMDird
(hr mg/L)
BMDLird
(hr mg/L)
BMDo.ssd
(hr mg/L)
BMDLo.5sd
(hr mg/L)
BMDisd (hr
mg/L)
BMDLisd
(hr mg/L)
Basis for
model
selection
p-value
AIC
Exponential
(M2)
<0.0001
1286.5
19.8
15.8
4281
3524
5543
4887
While none of
the models
had an
acceptable p-
value (>0.1)
the visual fit
appears
adequate, the
lowest AIC,
the Power
model was
selected.
Exponential
(M3)
<0.0001
1263.1
2466
901
6721
5432
7486
6504
Exponential
(M4)
<0.0001
1360.1
0.720
0.0760
598
473
1196
946
Exponential
(M5)
<0.0001
1265.0
3343
2128
6394
5479
7045
6285
Hill
<0.0001
1265.0
4177
2133
6091
5481
6478
5858
Power
<0.0001
1263.0
3343
2128
6394
5479
7045
6285
Polynomial
4°
<0.0001
1271.7
1432
135
4827
4537
5741
5534
Polynomial
3°
<0.0001
1292.4
743
133
3958
3731
4986
4786
Polynomial
2°
<0.0001
1329.7
211
148
2714
2538
3838
3589
Linear
<0.0001
1358.1
0.720
0.0760
598
473
1196
946
Notes:
a Modeled variance case presented (BMDS Test 2 p-value = <0.0001), selected model in bold; scaled residuals for selected
model for doses 0,156.5, 319, 660.8,1144, 2503, 5674 and 9231 hr mg/L were -1.42, -0.62,1.41, 0.4,1.1, -0.603, 0.299 and
-0.00462, respectively.
Page 25 of 84
-------
Power M odei. with BM R ofO.01 Rel. Dev. tor the BM D and 0.95 Lower Confidence Limit tor the BMDL
100
80
20
0
4000
dose
13:03 12/15 2014
Figure 3-2 Plot of Mean Response by Dose, with Fitted Curve for Selected Model for Resorptions
in Rat Exposed to NMP via Gavage or Inhalation (Saillenfait et al. (2003; 2002))
BMR = 1% Relative Deviation; AUC as Dose Shown in hr mg/L
Power Model. (Version: 2.18; Date: 05/19/2014)
The form of the response function is: Y[dose] = control + slope * doseApower
A modeled variance is fit
Benchmark Dose Computation.
BMR = 1% Relative deviation
BMD = 3343.09
BMDL at the 95% confidence level = 2127.52
Parameter Estimates
Variable
Estimate
Default Initial
Parameter Values
lalpha
4.75548
5.10412
rho
0.150959
0
control
6.01205
3.4
slope
4.05331E-27
0.0564664
power
7.14249
0.625198
Page 26 of 84
-------
Table of Data and Estimated Values o
Interest
Dose
N
Obs Mean
Est Mean
Obs Std Dev
Est Std Dev
Scaled Resid
0
45
3.4
6.01
7.13
12.3
-1.42
156.5
20
4.3
6.01
4.1
12.3
-0.62
319
20
9.9
6.01
22.3
12.3
1.41
660.8
25
7
6.01
9.4
12.3
0.4
1144
22
8.9
6.01
21.2
12.3
1.1
2503
24
4.5
6.02
6.6
12.3
-0.603
5674
25
9.4
8.64
8.9
12.7
0.299
9231
25
91
91
16
15.2
-0.00462
Likelihoods of Interest
Model
Log(likelihood)
# Param's
AIC
A1
-624.644958
9
1267.289916
A2
-570.082153
16
1172.164306
A3
-595.035542
10
1210.071083
fitted
-626.519051
5
1263.038102
R
-806.807094
2
1617.614189
Tests of Interest
Test
2*lojj( Likelihood
Ratio)
Test df
p-value
Test 1
473.45
14
<0.0001
Test 2
109.126
7
<0.0001
Test 3
49.9068
6
<0.0001
Test 4
62.967
5
<0.0001
Page 27 of 84
-------
3.3 Results for Sitarek et al., 2012
Table 3-3-4 Model Predictions for Fetal Mortality in Rats Exposed to NMP by Gavage Using Cmax
as the Dose Metric (Sitarek et al.. 2012)
Model3
Goodness of fit
BMDird
(mg/L)
BMDLird
(mg/L)
BMDo.ssd
(mg/L)
BMDo.ssd
(mg/L)
BMDisd
(mg/L)
BMDisd
(mg/L)
Basis for
model
selection
p-value
AIC
Exponential
(M2)
<0.0001
7701.7
0.0578
0.0403
181
0.341
185
26.4
No models
provided an
adequate fit
and a valid
BMDL
estimate,
therefore no
model was
selected.
Exponential
(M3)
<0.0001
1.8E+17
1.1E+15
1.1E+15
3.9E+15
3.9E+15
3.9E+15
3.9E+15
Exponential
(M4)
errorb
error
error1'
error
error1'
error
Exponential
(M5)
N/Ac
errorb
error
error1'
error
errorb
error
Power
<0.0001
4.2143
465
83.1
634
471
658
567
Polynomial
2°
<0.0001
11.247
31.9
15.0
471
351
666
496
Linear
<0.0001
20.871
1.94
4.30E-05
457
241
915
482
Hill
N/Ac
8.2143
464
83.2
633
300
658
324
Notes:
a Modeled variance case presented (BMDS Test 2 p-value = <0.0001, BMDS Test 3 p-value = <0.0001), no model was
selected as a best-fitting model.
b BMD or BMDL computation failed for this model.
c No available degrees of freedom to calculate a goodness of fit value.
Page 28 of 84
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4 Benchmark Dose Modeling of Male Fertility, Female Fecundity, Litter
Size and Pup Death in Exxon, 1991
BMD modeling for reduced male fertility, female fecundity, and reduced litter size described in a 2-
generation reproductive study in rats exposed through diet (Exxon. 1991) was performed using
USEPA's BMD Software package version 3.1.1 (BMDS 3.1.1) or 2.7 (BMDS 2.7) in a manner
consistent with Benchmark Dose Technical Guidance.
In the Exxon (1991) study, two generations of both sexes were dosed daily for at least ten weeks prior to
mating and throughout the mating period. Target doses for the exposed groups were 50, 160 and 500
mg/kg-day. Individual litter data reported in Appendices to the Exxon ( >91) report were used for the
determination of dichotomous response incidence and continuous response means and standard
deviations modeled in this report.
The strongest dose-responses for reproductive effects in the Exxon (1991) study were observed for
reduced Male Fertility Index and Female Fecundity Index in the first (P2/F2A; Table 73 of the Exxon
report) and second (P2/F2B; Table 74 of the Exxon report) litters of the P2 (F1A) 2nd generation parents.
4.1 Overall BMD Modeling Approach for Exxon 1991 Data
Benchmark dose software version 3.1.1 ( ' • 3.1.1) was used to analyze male fertility, female
fecundity and litter size. The pup death endpoint was analyzed using BMDS 2.7 because it contains the
larger suite of nested dichotomous models.2 Nested dichotomous models are preferred for this endpoint
because they contain an intra-litter correlation coefficient for the assessment of litter-specific responses.
Only BMDS models that use likelihood optimization and profile likelihood-based confidence intervals
were used in this analysis. All continuous models applied assume normal response distribution. Also, the
benchmark response levels and dose metrics for the analysis are:
• Fertility and Fecundity for P2/F2A and P2 F2Bparental rats - estimate BMDs for 10%
extra risk using PBPK estimates of average daily blood concentrations for young (50 g) rat as
doses (four datasets), plus a sensitivity analysis using average daily blood concentrations for
250 g, 350 g and 450 g rats.
• Litter Size for P2/F2A andP2/P2B - estimate BMDs for 1 SD change from control mean
using PBPK estimates of average daily blood concentrations for young (50 g) rat and GD 6-
21 dams as doses (four datasets)
• Pup death for P2 I<2A andP2/F2B - estimate BMDs for death at Day 0 and by day 4 for
10%. 5% and 1% extra risk using PBPK estimates of average daily blood concentrations for
GD 6-21 dam as doses (four datasets)
Standard and non-standard forms of these models- (defined for each endpoint below) were run
separately in BMDS 3.1.1, but EPA model selection procedures ( ) were applied only to the
results of the standard model runs when adequate fit was achieved with any standard model. Since
2 BMDS 3.1.1 contains the same NLogistic model, which is preferred because it has received the more extensive QA testing
and is deemed to be the most reliable nested model, but NCTR and RaiVR models are provided as alternatives in this report.
3 The set of standard models are identified in accordance with EPA BMD technical guidance (EPA. 2012) and are the default
models in BMDS 3.1.1. Non-standard models are the remaining (non-default) models available in BMDS 3.1.1.
Page 29 of 84
-------
adequate model fits were obtained in all cases for the standard model suites, no non-standard modeling
results are shown or discussed in this report.
Model Restrictions and Model Selection
Restrictions for BMDS 3.1.1 models are defined in the 6MDS 3.1.1 User Guide and are applied in
accordance with EPA BMD Technical Guidance ( ). For each BMD analysis, a single preferred
model was chosen from among the preferred standard set of models (noting instances where consideration
of non-standard models may be justified) in accordance with EPA BMD Technical Guidance ( ).
For continuous responses, dose group response standard deviation (SD) was modeled assuming constant
variance across dose groups. If adequate fit (p>0.1) was not achieved for this variance model a non-
constant variance assumption that models SD as a power function of the mean was applied (EPA. 2012.).
Nested dichotomous models were run two ways, with intra-litter correlation (ILC) coefficients estimated
and with ILC coefficients assumed to be zero. Because potential litter-specific covariates (LSCs) such as
dam BW are affected by dose, no appropriate LSC could be determined and LSCs were not estimated in the
BMDS nested dichotomous model runs.
4.2 PBPK Analysis for Exxon 1991 Data
Details of the PBPK models for rats and humans are provided in Appendix I of the NMP Risk
Evaluation. The models were developed to describe dosimetry in adult females during pregnancy and so
were slightly adapted to estimate dosimetry in juvenile (post-weaning) rats and adult men.
Because NMP has a relatively short half-life in both rats and humans, exposures only need to be
simulated for several days to a week to determine the internal dosimetry from a consistent exposure
pattern, such as occurs in an animal bioassay or in the workplace (5 day/week). Therefore, adult human
single-day or workplace exposures outside of pregnancy were assumed to be adequately represented by
running the model for the first day or week of pregnancy, when physiological changes are minimal.
Also, physiological differences between men and women were assumed to have minimal impact on the
predicted dosimetry, except that a male-specific body weight (BW) and hand surface area (SA) were
used to estimate dosimetry in men. Changing the BW also affects cardiac output, respiration, and
metabolism, which all scale as BW°75 in the model. Exposures were simulated for a single day
(residential consumer use) or a week (workplace, with 5 d/w exposure) and the average daily area-
under-the-curve (AUC) blood concentration4 was calculated.
For the rat, where pregnancy only lasts 21 days, the model code was modified to allow a user-specified
day for the start of gestation (GSTART), so results for non-pregnant animals could be obtained; i.e.,
with time < GSTART. As for humans, physiological differences between males and females were
assumed to not significantly impact internal dosimetry, hence the non-pregnant female model was used
to simulate male dosimetry. Simulations for post-weaning juvenile animals in the Exxon (1991) bioassay
were conducted by setting the (initial) BW to 50 g (and for comparison, 250 g, 350 g and 450 g).
Because metabolism is scaled as BW°75 in the rats (as well as humans) the internal dose decreases as
BW decreases, so using this BW yields the lowest estimated internal dose for post-weaning rats
(weaning presumed to occur at about this BW). Using this BW in dose-response analysis for fertility and
4 Since the 24-hour AUC can vary from day to day, in particular for workplace scenarios, a time-averaged AUC is computed
as AUCavg = AUC(averaging time)*(24 h)/(averaging time), where "averaging time" is typically a week. The average blood
concentration is simply C(ivg = AUC(averaging time)/(averaging time). Hence Cavg = AUCavg/(24 h).
Page 30 of 84
-------
fecundity provides a lower bound on the internal dose that could give rise to those effects, since they
could result from toxicity at any point in development or during maturity. Target exposure levels (50,
160, and 500 mg/kg/d) were used as exposure levels, exposure was simulated for one-week to go beyond
any initial accumulation and the average blood concentration (Cavg) in the last day of exposure used as
internal dose. Food consumption was assumed to occur 12 h/d, at a constant rate over the 12 h to match
the target exposure. Results are given in Table 4-1.
Table 4-1 PBPK-predicted average blood concentrations (Cavg, mg/L) in juvenile rats
Exposure rate
(mg/kg/d)
Cavg (50 g
rat)
Cavg (250 g
rat)
Cavg (350 g
rat)
Cavg (450 g
rat)
0
0
0
0
0
50
13.9
21.1
23.1
24.6
160
48.4
75.2
82.6
88.6
500
181.4
292.6
324.0
349.8
The existing PBPK model does not describe lactational dosimetry, hence the analysis did not include
exposure during that period.
Since effects on litter size and pup viability could result from exposure during gestation, for these
endpoints Cavg in the rat dam over gestation days (GDs) 6-21 days of gestation was estimated. For
simulation of gestation, group-specific mean BW on GD 0 from Table 53 (P2/F2A) and Table 56
(P2/F2B) of the Exxon (1991) report were used to set the initial BW of the animals. The gestational BW
gain simulated by the model depended on the number of fetuses (NUMFET), an input parameter. Since
group-specific BW values were also given on GD 20 (Tables 53 and 56 of the Exxon report), a nominal
NUMFET was selected for each group to match, as closely as possible, the GD 20 BW value, though the
NUMFET did not necessarily match the average number actually born. This choice was made since the
BW impacts the internal dose, so it was considered most important to match the BW increase. The dose
rates for each exposure group were calculated as the average of measured doses for days 6-20 from
Tables 67 (P2/F2A) and 69 (P2/F2B) of the Exxon (1991) report. The resulting internal doses are given
in Table 4-2 and 4-3.
Table 4-2 PBPK-predicted average blood concentrations (Cavg, mg/L) during gestation for
P2/F2A
GD 0
GD 6-20
Predicted GD 20 BW
GD 6-21
BW (kg)
Exposure rate
(kg)
Cavg
(mg/kg/d)
(# fetuses simulated)
(mg/L)
0.3243
52.475
0.4505 (17)
26.12
0.3054
166.75
0.4394 (19)
92.55
0.2815
494.1
0.3872 (14)
326.1
Page 31 of 84
-------
Table 4-3 PBPK-predicted average blood concentrations (Cavg, mg/L) during gestation for
P2/F2B
GDO
GD 6-20
PredictedGD 20 BW
BW (kg)
Exposure rate
(kg)
GD 6-21
(mg/kg/d)
(# fetuses simulated)
Cavg (mg/L)
0.3706
49.350
0.5075 (18)
25.25
0.3536
156.70
0.4935 (19)
89.03
0.3187
466.63
0.4188 (12)
311.9
For human workplace and residential exposures, input parameters were specified in Excel spreadsheets.
For workplace exposures, estimated air concentrations were assumed to be constant over each period of
use, but the air concentration, liquid concentration (weight fraction), and duration of use varied between
scenarios. Internal average blood concentrations for varying levels of protective equipment (face mask
and/or gloves with varying protection factors (PFs)) were estimated assuming a five-day work week in
which the exposure was repeated each day followed by two days without exposure. Residential
applications were assumed to occur for a single day and air-concentration time-courses estimated for
each application, along with liquid weight fraction and dermal contact duration specific to each use
scenario. These inputs were read by a model script from Excel spreadsheets. For the analysis of potential
for effect on male fertility, BW and hand surface area (SA) were set to male-specific values. For the
analysis of potential for gestational effect, BW and SA were set to female-specific values. Residential
application evaluated exposure for both adult and teenage women. Model results are written back to the
Excel spreadsheet from which exposure inputs were obtained.
Since human internal doses are calculated as 24-h average AUC values, these must be divided by 24 h
before comparison to Cavg BMD(L) values, or the CavgBMD(L) values multiplied by 24 h, prior toMOE
calculation.
Page 32 of 84
-------
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
4.3 Summary of BMD Modeling for Exxon, 1991 Data
Table 4-4 BMD Modeling Summary for Exxon (1991)
Sec.
Response
Basis for
Internal Dose
Calculations
Selected
Model2
BMR
BMD3
(mg/L)
BMDL3
(mg/L)
BMDU3
(mg/L)
BMD4
24hr AUC
(h mg/L)
BMDL4
24hr AUC
(h mg/L)
4.4.1
P2/F2A Male Rat Fertility
Young rat (50 g)
Log-Logistic
10% ER
20.5
10.9
81.7
492
262
4.4.2
P2/F2B Male Rat Fertility
Young rat (50 g)1
Log-Logistic
10% ER
14.2
7.64
65.1
341
183
4.4.3
P2/F2A Female Rat Fecundity
Young rat (50 g)
Log-Logistic
10% ER
35.9
16.7
179
862
401
4.4.4
P2/F2B Female Rat Fecundity
Young rat (50 g)
Log-Logistic
10% ER
17.5
8.40
58.4
420
202
4.5.1
P2/F2A Litter Size
Young rat (50 g)
Polynomial 3
1 SD
203
151
715
4872
3624
4.5.2
P2/F2B Litter Size
Young rat (50 g)
Linear
1 SD
153
99.6
332
3672
2390
4.5.3
P2/F2A Litter Size5
Dam (GD 6-21)
Polynomial 3
1 SD
364
274
1280
8736
6576
4.5.4
P2/F2B Litter Size5
Dam (GD 6-21)
Linear
1 SD
265
172
575
6360
4128
4.6.1
P2/F2A Pup Death at Day 0
(stillborn)
Dam (GD 6-21)
NLogistic - ILC
5% ER
327
205
NC
7848
4920
1% ER
281
49.3
NC
6744
1183
4.6.2
P2/F2B Pup Death at Day 0
(stillborn)
Dam (GD 6-21)
No Model
Selected
5% ER
NA
NA
NA
NA
NA
1% ER
NA
NA
NA
NA
NA
4.6.3
P2/F2A Pup Death by Day 4
Dam (GD 6-21)
No Model
Selected
5% ER
NA
NA
NA
NA
NA
1% ER
NA
NA
NA
NA
NA
4.6.4
P2/F2B Pup Death by Day 4
Dam (GD 6-21)
No Model
Selected
5% ER
NA
NA
NA
NA
NA
1% ER
NA
NA
NA
NA
NA
1 BMDL estimates from the selected model (Log-Logistic) for this most sensitive endpoint using internal doses based on 250 g, 350 g and 450 g rats, were 12.1, 13.4 and 14.4 mg/L,
respectively (details of these results and results for the other fertility and fecundity endpoints are available in the supplemental BMDS 3.1.1 Excel Result Workbook files associated
with this report).
2 As described in Section 4.1, BMDs were derived from the standard set of models as defined in the EPA BMD technical guidance and as identified in BMDS 3.1.1 as defaults. Since the
standard approach gave adequate results for all endpoints, non-standard models were not considered for BMD derivations.
3 BMD, BMDL and BMDU values are in terms of average concentration over 24 hrs and are reported to more than 3 significant figures in the tables in Section 4.4, 4.5 and 4.6. This has
been done to facilitate QC (i.e., replication of the results to a higher number of significant figures gives greater assurance that QA model runs have been performed using the same
modeling options).
4Adjusted BMD and BMDL are in terms of 24-hour AUC blood concentration. These units are directly comparable with BMDLs previously calculated for the NMP risk evaluation
'Effects on litter size during gestation are of interest for acute exposure and would therefore be most appropriately evaluated based on maximum concentrations as opposed to 24hr
average or AUC concentrations shown here.
NC = Not Calculated; NA = Not Applicable
-------
4.4 Results of BMD Modeling of P2 Male and Female Fertility Indices
(Exxon, 1991)
The strongest dose-responses for reproductive effects in the Exxon (1991) study were observed for
reduced Male Fertility Index and Female Fecundity Index in the first (P2/F2A; Table 73 of the Exxon
report) and second (P2/F2B; Table 74 of the Exxon report) litters of the P2 (F1A) 2nd generation parents.
Incidence data for these effects were obtained from Appendices AF (P2/F2A parents) and AG (P2/F2B
parents) of the Exxon (1991) report. Because BMDS models dichotomous data using dose-response
curves that are increasing in dose-response, the results reported in Appendices AF and AG in terms of
successful impregnations were inverted to obtain incidence data in terms of "number of males
unsuccessful at impregnating any female" per "number of males used for mating" (Males Unsuccessful/
Males Used) and "number of females that did not get pregnant" per "number of females sperm positive
(confirmed mated or confirmed pregnant)" (Females Unsuccessful/Females Mated). These ratios were
derived slightly differently from the Male Fertility and Female Fecundity indices shown in Tables 73
and 74 of the Exxon (1991) report in that a confirmed pregnancy was counted as "sperm positive"
regardless of whether the mating was "confirmed" (cases where this occurred are identified with
footnotes in the tabular results of this Section).
Because of the existing uncertainty regarding the lifestage "window of toxicity," and the possibility that
reproductive effects of concern could have been associated with early life exposures, the BMD analyses
of potential reproductive effects were performed using PBPK estimates of internal doses that assume an
early lifestage rat body weight of 50 g. A sensitivity analysis was performed on the P2/F2B Male Rat
Fertility to determine the impact of the body weight assumption. As indicated in Footnote 1 of the table
in Section 4.3, BMDL estimates for this most sensitive endpoint increased by less than 2-fold for body
weight assumptions at or below 450 g. The following standard and non-standard dichotomous models
and general modeling options were used to fit fertility incidence data.
Standard Dichotomous Models Applied to Fertility and Fecundity Responses:
• Gamma-restricted
• Log-Logistic-restricted
• Multistage-restricted; from degree = 1 to degree = # dose groups - 1
• Weibull-restricted
• Dichotomous Hill-unrestricted
• Logistic
• Log-Probit-unrestricted
• Probit
Non-Standard Dichotomous Models Applied to Fertility and Fecundity Responses:
• Dichotomous Hill-restricted
• LogProbit-restricted
• Gamma-unrestricted
• Log-Logistic-unrestricted
• Multistage-unrestricted
• Weibull-unrestricted
Page 34 of 84
-------
General Model Options Used for Fertility and Fecundity Dichotomous Responses:
• Benchmark Response (BMR): 0.1 (10%) Extra Risk
• Confidence Level: 0.95
• Background: Estimated
Page 35 of 84
-------
4,4.1 P2/F2A Male Fertility (Males Unsuccessful/Males Used; Exxon Appendix AF)
mg/L Blood - 50 g Rat
N
Incidence
0
29
2
13.9
29
8
48.4
29
8
181.4
30
16
Summary of BMDS 3.1.1 Modeling Results for P2/F2A Male Rat Fertility (Exxon,
1991)
Table 4-5 Model Predictions for Reduced Male Fertility in P2/F2A Male Rats (Exxon, 1991)
Standard
Models
Restriction*
*
10% Extra Risk
(mg/L blood - 50 g
Rat)
P Value
AIC
BMDS
Recommend
s
BMDS Recommendation Notes
BMD
BMD
L
BMDU
Gamma
Restricted
28.82
54
18.06
77
106.50
62
0.221224
4
131.36474
26
Viable -
Alternate
Log-
Losistic*
Restricted
20.47
39
10.93
76
81.732
23
0.267407
3
130.87451
55
Recommend
ed
Basis: Lowest BMDL In a > 3-
Fold BMDL Range
Lowest AIC
Multistase
Desree 3
Restricted
28.82
54
18.06
78
109.51
57
0.221224
131.36474
26
Viable -
Alternate
Multistase
Desree 2
Restricted
28.82
54
18.06
75
91.607
10
0.221224
1
131.36474
26
Viable -
Alternate
Multistase
Desree 1
Restricted
28.82
53
18.06
76
56.969
40
0.221223
8
131.36474
26
Viable -
Alternate
Weibull
Restricted
28.82
54
18.06
76
115.14
04
0.221223
9
131.36474
26
Viable -
Alternate
Dichotom
ous Hill
Unrestricted
4.245
66
0.000
24
41.015
37
0.309315
6
131.38255
36
Questionable
BMD/BMDL ratio > 20
BMD/BMDL ratio > 3
BMD 3x lower than lowest non-zero
dose
BMDL lOx lower than lowest non-
zero dose
Losistic
NA
51.42
08
38.19
85
79.828
21
0.162073
5
132.33267
84
Viable -
Alternate
Los-Probit
Unrestricted
4.642
11
0.000
37
37.710
69
0.294224
6
131.45311
68
Questionable
BMD/BMDL ratio > 20
BMD/BMDL ratio > 3
BMD 3x lower than lowest non-zero
dose
BMDL lOx lower than lowest non-
zero dose
Probit
NA
48.86
14
36.41
63
77.278
41
0.166761
4
132.24053
29
Viable -
Alternate
*Selected Model (Green); residuals for doses 0, 13.9, 48.4, and 181.4 were -0.811610042, 1.353899534, -0.296031585 and -0.242023672, respectively.
"Restrictions defined in the BMDS 3.1.1 User Guide: NA = Not Applicable
Page 36 of 84
-------
1
0.9
0.8
0.7
0.6
I 0.5
(D
al
BMDS 3.1.1 Standard Model Plots for P2/F2A Male Rat Fertility
(Males Unsuccessful/Males Used) vs NMP Blood Concentration - 50 g
Rat (Exxon, 1991, Appendix AF)
(
50
100
Dose
150
¦ Frequentist Gamma Estimated
Probability
¦ Frequentist Log-Logistic Estimated
Probability
Frequentist Multistage Degree 3
Estimated Probability
• Frequentist Multistage Degree 2
Estimated Probability
¦ Frequentist Multistage Degree 1
Estimated Probability
¦ Frequentist Weibull Estimated
Probability
¦ Frequentist Dichotomous Hill
Estimated Probability
¦ Frequentist Logistic Estimated
Probability
¦ Frequentist Log-Probit Estimated
Probability
¦ Frequentist Probit Estimated
Probability
Page 37 of 84
-------
Selected Model - Log-Logistic (Restricted) - Extra Risk, BMR = 0.1
User Input
Info
Model
Log-Logistic vl.O
Dataset Name
P2F2A Male Fertility
User notes
[Add user notes here]
Model
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Backgroun
d
Estimated
Model
Data
Dependent
Variable
[Dosel
Independen
t Variable
[Incidence!
Total # of
Observatio
ns
4
Model Results
Benchmark Dose
BMD
20.4738478
BMDL
10.93759459
BMDU
81.7322316
AIC
130.8745155
P-value
0.267407255
D.O.F.
2
Chi2
2.637964966
Model Parameters
# of Parameters
3
Variable
Estimate
£
0.117496501
a
-5.216372932
b
Bounded
Goodness of Fit
Dose
Estimated Probability
Expected
Observed
Size
Scaled
Residual
0
0.117496501
3.407398541
2
29
-0.81161
13.9
0.17939856
5.202558252
8
29
1.3538995
48.4
0.301079065
8.731292894
8
29
-0.296032
181.4
0.555291468
16.65874405
16
30
-0.242024
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-62.1675397
4
.
.
.
Fitted Model
-63.43725776
2
2.53943612
2
0.2809108
Reduced Model
-70.51432209
1
16.6935648
3
0.0008171
Page 38 of 84
-------
P2/F2A Male Rat Fertility (Males Unsuccessful/Males Used) vs NMP
Blood Concentration - 50 g Rat (Exxon, 1991; Appendix AF) - Log-
Logistic Model with BMR of 10% Extra Risk for the BMD and 0.95
Lower Confidence Limit for the BMDL
0.9
0.8
Estimated Probability
^^Response at BMD
O Data
BMD
BMDL
Page 39 of 84
-------
4.4.2 P2/F2B Male Fertility (Males Unsuccessful/Males Used; Exxon Appendix AG)
mg/L Blood - 50 g Rat
N
Incidence
0
30
5
13.9
29
9
48.4
30
12
181.4
29
19
Summary of BMDS 3.1.1 Modeling Results for P2/F2B Male Rat Fertility (Exxon,
1991)
Table 4-6 Model Predictions for Reduced Male Fertility in P2/F2B Male Rats (Exxon, 1991)
Standard
Models
Restriction*
*
10% Extra Risk
(mg/L blood - 50 g
Rat)
P Value
AIC
BMDS
Recommend
s
BMDS Recommendation Notes
BMD
BMD
L
BMDU
Gamma
Restricted
21.46
13
13.74
89
76.520
64
0.666630
6
145.51839
72
Viable -
Alternate
Log-
Losistic*
Restricted
14.21
25
7.638
24
65.118
25
0.824828
3
145.08067
89
Recommend
ed
Basis: Lowest BMDL In a > 3-
Fold BMDL Range
Lowest AIC
Multistase
Desree 3
Restricted
21.46
13
13.74
89
87.342
37
0.666630
6
145.51839
72
Viable -
Alternate
Multistase
Desree 2
Restricted
21.46
13
13.74
87
75.005
23
0.666630
9
145.51839
72
Viable -
Alternate
Multistase
Desree 1
Restricted
21.46
13
13.74
88
40.467
12
0.666630
6
145.51839
72
Viable -
Alternate
Weibull
Restricted
21.46
13
13.74
89
80.304
69
0.666630
6
145.51839
72
Viable -
Alternate
Dichotom
ous Hill
Unrestricted
8.677
17
0.171
04
60.827
28
0.656447
9
146.89849
18
Questionable
BMD/BMDL ratio > 20
BMDL lOx lower than lowest non-
zero dose
Losistic
NA
36.72
71
27.09
45
56.560
66
0.442632
1
146.39715
35
Viable -
Alternate
Los-Probit
Unrestricted
9.269
62
0.241
78
59.565
93
0.616103
1
146.95220
17
Questionable
BMD/BMDL ratio > 20
BMDL lOx lower than lowest non-
zero dose
Probit
NA
35.70
14
26.71
57
55.327
79
0.453368
9
146.34376
72
Viable -
Alternate
*Selected Model (Green); residuals for doses 0, 13.9, 48.4 and 181.4 were -0.300662226, 0.518709072, -0.122358174 and -0.103594189, respectively.
"Restrictions defined in the BMDS 3.1.1 User Guide: NA = Not Applicable
Page 40 of 84
-------
BMDS 3.1.1 Standard Model Plots for P2/F2B Male Rat Fertility
(Males Unsuccessful/Males Used; Appendix AG) vs NMP Blood
Concentration - 50 g Rat (Exxon, 1991)
100
Dose
• Frequentist Gamma Estimated
Probability
• Frequentist Log-Logistic Estimated
Probability
Frequentist Multistage Degree 3
Estimated Probability
• Frequentist Multistage Degree 2
Estimated Probability
• Frequentist Multistage Degree 1
Estimated Probability
¦ Frequentist Weibull Estimated
Probability
• Frequentist Dichotomous Hill
Estimated Probability
¦ Frequentist Logistic Estimated
Probability
¦ Frequentist Log-Probit Estimated
Probability
• Frequentist Probit Estimated
Probability
Page 41 of 84
-------
User Input
Selected Model - Log-Logistic (Restricted) - Extra Risk, BMR = 0.1
Info
Model
Log-Logistic vl.O
Dataset Name
P2F2B Male Fertility
User notes
[Add user notes here]
Model
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Backgroun
d
Estimated
Model
Data
Dependent
Variable
[Dosel
Independen
t Variable
rincidencel
Total # of
Observatio
ns
4
Model Results
Benchmark Dose
BMD
14.21245366
BMDL
7.638241538
BMDU
65.11824629
AIC
145.0806789
P-value
0.824828266
D.O.F.
2
Chi2
0.385160154
Model Parameters
# of Parameters
3
Variable
Estimate
£
0.188119322
a
-4.851343176
b
Bounded
Goodness of Fit
Dose
Estimated Probability
Expected
Observed
Size
Scaled
Residual
0
0.188119322
5.643579645
5
30
-0.300662
13.9
0.267697459
7.763226311
9
29
0.5187091
48.4
0.410991312
12.32973936
12
30
-0.122358
181.4
0.664257058
19.26345469
19
29
-0.103594
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-70.35048621
4
.
.
.
Fitted Model
-70.54033943
2
0.37970644
2
0.8270805
Reduced Model
-78.43743444
1
16.1738965
3
0.0010446
Page 42 of 84
-------
P2/F2B Male Rat Fertility (Males Unsuccessful/Males Used) vs NMP
Blood Concentration - 50 g Rat (Exxon, 1991, Appendix AG) - Log-
Logistic Model with BMR of 10% Extra Risk for the BMD and 0.95
Lower Confidence Limit for the BMDL
0.9
Estimated Probability
BMDL
Page 43 of 84
-------
4.4.3 P2/F2A Female Fecundity (Females Unsuccessful/Females Mated; Exxon Appendix
AF)
mg/L Blood - 50 g Rat
N
Incidence
0
29*
2
13.9
29**
6
48.4
28
7
181.4
23
9
* Includes 1 presumed mating (JAB 149 with JAB273) that was not "Confirmed" but resulted in pregnancy of JAB273
** Includes 1 presumed mating (JAB008 with JAB 105) that was not "Confirmed" but resulted in pregnancy of JAB 105
Summary of BMDS 3.1.1 Modeling Results for P2/F2A Female Rat Fecundity (Exxon,
1991)
Table 4-7 Model Predictions for Reduced Fecundity in P2/F2A Female Rats (Exxon, 1991)
Standard
Models
Restriction*
*
10% Extra Risk
(mg/L blood - 50 g
Rat)
P Value
AIC
BMDS
Recommend
s
BMDS Recommendation Notes
BMD
BMD
L
BMDU
Gamma
Restricted
44.96
90
24.27
97
166.87
43
0.410732
8
112.25409
63
Viable -
Alternate
Log-
Losistic*
Restricted
35.85
00
16.70
86
178.83
94
0.464483
7
111.95596
85
Recommend
ed
Basis: Lowest AIC
Multistase
Desree 3
Restricted
44.96
9
24.27
93
152.75
87
0.410732
9
112.25409
63
Viable -
Alternate
Multistase
Desree 2
Restricted
44.96
90
24.27
97
145.56
55
0.410732
8
112.25409
63
Viable -
Alternate
Multistase
Desree 1
Restricted
44.96
90
24.27
94
139.99
63
0.410732
9
112.25409
63
Viable -
Alternate
Weibull
Restricted
44.96
90
24.27
97
176.62
68
0.410732
8
112.25409
63
Viable -
Alternate
Dichotom
ous Hill
Unrestricted
6.584
76
0
78.866
85
NA
114.50099
14
Unusable
BMD computation failed; lower
limit includes 0 BMDL not
estimated
d.f.=0 (Goodness of fit test cannot
be calculated)
Losistic
NA
72.81
42
49.22
49
179.07
43
0.311254
6
112.97438
42
Viable -
Alternate
Los-Probit
Unrestricted
7.047
68
0
74.365
06
0.736000
8
112.51903
46
Unusable
BMD computation failed; lower
limit includes 0 BMDL not
estimated
Probit
NA
69.29
99
46.38
35
174.67
04
0.320756
4
112.89541
63
Viable -
Alternate
*Selected Model (Green); residuals for doses 0, 13.9, 48.4 and 181.4 were -0.754747582, 0.857664083, 0.263750831 and -0.398574381, respectively.
"Restrictions defined in the BMDS 3.1.1 User Guide: NA = Not Applicable
Page 44 of 84
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
BMDS 3.1.1 Standard Model Plots for P2/F2A Female Rat Fecundity
(Females Unsuccessful/Females Mated) vs NMP Blood Concentration
- 50 gRat (Exxon, 1991, Appendix AF)
0.9
0.8
0.7
0.6
• Frequentist Gamma Estimated
Probability
• Frequentist Log-Logistic Estimated
Probability
Frequentist Multistage Degree 3
Estimated Probability
• Frequentist Multistage Degree 2
Estimated Probability
• Frequentist Multistage Degree 1
Estimated Probability
¦ Frequentist Weibull Estimated
Probability
• Frequentist Dichotomous Hill
Estimated Probability
¦ Frequentist Logistic Estimated
Probability
¦ Frequentist Log-Probit Estimated
Probability
• Frequentist Probit Estimated
Probability
50
100
Dose
150
O Data
This document is a draft for review purposes only and does not constitute Agency policy.
45
DRAFT-DO NOT CITE OR QUOTE
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
Selected Model - Log-Logistic - Extra Risk, BMR = 0.1
User Input
Info
Model
Log-Logistic vl.O
Dataset Name
P2F2A Female Fecundity
User notes
[Add user notes here]
Model
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Backgroun
d
Estimated
Model
Data
Dependent
Variable
mg/L Blood 50 g Rat
Independen
t Variable
Females LTnsuccessfiil
Total # of
Observatio
ns
4
Model Results
Benchmark Dose
BMD
35.85003887
BMDL
16.70857886
BMDU
178.8394143
AIC
111.9559685
P-value
0.464483699
D.O.F.
2
Chi2
1.53365763
Model Parameters
# of Parameters
3
Variable
Estimate
g
0.11340654
a
-5.776569229
b
Bounded
Goodness of Fit
Dose
Estimated Probability
Expected
Observed
Size
Scaled
Residual
0
0.11340654
3.288789653
2
29
-0.754748
13.9
0.150024089
4.350698589
6
29
0.8576641
48.4
0.22905425
6.41351901
7
28
0.2637508
181.4
0.432477945
9.946992746
9
23
-0.398574
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-53.20227182
4
Fitted Model
-53.97798425
2
1.55142486
2
0.4603757
Reduced Model
-57.45827043
1
8.51199723
3
0.0365346
This document is a draft for review purposes only and does not constitute Agency policy.
46
DRAFT-DO NOT CITE OR QUOTE
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
P2/F2A Female Rat Fecundity (Females Unsuccessful/Females Mated)
vs NMP Blood Concentration - 50 g Rat (Exxon, 1991, Appendix AF) -
Log-Logistic Model with BMR of 10% Extra Risk for the BMD and 0.95
Lower Confidence Limit for the BMDL
0.9
0.8
0.7
Estimated Probability
^^Response at BMD
O Data
BMD
BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
47
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
4.4.4 P2/F2B Female Fecundity (Females Unsuccessful/Females Mated; Exxon Appendix
AG)
mg/L Blood - 50 g Rat
N
Incidence
0
27
2
13.9
29*
9
48.4
28
10
181.4
21**
11
* Includes 2 presumed matings (JAB194 with JAB279; JAB201 with JAB293) not "Confirmed" but resulting in
pregnancies
** Includes 1 presumed mating (JAB022 with JAB 134) that was not "Confirmed" but resulted in pregnancy of JAB 134
Summary of BMDS 3.1.1 Modeling Results for P2/F2B Female Rat Fecundity (Exxon,
1991)
Table 4-8 Model Predictions for Reduced Fecundity in P2/F2B Female Rats (Exxon, 1991)
Standard
Models
Restriction*
*
10% Extra Risk
(mg/L blood - 50 g
Rat)
P Value
AIC
BMDS
Recommend
s
BMDS Recommendation Notes
BMD
BMD
L
BMDU
Gamma
Restricted
27.75
96
15.94
81
82.142
00
0.134929
9
123.98854
15
Viable -
Alternate
Log-
Losistic*
Restricted
17.45
28
8.395
86
58.448
82
0.192512
3
123.02937
23
Recommend
ed
Basis: Lowest AIC
Multistase
Desree 3
Restricted
27.75
98
15.94
82
97.117
40
0.134930
6
123.98854
15
Viable -
Alternate
Multistase
Desree 2
Restricted
27.75
98
15.94
82
87.010
75
0.134930
6
123.98854
15
Viable -
Alternate
Multistase
Desree 1
Restricted
27.76
19
15.94
83
68.871
17
0.134946
123.98854
16
Viable -
Alternate
Weibull
Restricted
27.76
00
15.94
83
84.747
89
0.134931
8
123.98854
15
Viable -
Alternate
Dichotom
ous Hill
Unrestricted
1.071
72
0
18.132
80
NA
123.92613
36
Unusable
BMD computation failed; lower
limit includes 0
BMDL not estimated
BMD lOx lower than lowest non-
zero dose
d.f.=0 (Goodness of fit test cannot
be calculated)
Losistic
NA
49.48
25
34.00
90
100.18
99
0.089017
8
125.22780
17
Questionable
Goodness of fit p-value <0.1
Los-Probit
Unrestricted
1.359
20
0
18.120
44
0.660457
3
121.93944
43
Unusable
BMD computation failed; lower
limit includes 0
BMDL not estimated
BMD lOx lower than lowest non-
zero dose
Probit
NA
47.44
59
32.80
38
97.343
69
0.091838
3
125.13199
18
Questionable
Goodness of fit p-value <0.1
*Selected Model (Green); residuals for doses 0, 13.9, 48.4 and 181.4 were -0.976071189, 1.341257654, 0.170425804 and -0.717257235, respectively.
"Restrictions defined in the BMDS 3.1.1 User Guide: NA = Not Applicable
This document is a draft for review purposes only and does not constitute Agency policy.
48
DRAFT-DO NOT CITE OR QUOTE
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
BMDS 3.1.1 Standard Model Plots for P2/F2B Female Rat Fecundity
(Females Unsuccessful/Females Mated) vs NMP Blood Concentration
- 50 gRat (Exxon, 1991, Appendix AG)
0.9
0.8
0.7
• Frequentist Gamma Estimated
Probability
¦ Frequentist Log-Logistic Estimated
Probability
Frequentist Multistage Degree 3
Estimated Probability
¦ Frequentist Multistage Degree 2
Estimated Probability
¦ Frequentist Multistage Degree 1
Estimated Probability
¦ Frequentist Weibull Estimated
Probability
¦ Frequentist Dichotomous Hill
Estimated Probability
¦ Frequentist Logistic Estimated
Probability
¦ Frequentist Log-Probit Estimated
Probability
¦ Frequentist Probit Estimated
Probability
O Data
100
Dose
This document is a draft for review purposes only and does not constitute Agency policy.
49
DRAFT-DO NOT CITE OR QUOTE
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
Selected Model - Log-Logistic (Restricted) - Extra Risk, BMR = 0.1
User Input
Info
Model
Log-Logistic vl.O
Dataset Name
P2F2B Female Fecundity
User notes
[Add user notes here]
Model
Options
Risk Type
Extra Risk
BMR
0.1
Confidence
Level
0.95
Background
Estimated
Model Data
Dependent
Variable
[Dose]
Independent
Variable
[Incidence]
Total # of
Observation
s
4
Model Results
Benchmark Dose
BMD
17.45276136
BMDL
8.395858147
BMDU
58.44881649
AIC
123.0293723
P-value
0.192512349
D.O.F.
2
Chi2
3.295189957
Model Parameters
# of Parameters
3
Variable
Estimate
8
0.139072629
a
-5.056722458
b
Bounded
Goodness of Fit
Dose
Estimated Probability
Expected
Observed
Size
Scaled
Residual
0
0.139072629
3.754960985
2
27
-0.976071
13.9
0.209064738
6.062877397
9
29
1.3412577
48.4
0.341865741
9.572240753
10
28
0.1704258
181.4
0.600472417
12.60992076
11
21
-0.717257
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-57.87277378
4
.
.
.
Fitted Model
-59.51468613
2
3.2838247
2
0.1936094
Reduced Model
-64.55874867
1
13.3719498
3
0.0038975
This document is a draft for review purposes only and does not constitute Agency policy.
50
DRAFT-DO NOT CITE OR QUOTE
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
P2/F2B Female Rat Fecundity (Females Unsuccessful/Females
Mated) vs NMP Blood Concentration - 50 g Rat (Exxon, 1991;
Appendix AG) - Log-Logistic Model with BMR of 10% Extra Risk
for the BMD and 0.95 Lower Confidence Limit for the BMDL
0.9
0.8
Estimated Probability
BMDL
This document is a draft for review purposes only and does not constitute Agency policy.
51
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
4.5 Results of BMD Modeling of P2 Litter (Exxon, 1991)
The next most sensitive dose-related reproductive effect noted in the Exxon (1991) study, other than the
reduction in male fertility and female fecundity, was the reduction in litter size, which was most
pronounced for the first (F2A) and 2nd (F2B) P2 rat litters. However, the Exxon (1991) study also
reported a dose-related increase in pup death by postnatal day 4 that was also most pronounced in the
F2A and F2B litters of the P2 parental rats. Thus, the extent to which the reduction in litter size is due to
reproductive effects on the parents or gestational effects on the fetus is not clear, and the Exxon (1991)
reproductive study design does not allow for a definitive investigation of that question (e.g., the number
of implantations and resorptions were not identified). For these reasons, the litter size reduction effect
was analyzed three ways (see Section 4.2 for PBPK modeling details):
1. Model litter size means and SD (live and stillborn pups) using BMDS continuous models
against estimates of internal doses to young (50 g) parental rats (Sections 4.5.1 and 4.5.2).
2. Model litter size means and SD (live and stillborn pups) using BMDS continuous models
against estimates of internal doses to P2 maternal rats during GD 6-21 (Sections 4.5.3 and
4.5.4).
3. Model pup death at day 0 (stillborn) and by postnatal day 4 per total pups born as incidence
data using BMDS nested dichotomous models against estimates of internal doses to P2
maternal rats during GD 6-21 (Section 4.6).
Individual litter data that allows for the calculation of dose-specific means and standard deviations for
litter size are available in Appendix AJ (for P2/F2A litters) and AK (for P2/FB litters) of the Exxon
( ) report.
Standard and nonstandard continuous models (defined below) were used to fit litter size data. BMDs
were estimated for 1 SD change from control mean. Internal doses used for BMD modeling were based
on PBPK estimates of average daily blood concentrations for young (50 g) rat and GD 6-21 dams.
Standard Continuous Models Applied to Litter Size Response:
• Exponential 2-restricted
• Exponential 3-restricted
• Exponential 4-restricted
• Exponential 5-restricted
• Hill-restricted
• Polynomial Degree 3-restricted
• Polynomial Degree 2-restricted
• Power-restricted
• Linear
Non-Standard Continuous Models Applied to Litter Size Response:
• Hill-unrestricted
• Polynomial Degree 3-unrestricted
This document is a draft for review purposes only and does not constitute Agency policy.
52
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
• Polynomial Degree 2-unrestricted
• Power-unrestricted
General Model Options Used for Litter Size Continuous Response:
• Benchmark Response (BMR): 1 Standard Deviation (SD) Change from Control Mean
• Confidence Level: 0.95
• Background: Estimated
This document is a draft for review purposes only and does not constitute Agency policy.
53
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
4.5.1 P2/F2A Litter Size - 50 g Rat (Exxon Appendix AJ, "
mg/L Blood - 50 g Rat
N
Mean
SD
0
27
15.2592593
3.558225
13.9
23
13.2608696
4.937955
48.4
21
14.9047619
3.871754
181.4
14
11.6428571
3.272429
otal Pups Born")
Summary of BMDS 3.1.1 Modeling Results for P2/F2A Litter Size - 50 g Rat (Exxon,
1991)
Table 4-9 Model Predictions for Litter Size in P2/F2A Rats Based on Post-weaning Exposure
(Exxon, 1991)
Standard
Models
Restriction
**
BMR = 1 Standard
Deviation (mg/L blood
- 50 g Rat)
P Value
AIC
BMDS
Recommend
s
BMDS Recommendation Notes
BMD
BMD
L
BMDU
Exponential
2 (CV)
Restricted
264.2
77
140.4
44
1032.8
40
0.131786
1
483.41059
57
Viable -
Alternate
BMD higher than maximum dose
Exponential
3 (CV)
Restricted
190.0
60
149.0
59
788.76
70
0.062595
5
484.82469
12
Questionable
Goodness of fit p-value <0.1
BMD higher than maximum dose
Exponential
4 (CV)
Restricted
264.1
20
140.4
42
1032.8
35
0.131786
5
483.41059
02
Viable -
Alternate
BMD higher than maximum dose
Exponential
5 (CV)
Restricted
190.1
71
149.0
60
788.74
98
NA
486.82469
61
Questionable
BMD higher than maximum dose
d.f.=0 (Goodness of fit test cannot
be calculated)
Hill (CV)
Restricted
-9999
0
Infinity
0.062597
7
484.82463
33
Unusable
BMD computation failed
BMD not estimated
BMDL not estimated
Goodness of fit p-value <0.1
Polynomial
Degree 3
(CV)
Restricted
202.6
96
150.6
74
714.95
64
0.171851
8
482.87969
17
Recommend
ed
Basis: Lowest AIC
BMD higher than maximum dose
Polynomial
Desree 2
(CV)
Restricted
214.0
35
148.9
14
757.40
27
0.160527
3
483.01602
8
Viable -
Alternate
BMD higher than maximum dose
Power (CV)
Restricted
183.7
83
182.1
12
698.81
91
0.062598
3
484.82461
5
Questionable
Goodness of fit p-value <0.1
BMD higher than maximum dose
BMDL higher than maximum dose
Linear (CV)
NA
248.9
15
145.0
61
875.68
12
0.136434
3
483.34127
Viable -
Alternate
BMD higher than maximum dose
*Selected Model (Green); Constant variance case presented (Test 2 p-value = 0.24158); scaled residuals for doses 0, 13.9, 48.4 and 181.4 were 0.958706516,
-1.509731959. 0.501737513 and -0.010801354. respectively.
"Restrictions defined in the BMDS 3.1.1 User Guide; NA = Not Applicable; CV = Constant Variance Model; NCV = Non-Constant Variance Model
This document is a draft for review purposes only and does not constitute Agency policy.
54
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
18
BMDS 3.1.1 Standard Model Plots for P2/F2A Litter Size (Exxon,
1991; Appendix AJ, "Total Pups Born") vs NMP Blood Concentration-
50 g Rat
16
o T
14
12
<1) 10
to
C
o
Q.
to
OJ o
Cd 8
o
o
50
100
Dose
150
• Frequentist Exponential Degree 2
Estimated Probability
¦ Frequentist Exponential Degree 3
Estimated Probability
Frequentist Exponential Degree 4
Estimated Probability
• Frequentist Exponential Degree 5
Estimated Probability
¦ Frequentist Hill Estimated Probability
• Frequentist Polynomial Degree 3
Estimated Probability
• Frequentist Polynomial Degree 2
Estimated Probability
• Frequentist Power Estimated
Probability
• Frequentist Linear Estimated
Probability
O Data
This document is a draft for review purposes only and does not constitute Agency policy.
55
DRAFT-DO NOT CITE OR QUOTE
-------
Selected Model - Polynomial Degree 3 (Restricted) - Extra Risk,
User Input
N-Methylpyrrolidone (NMP) Benchmark Dose Report
BMR = 1 SD
Info
Model
Dataset Name
User notes
Dose-Response
Model
Polynomial degree 3 vl. 1
P2F2 A Litter Size
[Add user notes here]
M[dose] = g + bl*dose + b2*doseA2
+ ...
Model
Options
BMR Type
BMRF
Tail
Probability
Confidence
Level
Distribution
ISES
Std. Dev.
0.95
Normal
Model Data
Dependent
Variable
Independent
Variable
Total # of
Observations
Adverse
Direction
|Dose]
[Response]
85
Automatic
Model Results
Benchmark Dose
BMD
202.6960934
BMDL
150.6744181
BMDU
714.956421
AIC
482.8796917
Test 4 P-value
0.171851757
D.O.F.
2
Model Parameters
# of Parameters
5
Variable
Estimate
g
14.52128961
bl
Bounded
b2
Bounded
b3
-4.80285E-07
alpha
15.99813687
Goodness of Fit
Dose
Size
Estimated
Median
Calc'd
Median
Observed
Mean
Estimated
SD
Calc'd SD
Observed
SD
Scaled
Residual
0
27
14.52128961
15.2592593
15.2592593
3.9997671
3.558225
3.558225
0.958706516
13.9
23
14.51999975
13.2608696
13.2608696
3.9997671
4.937955
4.937955
1.509731959
48.4
21
14.466835
14.9047619
14.9047619
3.9997671
3.871754
3.871754
0.501737513
181.4
14
11.6544036
11.6428571
11.6428571
3.9997671
3.272429
3.272429
-0.01080135
Likelihoods of Interest
Model
Log Likelihood*
# of Parameters
AIC
A1
-236.6787228
5
483.357446
A2
-234.583299
8
485.166598
A3
-236.6787228
5
483.357446
fitted
-238.4398459
3
482.879692
R
-241.3113542
2
486.622708
Tests of Interest
Test
-2 *Log(Likelihood
Ratio)
Test df
p-value
1
13.45611034
6
0.03633832
2
4.190847665
3
0.24157981
3
4.190847665
3
0.24157981
4
3.522246101
2
0.17185176
This document is a draft for review purposes only and does not constitute Agency policy.
56
DRAFT-DO NOT CITE OR QUOTE
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
18
P2/F2A Litter Size (Exxon, 1991; Appendix AJ, "Total Pups Born") vs
NMP Blood Concentration-50 g Rat - Polynomial Degree 3 Model with
BMR of 1 Std. Dev. for the BMD and 0.95 Lower Confidence Limit for
the BMDL
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
4.5.2 P2/F2B Litter Size - 50 g Rat (Exxon Appendix AK, "Total Pups Born")
mg/L Blood - 50 g Rat
N
Mean
SD
0
25
15.24
2.947881
13.9
20
14.35
3.422449
48.4
18
14.39
3.972536
181.4
9
11
3.708099
Summary of BMDS 3.1.1 Modeling Results for P2/F2B Litter Size - 50 g Rat (Exxon,
1991)
Table 4-10 Model Predictions for Litter Size in P2/F2B Rats Based on Post-weaning Exposure
(Exxon, 1991)
Standard
Models
Restriction*
*
BMR = 1 Standard
Deviation (mg/L blood
- 50 g Rat)
P Value
AIC
BMDS
Recommend
s
BMDS Recommendation Notes
BMD
BMD
L
BMDU
ExDoncnti
al 2 (CV)
Restricted
151.2
11
90.01
44
358.88
07
0.710819
6
385.22188
7
Viable -
Alternate
ExDoncnti
al 3 (CV)
Restricted
156.9
52
90.56
26
352.68
54
0.435551
2
387.14718
89
Viable -
Alternate
ExDoncnti
al 4 (CV)
Restricted
151.1
78
90.01
45
358.86
85
0.710823
3
385.22187
65
Viable -
Alternate
ExDoncnti
al 5 (CV)
Restricted
156.9
62
50.81
64
352.69
1
NA
389.14720
32
Viable -
Alternate
BMD/BMDL ratio > 3
d.f.=0 (Goodness of fit test cannot
be calculated)
Hill (CV)
Restricted
79.46
42
51.86
12
Infinity
NA
389.31785
9
Questionable
d.f.=0 (Goodness of fit test cannot
be calculated)
Polvnoinia
1 Desree 3
(CV)
Restricted
162.7
87
100.2
64
324.54
83
0.478185
6
387.04221
2
Viable -
Alternate
Polvnoinia
1 Desree 2
(CV)
Restricted
159.7
31
100.1
02
326.25
31
0.467703
9
387.06660
93
Viable -
Alternate
Power
(CV)
Restricted
157.0
00
99.76
30
329.89
51
0.446602
9
387.11847
29
Viable -
Alternate
Linear
(CV)
NA
153.2
31
99.61
58
331.51
77
0.740097
5
385.14116
03
Recommend
ed
Basis: Lowest AIC
*Selected Model (Green); Constant variance case presented (Test 2 p-value = 0.60824); scaled residuals for doses 0, 13.9, 48.4 and 181.4 were 0.209483207,
-0.589116734. 0.445351928 and -0.100787718. respectively.
"Restrictions defined in the BMDS 3.1.1 User Guide; NA = Not Applicable; CV = Constant Variance Model; NCV = Non-Constant Variance Model
This document is a draft for review purposes only and does not constitute Agency policy.
58
DRAFT-DO NOT CITE OR QUOTE
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
18
BMDS 3.1.1 Standard Model Plots for P2/F2B Litter Size (Exxon,
1991; Appendix AK, "Total Pups Born") vs NMP Blood
Concentration-50g Rat
16
10
£
O
Q.
LO
CD
DC
• Frequentist Exponential Degree 2
Estimated Probability
¦ Frequentist Exponential Degree 3
Estimated Probability
Frequentist Exponential Degree 4
Estimated Probability
• Frequentist Exponential Degree 5
Estimated Probability
¦ Frequentist Hill Estimated Probability
• Frequentist Polynomial Degree 3
Estimated Probability
• Frequentist Polynomial Degree 2
Estimated Probability
• Frequentist Power Estimated
Probability
• Frequentist Linear Estimated
Probability
O Data
50
100
Dose
150
This document is a draft for review purposes only and does not constitute Agency policy.
59
DRAFT-DO NOT CITE OR QUOTE
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
Selected Model - Linear - Extra Risk, BMR = 1 SD
User Input
Info
Model
Dataset Name
User notes
Dose-Response
Model
Linear vl. 1
P2F2B Litter Size
[Add user notes here]
M[dose] = g + bl*dose
Model
Options
BMR Type
Std. Dev.
BMRF
1
Tail
Probability
-
Confidence
Level
0.95
Distribution
Type
Normal
Model Data
Dependent
Variable
[Dose]
Independent
Variable
[Response]
Total # of
Observations
72
Adverse
Direction
Automatic
Model Results
Benchmark Dose
BMD
153.2308251
BMDL
99.6158179
BMDU
331.5176516
AIC
385.1411603
Test 4 P-value
0.740097541
D.O.F.
2
Model Parameters
# of Parameters
3
Variable
Estimate
g
15.09893919
betal
-0.02197258
alpha
11.33585663
Goodness of Fit
Dose
Size
Estimated
Median
Calc'd
Median
Observed
Mean
Estimated
SD
Calc'd SD
Observed
SD
Scaled
Residual
0
25
15.09893919
15.24
15.24
3.36687639
2.947881
2.947881
0.209483207
13.9
20
14.79352033
14.35
14.35
3.36687639
3.422449
3.422449
-0.58911673
48.4
18
14.03546634
14.3888889
14.3888889
3.36687639
3.972536
3.972536
0.445351928
181.4
9
11.11311326
11
11
3.36687639
3.708099
3.708099
-0.10078772
Likelihoods of Interest
Model
Log Likelihood*
# of Parameters
AIC
A1
-189.2696069
5
388.539214
A2
-188.354168
8
392.708336
A3
-189.2696069
5
388.539214
fitted
-189.5705801
3
385.14116
R
-194.2508792
2
392.501758
Tests of Interest
Test
-2 *Log(Likelihood
Ratio)
Test df
p-value
1
11.79342232
6
0.06673919
2
1.830877708
3
0.60823876
3
1.830877708
3
0.60823876
4
0.601946577
2
0.74009754
This document is a draft for review purposes only and does not constitute Agency policy.
60
DRAFT-DO NOT CITE OR QUOTE
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
18
P2/F2B Litter Size (Exxon, 1991; Appendix AK, "Total Pups Born")
vs NMP Blood Concentration-50 g Rat - Linear Model with BMR of 1
Std. Dev. for the BMD and 0.95 Lower Confidence Limit for the
BMDL
16
12
d) 10
LO
£
O
Q.
LO
CD
R
c
5 {
Estimated Probability
^^Response at BMD
O Data
BMD
BMDL
20
40
60
80
100
120
140
160
180
Dose
This document is a draft for review purposes only and does not constitute Agency policy.
61
DRAFT-DO NOT CITE OR QUOTE
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
4.5.3 P2/F2A Litter Size - GD 6-21 Rat (Exxon Appendix A J, "Total Pu
mg/L Blood - GD 6-21
SD
Rat
N
Mean
15.259259
0
27
3
3.558225
13.260869
26.1207
23
6
4.937955
14.904761
92.5466
21
9
3.871754
11.642857
326.1056
14
1
3.272429
js Born")
Summary of BMDS 3.1.1 Modeling Results for P2/F2A Litter Size - GD 6-21 Rat (Exxon,
1991)
Table 4-11 Model Predictions for Litter Size in P2/F2A Rats Based on Gestational Exposure
(Exxon, 1991)
Standard
Models
Restriction*
*
BMR = 1 Standard
Deviation
(mg/L Blood - GD 6-
21 Rat)
P Value
AIC
BMDS
Recommend
s
BMDS Recommendation Notes
BMD
BMD
L
BMDU
ExDoncnti
al 2 (CV)
Restricted
479.8
77
254.4
30
1919.1
52
0.126001
7
483.50036
47
Viable -
Alternate
BMD higher than maximum dose
ExDoncnti
al 3 (CV)
Restricted
341.0
70
272.8
16
1398.6
51
0.062593
9
484.82473
34
Questionable
Goodness of fit p-value <0.1
BMD higher than maximum dose
ExDoncnti
al 4 (CV)
Restricted
479.8
45
254.4
27
1919.0
11
0.041809
485.50036
47
Viable -
Alternate
Goodness of fit p-value <0.1
BMD higher than maximum dose
ExDoncnti
al 5 (CV)
Restricted
335.9
07
105.7
78
369.62
51
NA
486.82461
64
Questionable
BMD/BMDL ratio > 3
BMD higher than maximum dose
d.f.=0 (Goodness of fit test cannot
be calculated)
Hill (CV)
Restricted
-9999
0
Infinity
NA
486.82461
56
Unusable
BMD computation failed
BMD not estimated
BMDL not estimated
d.f.=0 (Goodness of fit test cannot
be calculated)
Polvnomi
al Degree
3 (CV)
Restricted
364.3
94
273.7
96
1275.7
35
0.170808
482.89187
58
Recommend
ed
Basis: Lowest AIC
BMD higher than maximum dose
Polvnomia
1 Desree 2
(CV)
Restricted
384.9
61
270.0
21
1364.6
28
0.157874
4
483.04935
69
Viable -
Alternate
BMD higher than maximum dose
Power
(CV)
Restricted
329.9
08
275.4
82
1240.3
89
0.062598
3
484.82461
5
Questionable
Goodness of fit p-value <0.1
BMD higher than maximum dose
Linear
(CV)
NA
450.8
59
261.8
83
1618.6
56
0.130882
7
483.42435
33
Viable -
Alternate
BMD higher than maximum dose
*Selected Model (Green); Constant variance case presented (Test 2 p-value = 0.24158); scaled residuals for dosesO, 26.1207, 92.5466 and 326.1056were
0.954993534. -1.512767309. 0.511175014 and -0.013313118. respectively.
"Restrictions defined in the BMDS 3.1.1 User Guide; NA = Not Applicable; CV = Constant Variance Model; NCV = Non-Constant Variance Model
This document is a draft for review purposes only and does not constitute Agency policy.
62
DRAFT-DO NOT CITE OR QUOTE
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
18
BMDS 3.1.1 Standard Model Plots for P2/F2A Litter Size (Exxon, 1991;
Appendix AJ, "Total Pups Born") vs NMP Blood Concentration - GD 6-21
Rat
16
O
14
12
a) 10
C
o
Q.
to
(D
CC
O
O
¦ Frequentist Exponential Degree 2
Estimated Probability
• Frequentist Exponential Degree 3
Estimated Probability
Frequentist Exponential Degree 4
Estimated Probability
• Frequentist Exponential Degree 5
Estimated Probability
• Frequentist Hill Estimated Probability
• Frequentist Polynomial Degree 3
Estimated Probability
• Frequentist Polynomial Degree 2
Estimated Probability
• Frequentist Power Estimated
Probability
• Frequentist Linear Estimated
Probability
O Data
0 50
100
150
Dose
200
250
300
This document is a draft for review purposes only and does not constitute Agency policy.
63
DRAFT-DO NOT CITE OR QUOTE
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
Selected Model - Polynomial Degree 3 (Restricted) - Extra Risk, BMR = 1
User Input
Info
Model
Dataset Name
User notes
Dose-Response
Model
Polynomial degree 3 vl.l
P2F2A Litter Size GD 6-21
[Add user notes here]
M[dose] = g + bl*dose +
b2*doseA2+ ...
Model Options
BMR Type
Std. Dev.
BMRF
1
Tail Probability
-
Confidence Level
0.95
Distribution Type
Normal
Model Data
Dependent Variable
[Dose]
Independent
Variable
| Response |
Total # of
Observations
85
Adverse Direction
Automatic
Model Results
Benchmark Dose
BMD
364.3935627
BMDL
273.7956247
BMDU
1275.734624
AIC
482.8918758
Test 4 P-value
0.170808016
D.O.F.
2
Model Parameters
# of Parameters
5
Variable
Estimate
g
14.52409502
bl
Bounded
b2
Bounded
b3
alpha
-8.26711E-08
16.00042971
Goodness of Fit
Dose
Size
Estimated
Median
Calc'd Median
Observed
Mean
Estimated SD
Calc'd SD
Observed SD
Scaled
Residual
0
27
14.52409502
15.2592593
15.2592593
4.00005371
3.558225
3.558225
0.954993534
26.1207
23
14.52262166
13.2608696
13.2608696
4.00005371
4.937955
4.937955
-1.512767309
92.5466
21
14.45856578
14.9047619
14.9047619
4.00005371
3.871754
3.871754
0.511175014
326.1056
14
11.65708966
11.6428571
11.6428571
4.00005371
3.272429
3.272429
-0.013313118
Likelihoods of Interest
Model
Log Likelihood*
# of Parameters
AIC
A1
-236.6787228
5
483.357446
A2
-234.583299
8
485.166598
A3
-236.6787228
5
483.357446
fitted
-238.4459379
3
482.891876
R
-241.3113542
2
486.622708
Tests of Interest
Test
-2 *Log(Likelihood
Ratio)
Test df
p-value
1
13.45611034
6
0.03633832
2
4.190847665
3
0.24157981
3
4.190847665
3
0.24157981
4
3.534430134
2
0.17080802
This document is a draft for review purposes only and does not constitute Agency policy.
64
DRAFT-DO NOT CITE OR QUOTE
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
18
P2/F2A Litter Size (Exxon, 1991; Appendix AJ, "Total Pups
Born") vs NMP Blood Concentration- GD 6-21 Rat - Polynomial
Degree 3 Model with BMR of 1 Std. Dev. for the BMD and 0.95
Lower Confidence Limit for the BMDL
K 10
Estimated Probability
^^Response at BMD
O Data
BMD
BMDL
50
100
150
200
Dose
250
300
350
400
This document is a draft for review purposes only and does not constitute Agency policy.
65
DRAFT-DO NOT CITE OR QUOTE
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
4.5.4 P2/F2B Litter Size - GD 6-21 Rat (Exxon Appendix AK, "Total Pups Born")
mg/L Blood - GD 6-21
SD
Rat
N
Mean
0
25
15.24
2.947881
25.25
20
14.35
3.422449
89.03
18
14.39
3.972536
311.9
9
11
3.708099
Summary of BMDS 3.1.1 Modeling Results for P2/F2B Litter Size - GD 6-21 Rat (Exxon,
1991)
Table 4-12 Model Predictions for Litter Size in P2/F2B Rats Based on Gestational Exposure
(Exxon, 1991)
Standard
Models
Restriction
**
BMR = 1 Standard
Deviation
(mg/L Blood - GD 6-
21 Rat)
P Value
AIC
BMDS
Recommend
s
BMDS Recommendation Notes
BMD
BMD
L
BMDU
Exponential
2 (CV)
Restricted
262.3
67
156.2
09
625.51
00
0.682087
3
385.30440
9
Viable -
Alternate
Exponential
3 (CV)
Restricted
273.9
39
157.8
78
606.75
05
0.425303
6
387.17482
76
Viable -
Alternate
Exponential
4 (CV)
Restricted
262.3
75
156.2
08
625.49
80
0.682087
3
385.30440
9
Viable -
Alternate
Exponential
5 (CV)
Restricted
273.9
09
157.8
76
606.74
26
NA
389.17482
74
Questionable
d.f.=0 (Goodness of fit test cannot
be calculated)
Hill (CV)
Restricted
111.0
61
95.28
81
Infinity
NA
389.31790
07
Questionable
d.f.=0 (Goodness of fit test cannot
be calculated)
Polynomial
Desree 3
(CV)
Restricted
281.8
42
173.6
28
556.23
98
0.474588
5
387.05048
62
Viable -
Alternate
Polynomial
Desree 2
(CV)
Restricted
276.8
75
173.2
41
560.25
11
0.460642
8
387.08354
61
Viable -
Alternate
Power (CV)
Restricted
273.9
07
172.5
02
568.10
38
0.435155
4
387.14823
81
Viable -
Alternate
Linear
(CV)
NA
264.7
04
171.8
83
574.90
49
0.717494
385.20319
5
Recommend
ed
Basis: Lowest AIC
*Selected Model (Green); Constant variance case presented (Test 2 p-value = 0.60824); scaled residuals for selected model for doses 0, 25.25, 89.0333, and
311.8896 were 0.180266075. -0.593822034. 0.507945167 and -0.133410146. respectively.
"Restrictions defined in the BMDS 3.1.1 User Guide; NA = Not Applicable; CV = Constant Variance Model; NCV = Non-Constant Variance Model
This document is a draft for review purposes only and does not constitute Agency policy.
66
DRAFT-DO NOT CITE OR QUOTE
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
18
BMDS 3.1.1 Standard Model Plots for P2/F2B Litter Size (Exxon, 1991;
Appendix AK, "Total Pups Born") vs NMP Blood Concentration- GD 6-21
Rat
16
-------
N-Methylpyrrolidone (NMP) Benchmark Dose Report
Selected Model -Linear - Extra Risk, BMR = 1 SD
User Input
Info
Model
Dataset Name
User notes
Dose-Response
Model
Linear vl. 1
P2F2B Litter Size GD 6-21
[Add user notes here]
M[dose] = g + bl*dose
Model
Options
BMR Type
Std. Dev.
BMRF
1
Tail
Probability
-
Confidence
Level
0.95
Distribution
Type
Normal
Model Data
Dependent
Variable
Dos el
Independent
Variable
Responsel
Total # of
Observations
72
Adverse
Direction
Automatic
Model Results
Benchmark Dose
BMD
264.7037947
BMDL
171.8830314
BMDU
574.9048606
AIC
385.203195
Test 4 P-value
0.717494025
D.O.F.
2
Model Parameters
# of Parameters
3
Variable
Estimate
g
15.11856069
betal
-0.012724921
alpha
11.34568072
Goodness of Fit
Dose
Size
Estimated
Median
Calc'd
Median
Observed
Mean
Estimated
SD
Calc'd SD
Observed
SD
Scaled
Residual
0
25
15.11856069
15.24
15.24
3.36833501
2.947881
2.947881
0.180266075
25.25
20
14.79725643
14.35
14.35
3.36833501
3.422449
3.422449
-0.59382203
89.0333
18
13.98561894
14.3888889
14.3888889
3.36833501
3.972536
3.972536
0.507945167
311.8896
9
11.14979002
11
11
3.36833501
3.708099
3.708099
-0.13341015
Likelihoods of Interest
Model
Log Likelihood*
# of Parameters
AIC
A1
-189.2696069
5
388.539214
A2
-188.354168
8
392.708336
A3
-189.2696069
5
388.539214
fitted
-189.6015975
3
385.203195
R
-194.2508792
2
392.501758
Tests of Interest
Test
-2 *Log(Likelihood
Ratio)
Test df
p-value
1
11.79342232
6
0.06673919
2
1.830877708
3
0.60823876
3
1.830877708
3
0.60823876
4
0.663981316
2
0.71749403
This document is a draft for review purposes only and does not constitute Agency policy.
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
18
P2/F2B Litter Size (Exxon, 1991; Appendix AK, "Total Pups Born")
vs NMP Blood Concentration - GD 6-21 Rat - Linear Model with
BMR of 1 SD for the BMD and 0.95 Lower Confidence Limit for the
BMDL
16
12
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
4.6 Results of BMD Modeling of P2 Pup Death (Exxon, 1991)
Nested dichotomous models were applied to fit pup death for the P2/F2A and P2/F2B litters. Nested
dichotomous models are preferred for this endpoint because they contain an intra-litter correlation
coefficient for the assessment of litter-specific responses. Details regarding pup death at day 0 (stillborn)
and by day 4 are available in Appendix AJ (for P2/F2A litters) and AK (for P2/FB litters) of the Exxon
(1991) report.
The pup death endpoint was analyzed using BMDS 2.7 because it contains the larger suite of nested
dichotomous models. To assess intra-litter correlations (ILC) BMDS nested dichotomous models were
run two ways, with ILC coefficients estimated and with ILC coefficients assumed to be zero. Because
potential litter-specific covariates (LSCs) such as dam BW are affected by dose, LSCs were not assessed
in the BMDS nested dichotomous model runs. The following nested dichotomouse models and general
modeling options were used to the pup death incidence data.
Nested Dichotomous Models Applied to Pup Death Response5:
• NLogistic - Nested Logistic model with ILC coefficients assumed to be 0
• NLogistic-ILC - Nested Logistic model with ILC coefficients estimated
• NCTR - National Center for Toxicological Research model with ILC coefficients assumed to be
0
• NCTR-ILC - NCTR model with ILC coefficients estimated
• RaiVR - Rai and Van Ryzin model with ILC coefficients assumed to be 0
• RaiVR-ILC - Rai and Van Ryzin model with ILC coefficients estimated
General Model Options Used for Pup Death Nested Dichotomous Response:
• Benchmark Response (BMR): 10% (not shown in report), 5% and 1% Extra Risk
• Confidence Level: 0.95
• Background: Estimated
5 As indicated in the tables in 2.6, the NLogistic model is generally preferred because it has received the more extensive QA
testing, but the NCTR and RaiVR models are provided as alternative models.
This document is a draft for review purposes only and does not constitute Agency policy.
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
4,6.1 P2/F2A Pups Dead at Day 0 (Stillborn Day O/Total Pups Born; Exxon 1991
Appendix AJ)
Control
26.1207 avg. mg/L blood
GD6-21
92.5466 avg. mg/L blood
GD6-21
326.1056 avg. mg/L blood
GD6-21
Dam
N
Stillborn
Dam
N
Stillborn
Dam
N
Stillborn
Dam
N
Stillborn
JAB248
12
0
JAB02
9
17
0
JAB3
02
15
0
JAB3
25
13
0
JAB026
16
0
JAB03
2
17
0
JAB0
38
14
1
JAB3
27
12
0
JAB251
14
0
JAB27
9
14
2
JAB1
10
15
0
JAB0
41
13
8
JAB097
15
0
JAB 10
4
13
1
JAB3
05
16
1
JAB1
35
7
0
JAB254
9
0
JAB28
2
13
0
JAB1
13
20
1
JAB1
36
4
0
JAB 100
18
2
JAB28
5
16
1
JAB1
16
22
1
JAB0
45
14
0
JAB257
17
1
JAB28
8
17
0
JAB3
11
16
0
JAB0
50
12
0
JAB260
18
0
JAB03
5
14
1
JAB1
21
9
0
JAB3
36
11
0
JAB263
15
0
JAB 10
7
19
0
JAB3
19
15
0
JAB3
29
11
0
JAB266
15
0
JAB29
2
1
1
JAB3
22
14
0
JAB3
30
8
2
JAB269
18
1
JAB29
5
7
0
JAB3
20
3
0
JAB0
46
14
0
JAB 10
18
1
JAB34
7
16
0
JAB3
06
13
0
JAB3
28
14
0
JAB270
18
0
JAB29
8
5
0
JAB3
13
17
1
JAB1
34
16
1
JAB273
15
0
JAB34
8
19
1
JAB3
23
14
0
JAB3
41
14
1
JAB252
16
0
JAB29
3
5
0
JAB3
10
15
1
JAB028
18
1
JAB03
7
14
1
JAB1
17
14
0
JAB275
18
0
JAB34
9
16
0
JAB0
40
20
0
JAB255
16
0
JAB27
8
16
1
JAB3
09
14
1
JAB264
15
0
JAB 10
5
14
0
JAB0
39
16
0
JAB267
17
0
JAB29
7
15
0
JAB3
17
14
0
JAB262
17
0
JAB 10
6
17
0
JAB1
12
17
0
JAB 102
17
3
JAB28
1
6
0
JAB246
2
1
JAB29
0
14
0
JAB256
10
0
JAB098
15
0
JAB249
15
0
This document is a draft for review purposes only and does not constitute Agency policy.
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
JAB253
18
0
Summary of BMDS 3.1.1 Modeling Results for P2/F2A Pups Dead at Day 0 (Exxon,
1991)
Preferre
d
Models*
5% Extra Risk
1% Extra Risk
P Value
AIC
BMDS
Recommends
BMDS Recommendation Notes
BMD
BMDL
BMD
BMDL
NLoeistic
326.34
240.809
280.408
50.7883
0.0007
334.364
Questionable
BMD/BMDL ratio > 3
Goodness of fit p-value <0.1
NLosisti
c-ILC
327.095
205.186
281.145
49.3219
0.1017
313.315
Recommend
ed
Basis: Lowest AIC
BMD/BMDL ratio > 3 for 1% Extra
Risk
Alternative Models
NCTR
326.327
271.939
282.34
235.284
0
332.364
Questionable
Goodness of fit p-value <0.1
NCTR-
ILC
327.114
0.63378
5
327.114
0.63378
5
0.1103
311.315
Questionable
BMD/BMDL ratio > 20
RaiVR
281.131
234.276
281.131
234.276
0
332.364
Questionable
Goodness of fit p-value <0.1
RaiVR-
ILC
327.118
0.63378
5
280.539
0.47224
4
0.0867
311.315
Questionable
BMD/BMDL ratio > 20
*NLogistic is preferred because it is the more rigorously tested nested model. All nested models were restricted. Restrictions are defined in the BMDS 3.1.1 User Guide;
ILC = Intra-litter Correlation Coefficients estimated; Because potential litter-specific covariates (LSCs) such as dam BW are affected by dose, LSCs were not estimated.
**Selected Model (Green); the average scaled residual for dose group nearest the BMD05 and BMD01 were -0.3523 and -0.3523, respectively.
This document is a draft for review purposes only and does not constitute Agency policy.
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Selected Model Results- NLogistic- ILC, BMR = 0.01 and 0.05
Extra Risk
NLogistic Model. (Version: 2.20; Date: 04/27/2015)
Input Data File: C:/Users/jgift/BMDS2704/Data/NMP/P2F2A Dead Day 0/nln_P2F2A Day 0 Deaths_Nln-BMR01-Restrict-
noLSC.(d)
Tue Jul 30 22:03:20 2019
BMDS Model Run
The probability function is:
Prob. = alpha + thetal *Rij + [1 - alpha - thetal *Rij]/
[ 1 +exp(-beta-theta2 *Rij -rho *log(Dose))],
where Rij is the litter specific covariate.
Restrict Power rho >= 1.
Total number of observations = 85
Total number of records with missing values = 0
Total number of parameters in model = 9
Total number of specified parameters = 2
Maximum number of iterations = 500
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Number of Bootstrap Iterations per run: 1000
Bootstrap Seed: 1564538600
User specifies the following parameters:
thetal = 0
theta2 = 0
Default Initial Parameter Values
alpha = 0.02553
beta = -66.0821
thetal = 0 Specified
theta2 = 0 Specified
rho = 10.9041
phil = 0.0392728
phi2 = 0
phi3 = 0
phi4 = 0.310565
Parameter Estimates
-------
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
Variable
Estimate
Std. Err.
alpha
0.02553
0.00468854
beta
-66.0821
0.792172
rho
10.9041
0.0311563
phil
0.0392728
NA
phi2
0
Bounded
phi3
0
Bounded
phi4
0.310565
NA
Log-likelihood: -151.658 AIC: 313.315
Litter Data
Lit.-Spec. Litter Scaled
Dose Cov. Est._Prob. Size Expected Observed Residual
0.0000
2.0000
0.026
2
0.051
1
4.1730
0.0000
9.0000
0.026
9
0.230
0
-0.4236
0.0000
10.0000
0.026
10
0.255
0
-0.4400
0.0000
12.0000
0.026
12
0.306
0
-0.4686
0.0000
14.0000
0.026
14
0.357
0
-0.4928
0.0000
15.0000
0.026
15
0.383
0
-0.5036
0.0000
15.0000
0.026
15
0.383
0
-0.5036
0.0000
15.0000
0.026
15
0.383
0
-0.5036
0.0000
15.0000
0.026
15
0.383
0
-0.5036
0.0000
15.0000
0.026
15
0.383
0
-0.5036
0.0000
15.0000
0.026
15
0.383
0
-0.5036
0.0000
15.0000
0.026
15
0.383
0
-0.5036
0.0000
16.0000
0.026
16
0.408
0
-0.5136
0.0000
16.0000
0.026
16
0.408
0
-0.5136
0.0000
16.0000
0.026
16
0.408
0
-0.5136
0.0000
17.0000
0.026
17
0.434
0
-0.5230
0.0000
17.0000
0.026
17
0.434
0
-0.5230
0.0000
17.0000
0.026
17
0.434
1
0.6820
0.0000
17.0000
0.026
17
0.434
3
3.0920
0.0000
18.0000
0.026
18
0.460
0
-0.5318
0.0000
18.0000
0.026
18
0.460
1
0.6254
0.0000
18.0000
0.026
18
0.460
1
0.6254
0.0000
18.0000
0.026
18
0.460
0
-0.5318
0.0000
18.0000
0.026
18
0.460
0
-0.5318
0.0000
18.0000
0.026
18
0.460
2
1.7826
0.0000
18.0000
0.026
18
0.460
1
0.6254
0.0000
18.0000
0.026
18
0.460
0
-0.5318
26.1207
1.0000
0.026
1
0.026
1
6.1782
26.1207
5.0000
0.026
5
0.128
0
-0.3619
26.1207
5.0000
0.026
5
0.128
0
-0.3619
26.1207
6.0000
0.026
6
0.153
0
-0.3965
26.1207
7.0000
0.026
7
0.179
0
-0.4282
26.1207
13.0000
0.026
13
0.332
1
1.1748
26.1207
13.0000
0.026
13
0.332
0
-0.5836
26.1207
14.0000
0.026
14
0.357
0
-0.6056
26.1207
14.0000
0.026
14
0.357
2
2.7833
26.1207
14.0000
0.026
14
0.357
0
-0.6056
26.1207
14.0000
0.026
14
0.357
1
1.0888
26.1207
14.0000
0.026
14
0.357
1
1.0888
26.1207
15.0000
0.026
15
0.383
0
-0.6269
26.1207
16.0000
0.026
16
0.408
1
0.9376
26.1207
16.0000
0.026
16
0.408
0
-0.6474
26.1207
16.0000
0.026
16
0.408
0
-0.6474
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149
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
26.1207
16.0000
0.026
16
0.408
1
0.9376
26.1207
17.0000
0.026
17
0.434
0
-0.6674
26.1207
17.0000
0.026
17
0.434
0
-0.6674
26.1207
17.0000
0.026
17
0.434
0
-0.6674
26.1207
17.0000
0.026
17
0.434
0
-0.6674
26.1207
19.0000
0.026
19
0.485
1
0.7490
26.1207
19.0000
0.026
19
0.485
0
-0.7055
92.5466
3.0000
0.026
3
0.077
0
-0.2804
92.5466
9.0000
0.026
9
0.230
0
-0.4856
92.5466
13.0000
0.026
13
0.332
0
-0.5836
92.5466
14.0000
0.026
14
0.357
0
-0.6056
92.5466
14.0000
0.026
14
0.357
1
1.0888
92.5466
14.0000
0.026
14
0.357
0
-0.6056
92.5466
14.0000
0.026
14
0.357
1
1.0888
92.5466
14.0000
0.026
14
0.357
0
-0.6056
92.5466
14.0000
0.026
14
0.357
0
-0.6056
92.5466
15.0000
0.026
15
0.383
0
-0.6269
92.5466
15.0000
0.026
15
0.383
0
-0.6269
92.5466
15.0000
0.026
15
0.383
0
-0.6269
92.5466
15.0000
0.026
15
0.383
1
1.0101
92.5466
16.0000
0.026
16
0.408
0
-0.6474
92.5466
16.0000
0.026
16
0.408
1
0.9376
92.5466
16.0000
0.026
16
0.408
0
-0.6474
92.5466
17.0000
0.026
17
0.434
1
0.8703
92.5466
17.0000
0.026
17
0.434
0
-0.6674
92.5466
20.0000
0.026
20
0.511
1
0.6938
92.5466
20.0000
0.026
20
0.511
0
-0.7239
92.5466
22.0000
0.026
22
0.562
1
0.5925
326.1056
4.0000
0.073
4
0.291
0
-0.4031
326.1056
7.0000
0.073
7
0.509
0
-0.4379
326.1056
8.0000
0.073
8
0.582
2
1.0835
326.1056
11.0000
0.073
11
0.800
0
-0.4585
326.1056
11.0000
0.073
11
0.800
0
-0.4585
326.1056
12.0000
0.073
12
0.873
0
-0.4617
326.1056
12.0000
0.073
12
0.873
0
-0.4617
326.1056
13.0000
0.073
13
0.946
8
3.4649
326.1056
13.0000
0.073
13
0.946
0
-0.4645
326.1056
14.0000
0.073
14
1.018
1
-0.0085
326.1056
14.0000
0.073
14
1.018
0
-0.4669
326.1056
14.0000
0.073
14
1.018
0
-0.4669
326.1056
14.0000
0.073
14
1.018
0
-0.4669
326.1056
16.0000
0.073
16
1.164
1
-0.0663
Scaled Residual(s) for Dose Group Nearest the BMD
Minimum scaled residual for dose group nearest the BMD = -0.4669
Minimum ABS(scaled residual) for dose group nearest the BMD = 0.0085
Average scaled residual for dose group nearest the BMD = -0.3523
Average ABS(scaled residual) for dose group nearest the BMD = 0.3523
Maximum scaled residual for dose group nearest the BMD = -0.0085
Maximum ABS(scaled residual) for dose group nearest the BMD = 0.4669
Number of litters used for scaled residual for dose group nearest the BMD = 4
Observed Chi-square = 120.2685
Bootstrapping Results
This document is a draft for review purposes only and does not constitute Agency policy.
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196
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198
199
200
201
202
203
204
205
206
207
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209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
Number of Bootstrap Iterations per run: 1000
Bootstrap Chi-square Percentiles
Bootstrap
Run P-value 50th 90th 95th 99th
1 0.1020 80.1651 120.8799 132.3672 165.0942
2 0.0930 81.2319 117.9970 132.3763 160.2242
3 0.1050 81.1876 121.5273 137.2496 166.6223
Combined 0.1000 80.9778 120.2642 133.6763 165.0942
The results for three separate runs are shown. If the estimated p-values are sufficiently
stable (do not vary considerably from run to run), then then number of iterations is
considered adequate. The p-value that should be reported is the one that combines
the results of the three runs. If sufficient stability is not evident (and especially
if the p-values are close to the critical level for determining adequate fit, e.g., 0.05),
then the user should consider increasing the number of iterations per run.
To calculate the BMD and BMDL, the litter specific covariate is fixed
at the mean litter specific covariate of all the data: 14.035294
Benchmark Dose Computation
Specified effects = 0.01, 0.05
Risk Type = Extra risk
Confidence level = 0.95
BMDs = 281.145,327.095
BMDLs = 49.3219,205.186
This document is a draft for review purposes only and does not constitute Agency policy.
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
229 Selected Model Plots- NLogistic- ILC, BMR = 0.01 and 0.05 Extra Risk
Nested Logistic Model, with BMR of 1% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Nested Logistic
0.25
0.2
0.15
0.1
0.05
0
BMDL
3MD
0
50
100
150
200
250
300
dose
22:03 07/30 2019
Nested Logistic Model, with BMR of 5% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Nested Logistic
0.25
0.2
0.15
0.1
0.05
0
BMDL
BMD
0
50
100
150
200
250
300
dose
221 22:03 07/30 2019
232
This document is a draft for review purposes only and does not constitute Agency policy.
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
233 4,6.2 P2/F2B Pups Dead at Day 0 (Stillborn Day O/Total Pups Born; Exxon 1991
234 Appendix AK)
Control
25.25 avg. mg/L blood GD6-21
89.03 avg. mg/L blood GD6-21
311.9 avg. mg/L blood GD6-21
Dam
N
Stillborn
Dam
N
Stillborn
Dam
N
Stillborn
Dam
N
Stillborn
JAB245
18
3
JAB029
15
0
JAB302
19
0
JAB327
14
0
JAB248
14
0
JAB032
15
0
JAB038
14
1
JAB045
15
0
JAB026
16
0
JAB279
14
0
JAB110
15
0
JAB339
4
0
JAB251
12
0
JAB 104
18
7
JAB305
15
0
JAB329
14
13
JAB097
18
0
JAB288
15
0
JAB113
16
0
JAB330
13
0
JAB254
8
0
JAB035
15
0
JAB116
5
0
JAB343D
10
0
JAB 100
16
0
JAB 107
6
0
JAB308
6
0
JAB337
8
0
JAB257
16
2
JAB292
12
1
JAB311
17
0
JAB328
13
0
JAB260
18
0
JAB295
7
0
JAB121
13
0
JAB134
8
5
JAB266
11
0
JAB347
15
0
JAB 127
14
1
JAB269
14
0
JAB348
19
0
JAB130
17
0
JAB101
15
0
JAB293
19
1
JAB319
18
0
JAB270
20
0
JAB037
15
0
JAB320
17
0
JAB273
18
0
JAB349
16
0
JAB313
11
0
JAB252
11
1
JAB278
11
0
JAB040
18
1
JAB028
16
0
JAB105
18
0
JAB309
15
0
JAB275
15
0
JAB289
15
1
JAB039
11
0
JAB255
20
0
JAB297
13
0
JAB112
18
0
JAB264
14
0
JAB 106
16
0
JAB262
16
1
JAB290
13
0
JAB 102
17
1
JAB256
14
0
JAB098
11
1
JAB249
16
0
JAB253
17
0
235
236
237
238
Summary of BMDS 3.1.1 Modeling Results for P2/F2B Pups Dead at Day 0 (Exxon,
1991)
Standard
Models*
5% Extra Risk
1% Extra Risk
P Value
AIC
BMDS
Recommends
**
BMDS Recommendation Notes
BMD
BMDL
BMD
BMDL
NLoeistic
327.408
275.906
285.459
73.5614
0
246.193
Questionable
BMD/BMDL ratio > 3
Goodness of fit p-value <0.1
NLoeistic
-ILC
CF
CF
CF
CF
CF
209.115
Unusable
BMD computation fail; Lower limit
includes 0
Non-Standard Models
NCTR
327.13
0.88668
9
285.638
0.23745
6
0
244.193
Questionable
BMD/BMDL ratio > 20
Goodness of fit p-value <0.1
NCTR-
ILC
324.07
0.65928
9
283.317
0.19183
3
0.256,
0.224
206.511
Questionable
BMD/BMDL ratio > 20
RaiVR
327.208
0.88668
9
285.513
0.51411
5
0
244.193
Questionable
BMD/BMDL ratio > 20
Goodness of fit p-value <0.1
RaiVR-
ILC
324.124
0.65928
9
283.199
0.51702
1
0.2407
206.511
Questionable
BMD/BMDL ratio > 20
This document is a draft for review purposes only and does not constitute Agency policy.
78
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
239 *NLogistic is preferred because it is the more rigorously tested nested model. All nested models were restricted. Restrictions are
240 defined in the BMDS 3.1.1 User Guide: ILC = Intra-litter Correlation Coefficients estimated; Because potential litter-specific
241 covariates (LSCs) such as dam BW are affected by dose, LSCs were not estimated.
242 **No model selected as all models were questionable or unusable.
This document is a draft for review purposes only and does not constitute Agency policy.
79
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
243
244
245
4.6.3 P2/F2A Pups Dead by Day 4 (Dead
by Day 4/Total Pups Born; Exxon Appendix A J)
Control
26.1207 avg. mg/L blood
GD6-21
92.5466 avg. mg/L blood
GD6-21
326.1056 avg. mg/L blood
GD6-21
Dead
Dead
Dead
Dead
Dam
N
by Day
4
Dam
N
by Day
4
Dam
N
by Day
4
Dam
N
by Day
4
JAB248
12
0
JAB029
17
4
JAB302
15
0
JAB325
13
9
JAB026
16
0
JAB032
17
0
JAB038
14
1
JAB327
12
12
JAB251
14
0
JAB279
14
3
JAB 110
15
1
JAB041
13
13
JAB097
15
0
JAB 104
13
1
JAB305
16
1
JAB135
7
0
JAB254
9
0
JAB282
13
5
JAB 113
20
1
JAB136
4
0
JAB 100
18
2
JAB285
16
1
JAB 116
22
1
JAB045
14
2
JAB257
17
1
JAB288
17
0
JAB311
16
0
JAB050
12
12
JAB260
18
3
JAB035
14
1
JAB 121
9
0
JAB336
11
11
JAB263
15
2
JAB 107
19
2
JAB319
15
0
JAB329
11
1
JAB266
15
0
JAB292
1
1
JAB322
14
2
JAB330
8
8
JAB269
18
1
JAB295
7
0
JAB320
3
0
JAB046
14
0
JAB 10
18
1
JAB347
16
0
JAB306
13
0
JAB328
14
14
JAB270
18
0
JAB298
5
0
JAB313
17
1
JAB134
16
16
JAB273
15
0
JAB348
19
3
JAB323
14
1
JAB341
14
14
JAB252
16
2
JAB293
5
0
JAB310
15
1
JAB028
18
3
JAB037
14
1
JAB 117
14
0
JAB275
18
5
JAB349
16
0
JAB040
20
2
JAB255
16
2
JAB278
16
3
JAB309
14
1
JAB264
15
0
JAB 105
14
0
JAB039
16
2
JAB267
17
1
JAB297
15
1
JAB317
14
0
JAB262
17
0
JAB 106
17
0
JAB 112
17
0
JAB 102
17
10
JAB281
6
3
JAB246
2
2
JAB290
14
0
JAB256
10
0
JAB098
15
1
JAB249
15
0
JAB253
18
0
This document is a draft for review purposes only and does not constitute Agency policy.
80
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
246 Summary of BMDS 3.1.1 Modeling Results for P2/F2A Pups Dead by Day 4 (Exxon,
247
1991)
248 Table 4-15 Model Predictions for Pup Death at Day 4 in P2/F2A Rats (Exxon, 1991)
Standard
Models*
5% Extra Risk
1% Extra Risk
P Value
AIC
BMDS
Recommends
**
BMDS Recommendation Notes
BMD
BMDL
BMD
BMDL
NLoeistic
253.849
136.252
226.386
91.5542
0
771.038
Questionable
Goodness of fit p-value <0.1
NLoeistic
-ILC
257.878
132.515
231.394
88.2173
0.0317
608.697
Questionable
Goodness of fit p-value <0.1
Non-Standard Models
NCTR
261.47
217.891
232.338
193.615
0
769.038
Questionable
Goodness of fit p-value <0.1
NCTR-
ILC
267.663
223.052
240.654
200.545
0.0307,
0.0303
606.697
Questionable
Goodness of fit p-value <0.1
RaiVR
261.996
218.33
233.057
194.214
0
769.038
Questionable
Goodness of fit p-value <0.1
RaiVR-
ILC
267.488
222.907
240.412
200.344
0.0333,
0.034
606.697
Questionable
Goodness of fit p-value <0.1
249
250
251
252
253
*NLogistic is preferred because it is the more rigorously tested nested model. All nested models were restricted. Restrictions are
defined in the BMDS 3.1.1 User Guide: ILC = Intra-litter Correlation Coefficients estimated; Because potential litter-specific
covariates (LSCs) such as dam BW are affected by dose, LSCs were not estimated.
**No model selected as all models were questionable or unusable..
This document is a draft for review purposes only and does not constitute Agency policy.
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
254
255 4.6.4 P2/F2B Pups Dead by Day 4 (Dead by Day 4/Total Pups Born; Exxon Appendix
256 AK)
Control
25.25 avg. mg/L blood
GD6-21
89.03 avg. mg/L blood
GD6-21
311.9 avg. mg/L blood
GD6-21
Dead
Dead
Dead
Dead
Dam
N
by Day
4
Dam
N
by Day
4
Dam
N
by Day
4
Dam
N
by Day
4
JAB245
18
18
JAB029
15
0
JAB302
19
1
JAB327
14
14
JAB248
14
0
JAB032
15
0
JAB038
14
1
JAB045
15
2
JAB026
16
0
JAB279
14
0
JAB 110
15
1
JAB339
4
4
JAB251
12
0
JAB 104
18
7
JAB305
15
0
JAB329
14
14
JAB097
18
0
JAB288
15
0
JAB 113
16
0
JAB330
13
13
JAB254
8
0
JAB035
15
0
JAB 116
5
0
JAB343
D
10
10
JAB 100
16
0
JAB 107
6
0
JAB308
6
1
JAB337
8
8
JAB257
16
10
JAB292
12
1
JAB311
17
1
JAB328
13
13
JAB260
18
4
JAB295
7
1
JAB 121
13
1
JAB134
8
8
JAB266
11
0
JAB347
15
0
JAB 127
14
1
JAB269
14
0
JAB348
19
0
JAB130
17
1
JAB 101
15
0
JAB293
19
2
JAB319
18
0
JAB270
20
0
JAB037
15
2
JAB320
17
0
JAB273
18
2
JAB349
16
0
JAB313
11
0
JAB252
11
1
JAB278
11
1
JAB040
18
1
JAB028
16
2
JAB 105
18
2
JAB309
15
0
JAB275
15
1
JAB289
15
6
JAB039
11
0
JAB255
20
1
JAB297
13
0
JAB 112
18
0
JAB264
14
0
JAB 106
16
0
JAB262
16
3
JAB290
13
1
JAB 102
17
2
JAB256
14
0
JAB098
11
3
JAB249
16
0
JAB253
17
3
257
258
This document is a draft for review purposes only and does not constitute Agency policy.
82
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N-Methylpyrrolidone (NMP) Benchmark Dose Report
259 Summary of BMDS 3.1.1 Modeling Results for P2/F2B Pups Dead by Day 4 (Exxon,
1991)
260
261
262
Table 4-16 Model Predictions for Pup Death at Day 4 in P2/F2B Rats (Exxon, 1991)
Standard
Models*
5% Extra Risk
1% Extra Risk
P Value
AIC
BMDS
Recommends
BMDS Recommendation Notes
BMD
BMDL
BMD
BMDL
NLoeistic
229.655
126.176
206.373
92.1515
0
637.258
Questionable
BMD/BMDL ratio > 3
Goodness of fit p-value <0.1
NLoeistic
-ILC
229.334
114.81
209.236
85.9385
0.065,
0.053
468.948
Questionable
Goodness of fit p-value <0.1
Non-Standard Models
NCTR
243.777
203.148
218.255
181.88
0
635.258
Questionable
Goodness of fit p-value <0.1
NCTR-
ILC
250.449
208.707
228.766
190.639
0.0623,
0.0687
466.948
Questionable
Goodness of fit p-value <0.1
RaiVR
243.156
202.63
217.451
181.209
0
635.258
Questionable
Goodness of fit p-value <0.1
RaiVR-
ILC
250.449
208.707
228.766
190.639
0.059,
0.0603
466.948
Questionable
Goodness of fit p-value <0.1
263
264
265
266
267
268
*NLogistic is preferred because it is the more rigorously tested nested model. All nested models were restricted. Restrictions are
defined in the BMDS 3.1.1 User Guide: ILC = Intra-litter Correlation Coefficients estimated; Because potential litter-specific
covariates (LSCs) such as dam BW are affected by dose, LSCs were not estimated.
**No model selected as all models were questionable or unusable.
This document is a draft for review purposes only and does not constitute Agency policy.
83
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269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
N-Methylpyrrolidone (NMP) Benchmark Dose Report
5 References
Bart« (2007). The origins of the developmental origins theory. J Intern Med 261: 412-417.
http://dx.doi.ore :796.2007.01809.x
Becci nickerbocker. Ml; Reagan. EL; Parent. RA; Bumette. LW. (1982). Teratogenicity study of
N-methylpyrrolidone after dermal application to Sprague-Dawley rats. Fundam Appl Toxicol 2:
DuPont. (1990). Letter from E I DuPont de Nemours & Company to USEPA submitting comments
concerning the proposed test rule on n-methylpyrrolidone with attachment. (40-90107098). E I
Dupont De Nemours & Co.
Exxon. B. (1991). Project No. 236535, 26 Nov 1991. ((sponsored by GAF Corp., Wayne, USA), (as
cited in OECD, 2007)). Wayne, USA: GAF Corp.
Kavlock. RJ; Allen. BC; Faustman. EM: Kimmel. CA. (1995). Dose-response assessments for
developmental toxicity .4. Benchmark doses for fetal weight changes. Toxicol Sci 26: 211-222.
http://dx.doi.ore 36/faat. 1995.1092.
Poet. TS: Kirman v. 1 P^der. M; van Thriet. i _m > n'gas. ML: Hinderliter. PM. (2010). Quantitative risk
analysis for N-methyl pyrrolidone using physiologically based pharmacokinetic and benchmark
dose modeling. Toxicol Sci 113: 468-482. http://dx.doi.org >3/toxsci/kfp264
Reyes. L; Manalich. R. (2005). Long-term consequences of low birth weight [Review], Kidney Int
Suppl 68: S107-S111. http://dx.doi.oi _ 005.09718.x
Saillenfait. AM: Gallissot. F; Langonne. I: Sab at (2002). Developmental toxicity of N-methyl-2-
pyrrolidone administered orally to rats. Food Chem Toxicol 40: 1705-1712.
http://dx.doi.orE >0278-6915(02)00115-1
Saillenfait. AM: Gallissot. F; Mop (2003). Developmental toxicity of N-methyl-2-pyrrolidone in
rats following inhalation exposure. Food Chem Toxicol 41: 583-588.
http://dx.doi. ore >0278-6915(02)00300-9
Sitarek. K; Stetkiewicz. J: Wasowicz. W. (2012). Evaluation of reproductive disorders in female rats
exposed to N-methyl-2-pyrrolidone. Birth Defects Res B Dev Reprod Toxicol 95: 195-201.
(2015). TSCA work plan chemical risk assessment. N-Methylpyrrolidone: Paint stripper use
(CASRN: 872-50-4). In Office of Chemical Safety and Pollution Prevention. (740-R1-5002).
Washington, DC. https://www.epa.gov/sites/prodiiction/files/2015-
73-76.
.21001
This document is a draft for review purposes only and does not constitute Agency policy.
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