United States
Environmental Protection
1=1 m m Agency
EPA/690/R-14/004F
Final
1-08-2014
Provisional Peer-Reviewed Toxicity Values for
Dicyclopentadiene
(CASRN 77-73-6)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGERS
Zhongyu (June) Yan, PhD
National Center for Environmental Assessment, Cincinnati, OH
Q. Jay Zhao, PhD, MPH, DABT
National Center for Environmental Assessment, Cincinnati, OH
Evisabel Craig, PhD
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Ghazi Dannan, PhD
National Center for Environmental Assessment, Washington, DC
Anuradha Mudipalli, MSc, PhD
National Center for Environmental Assessment, Research Triangle Park, NC
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).
li
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS iv
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVs 1
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) 4
HUMAN STUDIES 10
Oral Exposures 10
Inhalation Exposures 10
Acute, Short-Term, and Long-Term Studies 10
Chronic-Duration Studies 10
ANIMAL STUDIES 10
Oral Exposures 10
Sub chronic-Duration Studies 10
Chronic-Duration Studies 14
Developmental Studies 14
Reproductive Studies 15
Inhalation Exposures 19
Sub chronic-Duration Studies 19
Chronic-Duration Studies 24
Developmental Studies 24
Reproductive Studies 25
OTHER DATA 26
Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity 29
DERIVATION OI PROVISIONAL VALUES 30
DERIVATION OF ORAL REFERENCE DOSES 31
Derivation of Subchronic Provisional RfD (Subchronic p-RfD) 32
Derivation of Chronic Provisional RfD (Chronic p-RfD) 34
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 35
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR 36
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 37
APPENDIX A. PROVISIONAL SCREENING VALUES 38
APPENDIX B. DATA TABLES 42
APPENDIX C. BMD MODELING OUTPUTS FOR DCPD 72
APPENDIX D. REFERENCES 73
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMCL
benchmark concentration lower confidence limit
BMD
benchmark dose
BMDL
benchmark dose lower confidence limit
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELrec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
POD
point of departure
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
RfC
inhalation reference concentration
RfD
oral reference dose
UF
uncertainty factor
UFa
interspecies uncertainty factor
UFC
composite uncertainty factor
UFd
database uncertainty factor
UFh
intraspecies uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
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PEER-REVIEWED PROVISIONAL TOXICITY VALUES FOR
DICYCLOPENTADIENE (CASRN 77-73-6)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (www.epa.gov/iris). the respective PPRTVs are removed
from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVs
Questions regarding the contents and appropriate use of this PPRTV assessment should
be directed to the U.S. EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
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INTRODUCTION
Dicyclopentadiene (DCPD), CAS No. 77-73-6, is a flammable, colorless, crystalline solid
(structure provided in Figure 1) with an unpleasant, camphor-like odor (NIOSH, 2010). DCPD
has a high vapor pressure at ambient temperatures, indicating volatility. DCPD, with a
molecular formula of C10H12, is the dimer of cyclopentadiene (CPD) formed by a Diels-Alder
addition reaction. DCPD is a highly reactive intermediate product originated from high
temperature cracking of petroleum fractions. DCPD is used for a wide range of resins including
aromatic hydrocarbons, unsaturated polyesters, phenolics, and epoxies; it is also used as a
chemical intermediate in the manufacture of insecticides, paints, varnishes, and flame retardants
for plastics. Table 1 provides basic physicochemical properties for DCPD.
Figure 1. DCPD Structure
Table 1. Physicochemical Properties of DCPD (CASRN 77-73-6)a
Property (unit)
Value
Boiling point (°C)
172
Melting point (°C)
32-34
Density (g/cm3)
0.98
Vapor pressure (mmHg at 20°C)
1.4
pH (unitless)
ND
Solubility in water (%by weight, g/100 mL at 20 °C)
0.02
Relative vapor density (air =1)
4.6-4.7
Molecular weight (g/mol)
132.2
"Source: NIOSH (2010); IPCS (2005).
ND = no data.
A summary of available toxicity values for DCPD from U.S. EPA and other
agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for DCPD (CASRN 77-73-6)
Source/Parameter"
Value
(Applicability)
Notes
Reference
Date
Accessed
Noncancer
ACGIH
8-hr TLV-TWA:
5 ppm
Based on upper respiratory tract,
lower respiratory tract, and eye
irritation.
ACGIH (2013)
NA
ATSDR
NV
NA
ATSDR (2012)
NA
Cal/EPA
NV
NA
Cal/EPA (2009)b
8-l-2013b
NIOSH
8-TWA: 5 ppm
NA
NIOSH (2010)
NA
OSHA
NV
NA
OSHA (2006,
2011)
NA
IRIS
NV
NA
U.S. EPA
8-2-2013
Drinking water
NV
NA
U.S. EPA
(2011a)
NA
HEAST
NV
NA
U.S. EPA
(2011b)
NA
CARA HEEP
NV
NA
U.S. EPA
(1994a)
NA
WHO
NV
NA
WHO
8-5-2013
Cancer
ACGIH
NV
NA
ACGIH (2013)
NA
IRIS
NV
NA
U.S. EPA
8-2-2013
HEAST
NV
NA
U.S. EPA
(2011b)
NA
IARC
NV
NA
IARC
NA
NTP
NV
NA
NTP (2011)
NA
Cal/EPA
NV
NA
Cal/EPA (2009)
NA
"Sources: American Conference of Governmental Industrial Hygienists (ACGIH); Agency for Toxic Substances
and Disease Registry (ATSDR); California Environmental Protection Agency (Cal/EPA); National Institute for
Occupational Safety and Health (NIOSH); Occupational Safety and Health Administration (OSHA); Chemical
Assessments and Related Activities (CARA); Health and Environmental Effects Profile (HEEP); World Health
Organization (WHO); Integrated Risk Information System (IRIS); Health Effects Assessment Summary Tables
(HEAST); International Agency for Research on Cancer (IARC); National Toxicology Program (NTP).
bThe Cal/EPA Office of Environmental Health Hazard Assessment (OEHHA) Toxicity Criteria Database
(http://oehlia.ca.gov/tcdb/index.asp') was also reviewed and found to contain no information on DCPD.
IDLH = immediately dangerous to life or health; NA = not applicable; NSRL = no significant risk level; NV = not
available; PEL = permissible exposure level; REL = recommended exposure level; TLV = threshold limit value;
TWA = time-weighted average.
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Literature searches were conducted on sources published from 1900 through
November 2013 for studies relevant to the derivation of provisional toxicity values for DCPD,
CAS No. 77-73-6. The following databases were searched by chemical name, synonyms, or
CASRN: ACGM, ANEUPL, AT SDR, BIOSIS, Cal/EPA, CCRIS, CD AT, ChemlDplus, CIS,
CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HERO, HMTC,
HSDB, IARC, INCHEM IPCS, IP A, ITER, IUCLID, LactMed, NIOSH, NTIS, NTP, OSHA,
OPP/RED, PESTAB, PPBIB, PPRTV, PubMed (toxicology subset), RISKLINE, RTECS,
TOXLINE, TRI, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA HEEP, U.S. EPA OW, and
U.S. EPA TSCATS/TSCATS2. The following databases were searched for relevant health
information: ACGIH, AT SDR, Cal/EPA, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA HEEP,
U.S. EPA OW, U.S. EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 3 provides an overview of the relevant database for DCPD and includes all
potentially relevant repeated short-term-, subchronic-, and chronic-duration studies. The phrase
"statistical significance," used throughout the document, indicates ap-walue of <0.05.
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Table 3. Summary of Potentially Relevant Data for DCPD (CASRN 77-73-6)
Category
Number Of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry"
Critical Effects
NOAEL'
BMDL/
BMCLa
LOAEL'
Reference
(Comments)
Notesb
Human
1. Oral
Acute0
ND
Short-termd
ND
Long-term6
ND
Chronicf
ND
2. Inhalation (mg/m3)"
Acute0
ND
Short-termd
ND
Long-term0
ND
Chronicf
15/0 workers in plastic
products and DCPD
recovery, retrospective,
evaluated births
1980-1997
No exposure
measures but
generally
exposed to
DCPD, CPD,
epoxy resin,
bisphenol A, and
epichlorohydrin
Statistically significant excess of
female births (6 males and
18 females, binomial test;
/?<0.01)
NDr
NDr
NDr
Okubo et al.
(2000)
PR
Animal
1. Oral (mg/kg-d)a
Subchronic
30/30, S-D rat, diet,
7 d/wk, 90 d
Males: 0, 6.3,
19.2, or 57.4
Females: 0, 7.2,
22.6, or 68.1
(Adjusted)
No biologically significant effects
M: 57.4
F: 68.1
DU
NDr
Hart (1976)
NPR8
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Table 3. Summary of Potentially Relevant Data for DCPD (CASRN 77-73-6)
Category
Number Of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry"
Critical Effects
NOAEL'
BMDL/
BMCLa
LOAEL'
Reference
(Comments)
Notesb
Subchronic
32/32, Swiss albino
mouse, diet, 7 d/wk,
90 d
Males: 0, 5.6,
17.0, or 49.5
Females: 0, 8.1,
22.7, or 68.4
(Adjusted)
No biologically significant effects
M: 49.5
F: 68.4
DU
NDr
Hart (1976)
NPR8
4/4, Beagle dog, diet,
7 d/wk, 13 wk
Males: 0, 2.7,
8.4, or 28.2
Females: 0, 2.7,
8.6, or 28.8
(Adjusted)
No biologically significant effects
M: 28.2
F: 28.8
DU
NDr
Hart (1980)
NPR8
Chronic
ND
Developmental
0/20 CRL:COBS CD
(SD) BR rats diet,
GDs 6-15
0,6.2, 21, or 63
No biologically significant effects
63
DU
NDr
Hart (1980)
NPR8
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Table 3. Summary of Potentially Relevant Data for DCPD (CASRN 77-73-6)
Category
Number Of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry3
Critical Effects
NOAEL'
BMDL/
BMCLa
LOAEL'
Reference
(Comments)
Notesb
Reproductive
10/20 CRL:COB (SD)
BR rat, diet,
3-generation
reproductive study
F0 generation
parents: Males:
0,3.6, or 34.2
Females: 0, 4.8,
or 48.1
(Adjusted)
F1 generation
parents: Males:
0,4.3, or 39.9
Females: 0, 7.8,
or 60.7
(Adjusted)
F2 generation
parents: Males:
0,4.6, or 44.1
Females: 0, 8.1,
or 73.1
(Adjusted)
F0 generation: no
compound-related effects in
F1 litter of pups; no dose-related
changes following gross necropsy
of F0 parents
F1 generation: no
compound-related effects in
F2 litter of pups; no dose-related
changes following gross necropsy
of F1 parents
F2 generation: statistically
significant reduction in mean pup
weight at weaning (but not at
birth) in F3b litter of pups at
highest exposure; no
compound-related effects in
F3 litter of pups; no dose-related
changes following gross necropsy
of F2 parents
M: 34.2
F: 48.1
DU
NDr
Hart (1980)
NPR8
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Table 3. Summary of Potentially Relevant Data for DCPD (CASRN 77-73-6)
Category
Number Of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry"
Critical Effects
NOAEL'
BMDL/
BMCLa
LOAEL'
Reference
(Comments)
Notesb
Reproductive
20/20, S-D rat, gavage,
continuous breeding
protocol, select
weanlings dosed
identically to parents
and bred
0, 10, 30, or 100
(Adjusted)
28% fewer F1 pups born live,
8% lower adjusted live F1 pup
weights, higher F1 pup mortality,
increased cumulative days to litter,
and decreased F1 pup survival in
high-dose F0 females; slight
decrease in pup weight in F2 at
30 mg/kg and in crossover mating
in DCPD-treated females;
increased liver and kidney weights
in both F1 and F2 generations;
histopathological changes in liver
in F2 at 30 and 100 mg/kg-d
10
DU
30
Jamieson et al.
(1995) (abstract
only)
NPR
6/24, mink, diet,
1-generation
reproductive study
(12 mo)
0,23.6, 42.4,
85.0, or 169.9
(Adjusted)
Statistically significant,
dose-related reduction in kit
weight (absolute) during
lactation at 42.4,85.0, and
169.9 mg/kg-d
23.6
DU
42.4
Aulerich et al.
(1979)
NPR,
PSg
Carcinogenic
ND
2. Inhalation (mg/m3)"
Subchronic
51/51, F344 rat,
6 hr/d, 5 d/wk, 13 wk
0,0.97, 4.9, or
49
Increased formation of hyaline
droplets in proximal convoluted
tubules of the kidneys in male
rats
M: 0.97
F: 49
DU
M: 4.9
F: NDr
Exxon (1980);
Dodd et al.
(1982); Bevan
et al. (1992)
NPR,
PS
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Table 3. Summary of Potentially Relevant Data for DCPD (CASRN 77-73-6)
Category
Number Of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry"
Critical Effects
NOAEL3
BMDL/
BMCLa
LOAEL3
Reference
(Comments)
Notesb
Subchronic
12/12, Harlan-Wistar
rat, 7 hr/d, 5 d/wk, 89 d
0, 22.2, 39.7, or
83.1
Histologic lesions in the kidneys
(i.e., round cell accumulations,
dilated tubules, casts, and tubular
degeneration) in both sexes at
concentrations >39.7 mg/m3;
effects were more severe and
frequent in males as compared to
females
22.2
DU
39.7
Kinkead et al.
(1971)
PR
45/45, B6C3Fi mouse,
vapor, 6 hr/d, 5 d/wk,
13 wk
0, 0.97, 4.9, or
49
Increased mortality reported at
49 mg/m3
4.9
NDr
49 (FEL)
Exxon (1980);
Dodd et al.
(1982)
NPR
3, male Beagle dog,
7 hr/d, 5 d/wk, 89 d
0, 10.0, 26.5, or
36.5
Increased absolute kidney weight
in male dogs
10
DU
26.5
Kinkead et al.
(1971)
PR
Chronic
ND
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
dosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to an adjusted daily dose (ADD in mg/kg-d) for oral noncancer effects and a human equivalent
concentration (HEC in mg/m3) for inhalation noncancer effects. All long-term exposure values (4 wk and longer) are converted from a discontinuous to a continuous
exposure. Values from animal developmental studies are not adjusted to a continuous exposure M= males, F= females.
bNotes: PS = principal study, PR = peer reviewed, NPR = not peer reviewed.
0 Acute = Exposure for 24 hr or less (U.S. EPA, 2002).
dShort-term = Repeated exposure for >24 hr <30 d (U.S. EPA, 2002).
"Long-term = Repeated exposure for >30 d <10% lifespan (based on 70-yr typical lifespan) (U.S. EPA, 2002).
fChronic = Repeated exposure for >10% lifespan (U.S. EPA, 2002).
8Study evaluated by IRIS for the assessment of the related compound diisopropyl methylphosphonate (DIMP).
DU = data unsuitable; GD = Gestational Day; ND = no data; NDr = not determined; S-D = Sprague-Dawley.
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HUMAN STUDIES
Oral Exposures
No studies were identified.
Inhalation Exposures
The effects of inhalation exposure of humans to DCPD have been evaluated in one
chronic-duration epidemiologic retrospective study looking at reproductive endpoints
(Okubo et al., 2000).
Acute, Short-Term, and Long-Term Studies
No studies were identified.
Chronic-Duration Studies
Okubo et al. (2000)
Okubo et al. (2000) is a published, peer-reviewed retrospective epidemiologic study
characterizing the offspring of 15 male Japanese workers (mean age of 36.1 ± 7.3 years) in a
plastic products and DCPC recovery facility. The workers were engaged in the same type of
work and exposed to a mixture of epoxy resin, DCPD, cyclopentadiene, bisphenol A, and
epichlorohydrin throughout the observation period (1980-1997). No concentration information
for this mixture was provided. Individual interviews were conducted with the workers in
March 1998 to determine the sex of offspring, birth year, paternal age at start of tenure with the
company, and working period until the birth of offspring.
Results showed that the average age at start of tenure with the company was
19.3 ±1.1 years (ranging from 19 to 22 years), and the average working period until the birth of
offspring was 9.5 ±3.7 years (Okubo et al., 2000). A statistically significant excess of female
births (6 males and 18 females, binomial test; p < 0.01) were fathered by the workers for the
observation period; however, the study authors reported no statistically significant relationship
between the sex ratio and birth year, paternal age at the birth of offspring, paternal age at start of
tenure with company, or the working period until the birth of offspring. Due to the small number
of cases (15) and the exposure to a mixture of chemicals (of which DCPD was one of many
chemicals used in the facility), the determination of a NOAEL or LOAEL is precluded.
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure of animals to DCPD have been evaluated in three
sub chronic-duration studies (Hart, 1976 [rat and mouse], 1980), one developmental toxicity
study (Hart, 1980) and three reproductive toxicity studies (Aulerich et al., 1979; Hart, 1980;
Jamieson et al., 1995) studies.
Subchronic-Duration Studies
Hart (1976)
Hart (1976) conducted a sub chronic-duration (90-day) oral toxicity study of DCPD
administered through the diet of rats for Litton Bionetics, Inc. Concentrations of 80-, 250-, and
50-ppm DCPD (purity 98-99%) to 30 male and 30 female Sprague-Dawley (S-D) rats per
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treatment group in a Purina Rat Chow diet, 7 days/week for 90 days. Average daily doses1 of 0,
6.3, 19.2, or 57.4 mg/kg-day for male rats and 0, 7.2, 22.6, or 68.1 mg/kg-day for female rats
have been calculated using time-weighted average body weights and food consumption
calculated on a weekly basis. The control group (30 male and 30 female) received standard feed
without DCPD. Body weights and food consumption were recorded on a weekly basis as were
animal appearance, behavior, and overt signs of toxicity or pharmacologic effects. Mortality was
assessed daily. Prior to the administration of the compound and again during the final week of
exposure, a veterinarian performed an ophthalmoscopic examination on each animal. Clinical
laboratory measurements were conducted on five rats per sex per group at Weeks 4 and 13
postdosing. These measurements included hemocytology (i.e., erythrocyte count, cell packed
volume, hemoglobin, and total and differential leukocyte counts), blood biochemistry
(i.e., glucose, blood urea nitrogen [BUN], serum glutamic oxaloacetic transaminase [SGOT],
alkaline phosphatase, serum glutamic pyruvic transaminase [SGPT], sodium, potassium, and
chloride), and urinalysis (i.e., color, specific gravity, pH, sugar, protein [albumin], ketones
[acetone], and microscopic examination of sediment). At study termination, animals were
necropsied. The following organs were removed and weighed: brain, thyroid, heart, liver,
spleen, kidneys, adrenal glands, testes (male), and ovaries (female). This study was not
peer-reviewed and did not report Good Laboratory Practice (GLP) compliance.
Results of the hemocytology and blood biochemistry analysis at the 4- and 13-week
interval show no treatment-related effects (Hart, 1976); the few instances of statistically
significant differences from control values are scattered, and the study author reported them as
having "no toxicological importance." Additionally, no deviations from normal baseline values
were obtained in the urinalysis results at either Week 4 or at the termination of the study
(Week 13). The absolute weights of various organs collected during necropsy were recorded and
presented as original data (see Tables B. 1 for males and B.2 for females); calculations of the
relative organ weights were also made (see Table B.3 for male rats and Table B.4 for female
rats). The study author did not provide statistical analyses of organ-weight data. An
independent statistical analysis performed for the purposes of this review revealed no
dose-dependent changes in absolute and relative organ-weights. In females, the few statistically
significant differences that were observed were not >10% change and do not meet the criterion
of biological significance. For male rats, a significant increase in thyroid weight was observed
that exceeded 10% compared to control. This increase was noted at all doses for both relative
and absolute thyroid weight but was statistically significant only in the low- and mid-dose groups
for absolute weight. Also, a biologically and statistically significant increase in absolute spleen
and adrenal weight at the mid dose only (i.e., no dose response) was observed. The results of the
histopathological examination show the presence of microscopic lesions. These lesions appeared
in all dose groups and were synonymous with those routinely encountered in rats (as reported by
the veterinary pathologist that examined the animals). Thus, it is difficult to interpret the
sporadic changes observed in organ weight. No other abnormalities were reported. The study
author did not define a NOAEL or LOAEL; however, based on the lack of observed toxicity at
any of the DCPD concentrations measured, the highest concentration (57.4 mg/kg-day for males
and 68.1 mg/kg-day for females) is considered the NOAEL. A LOAEL is precluded.
Average daily dose = dose in ppm x (food consumption body weight) x (days dosed total days). Average daily
dose = 80 ppm x (17.23 190.6) x (7 -f- 7) = 7.2 mg/kg-day.
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Hart (1976)
Hart (1976) also conducted a subchronic-duration (90-day) oral toxicity study of DCPD
on mice for Litton Bionetics, Inc. Swiss Albino mice, 32 male and 32 female, (64 mice per
exposure group) were exposed to 28-, 91-, or 273-ppm DCPD (purity 98-99%) in feed
7 days/week for 90 days. The control group (32 mice per sex) was fed a standard rodent chow
with no addition of DCPD. Average daily doses of 0, 5.6, 17.0, or 49.5 mg/kg-day for male mice
and 0, 8.1, 22.7, or 68.4 mg/kg-day for female mice were calculated using time-weighted average
body weights and weekly food consumption. The mice were housed in groups of five in
solid-bottom cages throughout the experiment. Body weights and food consumption were
recorded on a weekly basis, daily observations for mortality were made, and daily records for
appearance, behavior, and signs of toxic or pharmacologic effects were kept. Although a
recovery period of 2 and 4 weeks had been initially planned, this was later eliminated by
agreement with the project officer when no effects were observed; all surviving mice at the
termination of the experiment were sacrificed. Following sacrifice, each animal was subjected to
a gross necropsy where any abnormalities observed were recorded. The heart, liver, spleen,
kidneys, gonads, and adrenals and thyroid (both after fixation) were removed and weighed. The
following organ samples were also collected and preserved in 10% neutral formalin: brain,
pituitary, thyroid, lung, heart, liver, spleen, kidneys, adrenals, stomach, pancreas, small and large
intestine, mesenteric lymph node, nerve with muscle, testes with epididymis, seminal vesicles,
ovaries, uterus, bone marrow, urinary bladder, thoracic spinal cord, eye, rib junction, and any
additional organ structures showing lesions. A histopathologic examination was also performed
on five male and five female mice from both the control and highest (68.4 mg/kg-day) treatment
groups; tissues showing any abnormalities in the highest treatment group were subsequently also
examined in the lower dose groups. Tissues examined included brain, pituitary, thyroid, heart,
liver, spleen, kidneys, adrenals, stomach, pancreas, small and large intestine, mesenteric lymph
node, testes or ovaries, uterus or prostate, bone marrow, urinary bladder, and any other tissues
showing unusual lesions.
All mice but one survived until planned sacrifice (Hart, 1976). Because the mice were
housed as a group during the exposure (n = 5/group), the weights of the group, and not individual
mice, were recorded. The average body weight for each group was not found to be statistically
different; the author reported similar growth in all treatment groups. Food consumption values
were also calculated as averages for five mice per cage at each exposure concentration. The
author reported that no differences in food consumption were observed between the treatment
and control groups. No signs of toxicity were noted in any of the groups of mice throughout the
experiment. The study author did not provide statistical analyses of organ-weight data. An
independent statistical analysis revealed a statistically significant decrease in absolute and
relative thyroid weights in female mice at the mid dose but this decrease was not dose dependent
(see Tables B.5 and B.7). In male mice, sporadic differences in both absolute and relative organ
weights were observed (see Tables B.6 and B.8). In male mice, the only statistically significant
changes in absolute organ weight occurred at the mid dose and included decreases of >10% for
spleen and testes and 9% for kidney. Relative liver weight was also statistically significantly
decreased in male mice at all doses, but the decrease did not reach biological significance
(i.e. change was <10%). Relative spleen weight was statistically and biologically (i.e., >10%)
significantly decreased in the low and mid dose groups, but not in the high dose group. Relative
kidney weights were statistically significantly decreased at all doses, but only the mid dose was
biologically significant. Relative testes weights were statistically and biologically significantly
depressed at all doses, but no dose-response trend was observed. Following a histopathologic
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examination by a veterinary pathologist, all lesions observed in the study were those routinely
encountered in unexposed mice. These lesions were found in all dose groups and were not
different than those reported in controls. Thus, it is difficult to interpret the sporadic changes in
organ weights. No additional abnormalities were noted, and the study author concluded that no
evidence of toxicity occurred during the 13-week study following dietary administration of 0-,
5.6-, 17.0-, or 49.5- and 0-, 8.1-, 22.6-, or 68.4-mg/kg-day DCPD in male and female mice,
respectively. The study author did not define a NOAEL or LOAEL; however, based on the lack
of biologically significant effects at any of the DCPD concentrations measured, the highest
concentration (49.5 mg/kg-day in males and 68.4 mg/kg-day in females) is considered the
NOAEL. Identification of a LOAEL is precluded.
Hart (1980)
Hart (1980) conducted a sub chronic-duration (90-day) oral toxicity study of DCPD on
dogs for Litton Bionetics, Inc. Thirty-two purebred beagle dogs (16 male and 16 females, 5 to
6 months old) were received and housed individually in stainless steel cages. Prior to the
initiation of the study, all animals were subjected to a preliminary health screening, which
included clinical, biochemical, hematological, ophthalmological, and parasitological
examinations. Protozoan parasites (Giardia canis, Isopora and Trichomonas species) were
found in 16 (50%) of the dogs. The study author considered the parasites to be nonpathogenic
and cleared the dogs for use in the study. Eight dogs in each group (four male and four female)
were randomly assigned to treatment groups and exposed to 0-; 100-; 300-; and 1,000-ppm
DCPD (purity 98-99%). The doses were prepared in corn oil and blended into dog meal. All
dogs were given daily administrations of the compound through feed, 7 days/week, for 13 weeks;
based on reported time-weighted average body weight and food consumption data, average daily
doses of 0, 2.7, 8.4, or 28.2 mg/kg-day for males and 0, 2.7, 8.6, or 28.8 mg/kg-day for females
were calculated. Water was provided ad libitum. Animals were observed daily for general
appearance, behavior, food consumption, and fecal consistency. Body weights were recorded
weekly for each animal, and blood samples were collected from each dog at the initiation of the
study, as well as at Weeks 4, 8, and 13 for pathological determinations. Dogs were fasted
overnight prior to the collection of each sample. The study author did not report GLP
compliance status.
Blood collected from each animal was used for hematology (i.e., hemoglobin,
erythrocytes, leukocytes, differential count, and packed cell volume) and blood chemistry
(i.e., glucose, calcium, urea nitrogen, SGPT, SGOT, uric acid, alkaline phosphatase, total
protein, albumin, cholesterol, lactic dehydrogenase, phosphorus, and bilirubin). Following
overnight fasting, urinalysis was also performed on all animals at study initiation and at 8 and
13 weeks of exposure to measure specific gravity, pH, color, sugar, albumin, ketones, occult
blood, bilirubin, and a microscopic examination of sediment. Additionally, a veterinary
ophthalmologist performed examinations on each animal initially and again prior to study
termination. Animals were sacrificed at 94-97 days of exposure. Following termination, the
animals were weighed and subjected to a complete necropsy, with the following organs and
tissues weighed and preserved for analysis: brain, pituitary, spinal cord, eye, stomach, small and
large intestine, testes with epididymis, thyroid, pancreas, lung, heart, rib junction, gall bladder,
liver, spleen, kidneys, adrenal glands, prostate, ovary, uterus, bone marrow, skeletal muscle and
nerve, urinary bladder, mammary gland, mesenteric lymph node, and any other unusual lesions.
A veterinarian completed pathological evaluations of the tissues from dogs, representing both the
control and high-dose groups.
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No mortality was observed in any of the treatment groups throughout the duration of the
study (Hart, 1980). The recorded clinical observations showed no remarkable differences
between treated and control groups with the possible exception of a slightly higher frequency of
vomiting and soft stools among the treated dogs, especially those from the highest treatment
group (28.2 mg/kg-day for males and 28.8 mg/kg-day for females). However, similar
observations were made in some of the control animals and these effects (i.e., vomiting and soft
stools) were considered minor in all groups. Therefore, the biological significance of these
findings is not clear. No other dose-dependent effects were reported.
The study author concluded that the treatment concentrations produced no significant
toxicity with only minor intestinal distress (i.e., vomiting and soft stools) observed in dogs from
all treatment groups but also occasionally observed in the control animals. The author did not
report a NOAEL or LOAEL for the study. Due to a lack of treatment-related effects observed at
the highest dose administered, a NOAEL of 28.2 mg/kg-day for males and 28.8 mg/kg-day for
females is identified. Identification of a LOAEL is precluded because the highest dose tested is
considered a NOAEL.
Chronic-Duration Studies
No chronic-duration studies were identified.
Developmental Studies
Hart (1980)
Hart (1980) administered DCPD (purity >98%) daily at 0, 80, 250, and 750 ppm to
groups of 20 CRL:COBS CD (SD) BR pregnant rats in food on Gestational Days (GDs) 6-15.
Average doses of 0, 6.2, 21, and 63 mg/kg-day were calculated using time-weighted average
body weights and weekly food consumption. The study author examined the animals daily for
mortality and signs of toxicity and recorded body weights on GDs 0, 6, 9, 15, and 19. Food
consumption was measured during GDs 0-6, 6-16, and 16-19. The animals were sacrificed on
GD 19, and the visceral and thoracic organs (not otherwise specified) were examined. The
uterus was removed and examined. The number of implantations sites and their placement in the
uterine horns, live and dead fetuses, and resorption sites were recorded.
One third of the fetuses of each litter were fixed in Bouin's fluid and later examined for
changes to the soft tissues of the head and thoracic and visceral organs. The remaining fetuses
were examined for skeletal abnormalities. Statistical analysis of data used the litter as the basic
sampling unit. Dunnett's /-test was applied to body weights, food consumption, and litter
averages of pup weight; ratios were analyzed using a 2 x 2 contingency table with Yates'
correction; and discontinuous parameters were analyzed using the Wilcoxon Rank Sum method.
No deaths were observed in the control or treatment groups. One female rat in the
low-dose group appeared sick and emaciated, but examination at necropsy indicated that this was
not treatment related. No statistically significant differences were observed between any of the
treated groups and the control group with respect to mean body weight and food consumption.
Examination of the uterine contents at GD 19 revealed no effect from the treatment with DCPD
at any dose (see Table B.9). Fetuses in all treatment and control groups had subcutaneous
hematomas that were not considered to be treatment related.
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The sex ratio in the treated groups was not statistically different from the control group
(see Table B.10), and the results of the skeletal examination revealed common abnormalities that
were not treatment related (see Table B. 11). Based on these findings, the study author identified
a NOAEL of 63 mg/kg-day for maternal and fetal effects. A LOAEL for either maternal or fetal
toxicity was not identified for DCPD.
Reproductive Studies
Hart (1980)
Hart (1980) conducted a three-generation reproductive and developmental study in which
groups of 10 male and 20 female CRL:COB (SD) BR rats (Charles River Breeding Laboratories,
Inc., Portage, MI) were administered 0, 80, or 750 ppm (0, 87, and 92% of the desired
concentration, equivalent to 0, 69, or 690 ppm) DCPD (purity 98-99%; in corn oil) in diets
prepared weekly. The F0 generation was administered DCPD starting at 7 weeks prior to
mating. The length of treatment for each of the generations is not specified in the study report.
Parental rats in each generation were mated twice to produce "a" and "b" sets of offspring.
Adjusted daily doses for the male and female rats were calculated utilizing measured food
consumption and body-weight data. The adjusted daily doses for the F0 generation were 0, 3.6,
or 34.2 and 0, 4.8, or 48.1 mg/kg-day for male and female rats, respectively; 0, 4.3, or 39.9 and
0, 7.8, or 60.7 mg/kg-day for male and female rats in the F1 generation, respectively; and 0, 4.6,
or 44.1 and 0, 8.1, or 73.1 mg/kg-day for male and female rats in the F2 generation, respectively.
The F3 generation did not receive direct dietary treatment. Hereafter, the treatment groups are
referred to as "low" and "high," including in the data tables in Appendix B. Food (Purina
laboratory chow) and water were provided to the animals ad libitum. This study was not
peer-reviewed but a portion of the Hart (1980) study in which diisopropyl methylphosphonate
(DIMP) was administered with identical methodology as DCPD was evaluated by IRIS and
employed as the principal study for their assessment of DIMP (U.S. EPA, 1993). It is unclear if
this study was conducted according to GLP; no certificate is supplied in the report.
Mating began 7 weeks after administration initiation. At the end of the mating, females
were returned to individual cages for the gestation and lactation periods. One week following
the weaning of the first litter of pups (Fla), the F0 parental animals were remated, each male
with a different pair of females in the same exposure group. One week after weaning the second
litter (Fib), the F0 parents were sacrificed and necropsied. One male and two female Fib pups
from each litter became the parents for the next generation (F2). These animals were maintained
and treated identically to the F0 parental animals. When the Fib rats were approximately
100 days old, they were mated to produce F2a and F2b litters. The same procedure was used to
produce the F3a and F3b pups.
At Week 4 and during Weeks 8-9, the body weight and food consumption of the parent
rats were measured. These parameters were estimated and recorded prior to each mating. Rats
were observed daily for mortality and general toxicity, as well as any gross abnormalities in
pups, number of live and dead pups, pup mean body weight by sex at birth, number of animals
per sex at Day 4 of lactation, and number per sex and body weights at Day 21 (weaning). At
Day 4, each litter was reduced to eight total pups (four/sex when possible). For each generation,
gross necropsies were performed on one-third of the first litters at weaning.
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Results from the first generation (including the F0 parents and Fla and Fib offspring)
show that mortality occurred in one F0 female at the low dose; all other animals survived the
study, and the study author reported them as being in "generally good condition." No
statistically significant changes in body weight or food consumption were observed between
control and treatment groups in the F0 generation. No dose-related changes were reported
following the gross necropsy of the F0 parents. Observation revealed that one pup in the low
exposure litter had an opaque left eye, and one pup in the high treatment group had a crooked
tail. The author reported that such observations were not treatment related and therefore "not
meaningful." Similar results were reported in the Fib generation, with the control and treatment
group being comparable with respect to both litter data and pup observations. One instance of an
abnormality (a deformed hind foot) was reported in a pup exposed at the low level, but again, the
author did not consider this effect related to treatment.
In the second generation (comprising the Fib parents and F2a and F2b offspring), no
difference in body weights between the control and treatment-related groups was observed, with
the exception of a slight reduction (which was not statistically significant) in body weight in the
low-dose parental females at Week 20 and just prior to mating. Food consumption followed a
similar trend, with statistically significant reduced food consumption in both the males and
females in the high exposure group at Week 20. The F2a (see Table B. 12) and F2b (see
Table B.13) litter data showed no biologically significant differences between the control and
exposure groups. Fertility was reduced (25% and 15% of controls, respectively) in the high
female exposure group in both litters (F2a and F2b), but these reductions were not statistically
significant. The study author noted that one male in the 39.9-mg/kg-day treatment group in each
litter failed to sire a litter and that this may have been the cause of the decreased fertility in the
high-dose females. Although a statistically significant decrease in pup viability was observed in
the low-dose F2a litter, it is not considered biologically significant because no similar change
was observed in the high-dose F2a litter, and no toxicologically relevant changes were observed
in any of the F2b litters either. No gross lesions were found in the Fib parents during necropsy.
Both general and necropsy observations in the F3a and F3b offspring as well as gross
necropsy findings in the F2b parents did not yield any compound-related effects. A slight, but
statistically significant, reduction in mean pup weight at weaning was observed in the treatment
groups when compared to the controls in the high-dose group (see Table B. 14). The study author
indicated that this decrease in pup weight was not biologically significant due to the lack of
weight changes seen in the other litter (F3a) of this generation (see Table B. 15) or in prior
generations. However, there are no indications that this finding was caused by reduced
palatability (food consumption was not decreased in parents or offspring) or reductions in
maternal body weight (female F2 parental body weight was comparable to controls).
Furthermore, pup viability was not decreased compared to controls (in a statistically or
biologically significant manner), so the statistically significant decrease in body weight was not
likely affected by sample size. An overall reduction in female fertility compared to males was
observed in the F3a offspring (80 and 83% in the low and high treatment groups, respectively);
however, the fertility in the female control group was only 65%, and therefore, changes were
deemed not related to compound administration (see Table B.15). This lower overall fertility
also carried over to the F3b offspring, where fertility was 80 and 83% for low and high treatment
groups, respectively, but was not statistically significantly different from controls, which had a
fertility index of 85% (see Table B. 14).
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The study author concluded that dietary administration of DCPD to three successive
generations of male and female rats resulted in no deleterious effects in either general condition
or reproductive performance of the animals when compared to control rats. Based on the lack of
reproductive effects, NOAELs of 34.2 and 48.1 mg/kg-day for males and females, respectively,
are identified. Identification of a LOAEL is precluded.
Jamieson et al. (1995)
In a study conducted by Jamieson et al. (1995) and published as a Society of Toxicology
conference abstract, the reproductive effect of DCPD on S-D rats was assessed. Because the
study was published as a conference abstract, the study methods were not completely reported;
however, the following details were available. DCPD (purity not specified) was administered by
gavage (using corn oil as a vehicle control) at dose levels of 0, 10, 30, and 100 mg/kg-day to
male and female animals housed individually and then housed together for 16 weeks
(20 animals/sex/group). Newborn litters were sacrificed on Postnatal Day (PND) 1 following
evaluation, and litters born on Week 17 or later were reared to PND 21. At this time, selected
weanlings (Fl) were administered the same dose levels as their parents. On PND 81 ± 10,
F1 animals were housed together within groups for 1 week and necropsied after the delivery of a
litter (F2). The abstract did not report GLP compliance during the study, and the statistical tests
used for comparison of control and treatment groups were not stated.
Females exposed to 100 mg/kg-day exhibited higher Fl pup mortality, 28% fewer live
pups, 8% lower adjusted live Fl pup weight, and increased cumulative days to litter. At
30 mg/kg-day, female pup weight was decreased approximately 4%. In a crossover mating
study, pup weight was reduced (9%) in litters born to the DCPD-treated females; this effect was
not observed in litters produced from DCPD-treated males. Treatment with DCPD also affected
organ weight in Fl rats, with increases of 2, 7, and 17% in liver weight and increases of 16, 15,
and 16%) in kidney weight in males treated with 10, 30, and 100 mg/kg-day, respectively (data
not shown). When the livers of rats exposed to 30 and 100 mg/kg-day were evaluated
microscopically, an increase in clear cell foci was reported (data not shown). In the second (F2)
litter, exposure to 100 mg/kg-day DCPD caused a 12%> reduction in pup weight when liver and
kidney weights were increased in the Fl generation (data not shown).
The study authors concluded that, although reproductive effects were observed in both
generations, the effects were greater in the first generation than the second generation. The
doses which increased liver and kidney weights in the parents also produced systemic toxicity in
newborns, suggesting that DCPD is not selectively a reproductive toxicant. The authors did not
identify a NOAEL or LOAEL from the study results; however, based on the reduction in pup
survival and weight at birth observed during the study, a NOAEL of 10 mg/kg-day and a
LOAEL of 30 mg/kg-day are identified.
Aulerich et al. (1979)
Aulerich et al. (1979) is selected as the principal study for the derivation of the
subchronic and chronic p-RfDs. This report is not peer-reviewed but was evaluated by IRIS
for the assessment of DIMP (U.S. EPA, 1993). In this one-generation reproductive study, 30
(6 males and 24 females per dose group), 3-month old, dark variety minks were administered 0-,
100-, 200-, 400-, or 800-ppm (estimated as 0, 23.6, 42.4, 85.0, or 169.9 mg/kg-day for combined
male and female minks by the study authors through measured food consumption and
body-weight data; see Table B. 16) DCPD (purity >99%) in the diet for 12 months, equivalent to
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one reproductive season. The life span of a mink in captivity has been estimated to be up to
8 years (Basu, 2013); therefore, this 12-month reproductive study represents a chronic exposure
duration for the F0 animals as the treatment with DCPD occurred for greater than 10% of the
total mink life span. Mortality and other signs of toxic stress were recorded throughout the
duration of the experiment, although the frequency was not recorded. Body weight and feed
consumption were measured every 2 weeks, with the exception of the gestation period. Blood
samples (for packed cell volume and hemoglobin) and blood smears (for differential leukocyte
counts) were collected prior to the study initiation, at 3-month intervals through the study, and at
the conclusion of the study. All parameters were evaluated utilizing analysis of variance and
Dunnett's Mest. The authors did not report GLP compliance status.
Mating began on March 1, 1978, and continued for approximately 20 days, during which
females were introduced into the males' cages every fourth day for up to an hour (or until a
positive mating confirmation was made). Whenever possible, mating pairs in the same treatment
group were used. After successful breeding, the females were transferred to individual cages
with a nest box and provided with shredded wood, used for both insulation and nesting material
during whelping. During whelping (April 20-May 15), the nest boxes were checked daily for
evidence of kits; when found, newborn kits were sexed, and both mother and kit were weighed at
whelping and when kits were 1 month of age. Gestation length, litter size, sex ratio, kit
mortality, increase in kit biomass during lactation, and changes in the weight of the lactating
female were recorded. At study termination, all minks were weighed, blood samples collected
via cardiac puncture, and the animals sacrificed. The following whole organs were removed
during necropsy, weighed, and evaluated for pathomorphological changes: brain, liver, kidneys,
spleen, gonads, lungs, heart, and adrenal glands as well as portions of the intestine, stomach,
skeletal muscle, adipose tissue, and integument.
Chronic ingestion of DCPD in the diet of minks at concentrations up to 169.9 mg/kg-day
for 12 months did not result in treatment-related mortality in any of the groups (Aulerich et al.,
1979). Changes in body weight showed no dose-related trend, although in a few instances,
animals in the highest exposure group (169.9 mg/kg-day) were reported to have reduced body
weights compared to the control animals; however, when analyzed as a change in body-weight
percentage over the course of compound administration, these changes were not apparent (see
Table B.17). Feed consumption in the high dose group was initially reduced compared to
controls but was reported as greater than controls by study termination (although this change was
not reported as statistically significant). Changes in hematological values (including packed cell
volume, hemoglobin, and differential leukocyte counts) were equally inconsistent and not found
to be dose dependent.
No treatment-related effects on reproductive performance were reported in male or
female minks following exposure to DCPD. Whelping rates, gestation length, fecundity, kit
weight at birth, and secondary sex ratios were also unaffected. Although kit mortality was not
altered by DCPD, the absolute weight of kits during lactation was statistically significantly
depressed at Week 4 for animals in the 42.4-, 85.0-, or 169.9-mg/kg-day treatment groups (see
Table B.18). The study authors hypothesized that the reduced absolute weight was attributable
to either a toxicological effect on the kits through direct ingestion of the chemical in milk or
indirectly through a perturbation in maternal metabolism, which affected lactation. When the
organs were evaluated following study termination, the only statistically significant changes
reported between the treatment and control samples were a reduction in spleen weight in the
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85.0-mg/kg-day group (2.4 ± 0.16 vs. 3.3 ± 0.29 g, respectively) and a reduction in the weight of
the testes in the 169.9-mg/kg-day group (1.1 ± 0.1 vs. 1.8 ± 0.1 g, respectively; see Table B.19).
Although a reduction in spleen weight was reported at 85.0 mg/kg-day, this effect was not
observed in the highest dose group, and therefore, the study authors explained the reduction as
occurring from chance variation or sampling error. Likewise, the study authors explained the
reduction in testes weight observed in the high dose group as the normal seasonal reduction that
occurs in this species.
The study authors concluded that chronic ingestion of DCPD in the diet of minks had no
adverse effect on growth, survival, or reproductive performance. However, the absolute weight
of neonates from lactating dams fed 42.4-, 85.0-, or 169.9 mg/kg day DCPD was statistically
decreased in a dose-dependent manner compared to that of neonates for dams in the control or
low-dose group. Spleen weight was reduced at 85.0 mg/kg-day, and testes weight was reduced
at 169.9 mg/kg-day, respectively, but the study authors did not consider these reductions to be
treatment related. No NOAEL or LOAEL was reported in the study, but based on reductions in
the kit weight following 4 weeks of nursing at the three highest concentrations, a LOAEL of
42.4 mg/kg-day and a NOAEL of 23.6 mg/kg-day are identified.
Inhalation Exposures
The effects of inhalation exposure of animals to DCPD have been evaluated in four
sub chronic-duration studies (Exxon, 1980 [rat and mouse]; Dodd et al., 1982 [rat and mouse];
Bevan et al., 1992 [rat]; Kinkead et al., 1971 [rat and dog]).
Subchronic-Duration Studies
Exxon (1980); Dodd et al. (1982); Bevan et al. (1992)
Exxon (1980) is selected as the principal study for the derivation of the screening
subchronic and chronic p-RfCs. In a non-peer-reviewed subchronic-duration (90-day)
inhalation study performed by Exxon (1980) and reported in Dodd et al. (1982), Fischer 344
(F344) rats (51 male and 51 female rats per exposure concentration) were exposed to target
concentrations of 0-, 1-, 5-, or 50-ppm in air; actual air concentrations were 0-, 1.0-, 5.1-, or
51.0-ppm DCPD (purity 95%) for 6 hours/day, 5 days/week, for 13 weeks. The corresponding
HECs are calculated as 0, 0.97, 4.9, and 49 mg/m3. Nine animals/sex/concentration were
sacrificed at Weeks 3, 7, 14, 18, and 27 of the study, with Weeks 18 and 27 corresponding to
Weeks 4 and 13 postexposure. These sacrifice periods were identified as Groups A, B, C, D, and
E, respectively, throughout the remainder of the study report.
All animals were weighed the morning before the first exposure (reference weight), and
this value was subtracted from each subsequent weight measurement to obtain the change in
body weight throughout the course of the experiment. Body-weight measurements were taken
weekly for the first 4 weeks and then every 2 weeks for the remainder of the exposure. The
animals' weights were collected again prior to sacrifice. Mean food (see Table B.20) and water
consumption (see Table B.21) were measured during urine collection periods and standardized to
24-hour rates (Group B rats only), allowing comparisons to be made between measurement
periods for each exposure group. Each animal also underwent an ophthalmologic examination
(prior to sacrifice interval). Other tests included blood chemistry (prior to sacrifice interval),
histopathology of kidneys and urinary bladder following necropsy, and electron microscopy of
kidney tissue at the sacrifice intervals at Weeks 14 and 17. Additionally, upon sacrifice, a
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necropsy of the animal was performed, and the following organs removed and weighed: kidney
(left and right, weighed individually), lung, liver, and testes (males). The study authors did not
report GLP compliance status.
One male rat died accidently following the 16th exposure (reason not reported); no other
rat mortality was observed in the study. Observation of the rats during the 6-hour exposure
period indicated normal appearance of all rats. Several conditions recorded in the exposure
groups were also recorded in the control group including urogenital area wetness (females),
lacrimation, and alopecia (males). However, during the recovery period, these observations were
recorded only in exposed rats, not in control rats. No statistically significant changes in body
weight occurred in either the control or exposed rats throughout the study duration. Changes in
food consumption results were observed in male and female rats; however, the differences were
not related to the DCPD concentration or the number of exposures. A decrease in food
consumption was reported at 92 days postexposure in all DCPD exposure groups and was
accompanied by a depression in body weight at the 4.9-mg/m3 concentration level. However, the
biological significance of these findings was not assessed by the study authors.
Although concentration-related differences were observed with respect to blood analysis,
they were not found to be biologically significant. The following differences were observed:
hematology (e.g., depression in red blood cells of male rats at the highest exposure
concentration), serum chemistry (e.g., an increase in serum calcium and a decrease in alanine
aminotransferase in males exposed to 4.9 and 49 mg/m3 DCPD), and the ophthalmologic
examination (mild conjunctivitis with lacrimation in the eyes of male rats at both 4.9 and
49 mg/m3 in Group B; a nonreactive dilated pupil was observed in one control [Group C] and
one 49-mg/m3 female rat [Group D]; and two female rats exposed to 0.97 and one to 4.9 mg/m3
developed conjunctivitis with lacrimation in Group E).
The urinalysis results showed that the majority of male rats exposed to 49 mg/m3 and
many of the rats exposed to 4.9 mg/m3 DCPD had a decrease in urine specific gravity and
osmolality, which was concentration dependent and related to the number of DCPD exposures
and the concentration of DCPD (see Table B.22). Analysis of the urinary sediment content in
male rats showed evidence of toxic renal damage, with epithelial cells and epithelial cell casts
being found in rats from 8 completed exposures and after as much as 29 days of recovery (see
Table B.22). The presence of the epithelial cells and casts was reported as dependent on the
DCPD concentration. Trends in urinary excretion rates were also reported, including a
statistically significant decrease in calcium and sodium and an increase in potassium in the latter
part of the exposure regimen (in the 49-mg/m3 group; a similar trend was observed in the
4.9-mg/m3 group, although the values were not statistically significant). It is important to note
that these findings were solely identified in males, as no abnormal urinary findings were reported
in female rats.
The results of the gross necropsy showed an increased incidence of tubular hyperplasia
and a reticular pattern in the kidneys of males exposed to 49-mg/m3 DCPD. A similar reticular
pattern, accompanied by a generalized color change of the kidney, was observed in Group A
male rats exposed to 4.9 and 49 mg/m3 DCPD at an earlier sacrifice period. The study authors
reported no statistically significant differences in the gross lesions between exposed and control
groups and that these effects were reversible and no longer apparent at the end of the exposure
regimen or at recovery sacrifice. Organ weights followed a similar pattern, with a statistically
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significant increase in relative liver weights in male rats exposed to the highest concentration of
DCPD (Groups A, B, and C). However, the increases at 49 mg/m3 were not greater than
10% over controls (9.9, 4.8, and 6.9 in the A, B, and C groups, respectively). Although male rats
exposed to 0.97 mg/m3 also exhibited increased absolute liver weights, the body weights of the
animals exposed to 0.97 mg/m3 were greater than the body weights of control animals, so
changes in relative liver weight were minimal. A statistically significant increase in both relative
and absolute kidney weight for the left and/or right kidney was also found in male rats from
Groups A, B, and C exposed to 49 mg/m3 when compared to controls. However, these
differences were not consistently greater than 10% for all three groups, were reversible [not
observed by postexposure Day 29 (see Table B.23)]. Group E female rats exposed to 0.97- and
49-mg/m3 DCPD had a statistically significant decrease in the relative weight of the left kidney
only. Due to these decreases being slight and not observed in the right kidney, Exxon (1980) and
Dodd (1982) attributed the observation to body-weight gain throughout the course of the
experiment. No other instances of organ-weight differences were reported among
DCPD-exposed female rats.
Exxon (1980) and Dodd (1982) hypothesized that the kidney lesions, which progressively
worsened throughout the exposure and recovery phase of the study, were due to chronic
glomerulonephrosis, a common syndrome in F344 rats. This syndrome occurs in conjunction
with advancing age in both male and female rats. However, the presence of epithelial cells and
casts, regenerative epithelium (tubular hyperplasia), and dilation of the tubule in the kidneys,
coupled with the most severe effects being observed in male species, could be indicative of an
alpha 2u-globulin pathway. Although staining for hyaline droplets was not reported by Exxon
(1980) or Dodd (1982), Bevan et al. (1992) used data from Exxon (1980) to examine hyaline
droplets and quantify severity indices.
The histological examination of the kidneys from rats exposed to 4.9 and 49 mg/m3 by
Bevan et al. (1992) showed the formation of hyaline droplets in the proximal convoluted tubules
at a much greater level than the control rats (see Table B.24). The formation of these droplets
was concentration dependent in nature and later confirmed through electron microscopy. By
Week 13 of exposure, male rats exposed to 49 mg/m3 DCPD developed tubular proteinosis,
which persisted after the recovery period. Similar results were observed in the regenerative
epithelium, which increased in severity throughout the exposure (see Table B.25) and lessened
only minimally throughout the recovery. No liver or kidney changes were observed or reported
in female rats. A study by Hamamura et al. (2006), which performed immunohistochemical
analysis, suggests that hyaline droplets forming in male rats following DCPD exposure are
composed of alpha 2u-globulin. However, the Hamamura et al. (2006) study was short term,
exposed animals only through the oral route, and utilized a small sample size. Additionally, the
sub chronic-duration oral rat study by Hart (1976) utilized a larger sample size and higher DCPD
concentrations than Hamamura et al. (2006) but did not report any kidney effects. Taken
together, these data suggest that the relevance of the rat kidney lesions observed in the Exxon
(1980) study to humans cannot be discounted. Hence, the increased formation of hyaline
droplets in the kidneys of male rats is considered the critical effect, with a LOAEL of 4.9 mg/m3
and a NOAEL of 0.97 mg/m3. No biologically significant toxicity was observed in female rats at
any concentration tested (NOAEL of 49 mg/m3, the highest concentration tested).
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Kinkead etal. (1971)
In a peer-reviewed and published subchronic-duration inhalation toxicity study conducted
by Kinkead et al. (1971), groups of 12 male and 12 female Harlan-Wistar rats were exposed to
mean measured concentrations of 0-, 19.7-, 35.2-, and 73.8-ppm DCPD (isomeric mixture of
endo/exo DCPD in a 95:5 ratio, purity 96.7%) vapor in air for 7 hours/day, 5 days/week, for
89 days. The corresponding HECs are calculated as 0, 22.2, 39.7, and 83.1 mg/m3. Changes in
body weight after the 4th, 13th, 31st, 55th, 75th, and 89th days of the study, liver and kidney
weights, and gross and microscopic pathology were measured and reported. Twenty samples
from the thoracic and abdominal cavities were also collected for microscopic examination
following necropsy. The study authors did not report the GLP compliance status.
No deaths were reported in any animals throughout the study duration. Reported results
show that convulsions were observed in one female at 22.2 and 83.1 mg/m3 on Exposure
Days 45 and 19, respectively. Another female rat exposed to 22.2 mg/m3, likewise, exhibited
convulsions for 5 minutes on Day 45. The study authors reported no other exposure-related
clinical signs of toxicity. The mean body weight of both sexes was reduced in the 83.1 -mg/m3
groups after 4 days, but no statistically significant changes in body weight were reported at the
end of the 89-day exposure. Male rats exhibited increased absolute and relative liver and kidney
weights at all exposure concentrations, ranging from 14-20% for the liver and 20-25% for the
kidney (see Table B.26). However, the authors noted that body weights in exposed animals were
consistently higher (6—25%) compared to the control group, thus explaining the increase in liver
and kidney weights reported in the exposed groups. As further support, the study authors also
stated that these changes in organ and body weights were not concentration dependent and that
similar effects were not found in females. Concentration-related histologic kidney lesions were
reported in both sexes at concentrations >39.7 mg/m3. The kidney lesions were described as
"round cell accumulations, dilated tubules, casts and tubular degeneration" and were reported in
the 39.7- and 83.1-mg/m3 exposure groups. The study authors also noted that the kidney lesions
were more severe and frequent in males than in females, although severity scores were not
presented in the study results. Additionally, chronic pneumonia and bronchiectasis were
reported in three male rats from the highest exposure group, and although this was not
considered a biologically significant finding, it represents injury to the lung after repeated
inhalation of DCPD at this concentration. Other pathologic effects in the lung were not
concentration related, and no other effects were reported in the organs and tissues.
Based on concentration-related histologic kidney lesions (i.e., round cell accumulations,
dilated tubules, casts and tubular degeneration) that were reported in both sexes at concentrations
>39.7 mg/m3, the low concentration 22.2 mg/m3 is identified as aNOAEL, and the mid
concentration of 39.7 mg/m3 is identified as a LOAEL.
Exxon (1980); Dodd et al. (1982)
In a non-peer-reviewed subchronic-duration (90-day) inhalation study performed by
Exxon (1980) and reported in Dodd et al. (1982), B6C3Fi mice (45 male and 45 female mice per
exposure concentration) were exposed to target concentrations of 0-, 1-, 5-, or 50-ppm in air;
actual air concentrations were 0-, 1.0-, 5.1-, or 51.0-ppm DCPD (purity 95%) for 6 hours/day,
5 days/week, for 13 weeks. The corresponding HECs are calculated as 0, 0.97, 4.9, and
49 mg/m3. Nine animals/sex/concentration were sacrificed after Weeks 2, 6, and 13 of exposure
and at Weeks 4 and 13 postexposure. These sacrifice periods were identified as Groups A, B, C,
D, and E, respectively, throughout the remainder of the report. All animals were housed
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individually and weighed the morning before the first exposure (reference weight); this value
was subtracted from each subsequent weight measurement to obtain a change in body weight
throughout the course of the experiment. Body-weight measurements were taken weekly for the
first 5 weeks and then every 2 weeks for the remainder of the exposure. The animals were
weighed again prior to sacrifice. Food and water consumption rates were not reported in the
study. Each animal also underwent an ophthalmologic examination (prior to sacrifice interval; a
protocol deviation), blood chemistry (prior to sacrifice interval), and histopathology of kidneys
and urinary bladder following necropsy. Additionally, upon sacrifice of the animal, a necropsy
was performed, and the following organs removed and weighed: kidney (left and right, weighed
individually), lung, liver, and testes (males). The study authors did not report GLP compliance
status.
Mortality was high (approximately 20%) across all groups exposed to 49-mg/m3 DCPD;
10 male and 9 female mice died during the course of the study. The authors speculated that this
mortality may have been indicative of an exposure-related effect, as no more than two mice died
at any other DCPD exposure concentration. No clinical observation of changes in body weight
was reported prior to the mortality, although the probable cause of death could be attributed to
pulmonary congestion with some cases of renal failure. It is important to note that similar lung
lesions were not reported in animals from other exposure groups sacrificed during the course of
the study. All mice had a normal appearance after the 6-hour exposure period. Observations
recorded in the exposure groups were also recorded in the control group and included urogenital
area wetness (females), lacrimation, and alopecia. Mice of both sexes exhibited alopecia
throughout the study duration, which was as common in controls as in exposure groups.
Scattered incidences of statistically significant changes in body weight were reported for female
mice (see Table B.27) during both the exposure (Group C) and postexposure period (Group E) at
4.9 and 49 mg/m3. However, these changes were not concentration dependent and were not
observed in males.
Results from the blood analysis of the mice showed variability in serum data because an
insufficient quantity of blood was collected from many of the mice, prohibiting the establishment
of unequivocal results. Two toxic serum effects potentially related to DCPD exposure included
an elevated serum glucose level among male mice (see Table B.28) exposed to 49 mg/m3 DCPD
and a reduced serum albumin content (7% from control mean) in female mice (see Table B.29)
exposed to 4.9 and 49 mg/m3. The authors hypothesized that reduced serum albumin content
accompanied by an increase in the absolute liver weights of the 4.9-mg/m3 exposed females may
have indicated some liver dysfunction. However, increases in liver weight only occurred in
Group C females and were not concentration dependent. No biologically significant effects as a
result of DCPD exposure were found during the hematologic analysis in either sex. Only one
male mouse from the highest exposure group was found to have a mild case of conjunctivitis
during the ophthalmologic examination.
The results of the necropsy showed no gross findings in mice of either sex. Statistically
significant changes in liver and kidney organ weights were observed in Group C female mice
exposed to 4.9 mg/m3 DCPD (see Table B.30); however, no relationship between DCPD
exposure concentrations or the number of exposures was apparent. The study authors reported
no biologically significant histopathologic results for either male or female mice nor
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morphological changes associated with DCPD exposure. Because of the high mortality reported
following exposure to 49 mg/m3 DCPD, this concentration is considered a frank effect level
(FEL). The intermediate concentration of 4.9 mg/m3 is identified as the NOAEL.
Kinkead etal. (1971)
In this peer-reviewed subchronic-duration inhalation toxicity study, Kinkead et al. (1971)
exposed groups of three young male beagle dogs to 0-, 8.9-, 23.5-, or 32.4-ppm DCPD (isomeric
mixture of endo/exo DCPD in a 95:5 ratio, purity 96.7%) in air for 7 hours/day, 5 days/week, for
89 days. The corresponding HECs are calculated as 0, 10.0, 26.5, and 36.5 mg/m3. Observed
parameters of toxicity included clinical signs, hematocrit, total and differential white blood cell
counts, BUN, alanine transaminase (ALT), aspartate transaminase (AST), serum acid
phosphatase, and serum alkaline phosphatase values. Following sacrifice, the animals were
necropsied and body, liver, and kidney weights, as well as gross pathology measures were
recorded. Electrocardiograms and 28 samples of various tissues from the cranial, thoracic, and
abdominal cavities (including portions of the lung, liver, kidney, heart, spleen, adrenal, thyroid,
parathyroid, esophagus, diaphragm, lymph node, gall bladder, maxillary gland, tongue, stomach,
duodenum, pancreas, ileum, jejunum, colon, urinary bladder, prostate, testis, epididymis, brain,
pituitary, skin, and eye) were collected for microscopic examination. Hematologic and blood
chemistry tests were performed 6 days prior to the start of the study and on Exposure Days 20,
37, 65, and 85. Urine was collected for analysis 5 days prior to the initiation of the study and
after Days 21, 38, 68, and 87 of the study. This study was performed before GLP guidelines
were established.
The only exposure-related changes reported in any of the measurements consisted of
minimal changes in biochemical parameters (Kinkead et al., 1971); a slight increase in BUN and
acid phosphatase values was reported at Day 20 in the 36.5-mg/m3 exposure group, while
alkaline phosphatase values were increased at the same concentration after 85 days of exposure.
At 26.5 mg/m3, SGOT and acid phosphatase values increased after 20 days and were
accompanied by a minimal decrease in neutrophils noted on Day 85 of exposure at the same
DCPD concentration. Due to the inconsistency of observed biochemical changes, the study
authors reported that these findings were only isolated and, therefore, had no "physiological
significance." No biochemical changes were noted in dogs exposed to the lowest (10.0 mg/m3)
concentration, and no statistically significant deviations in body weight were reported.
Concentration-dependent increases in absolute liver and kidney organ weights (see Table B.31)
were observed, which reached 10% at >26.5 mg/m3 for the kidneys and 36.5 mg/m3 for the liver
when compared to controls.
No concentration-related pathological changes were observed in any of the exposure
groups. Splenic infarcts were present but were discounted as related to the exposure because
they are common in dogs and were not concentration related. Electrocardiograms performed on
all dogs at the conclusion of the study were also found to be normal. A NOAEL of 10.0 mg/m3
and a LOAEL of 26.5 mg/m3 is identified based on increased kidney weight in male dogs.
Chronic-Duration Studies
No studies were identified.
Developmental Studies
No studies were identified.
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Reproductive Studies
No studies were identified.
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OTHER DATA
Table 4 summarizes studies examining the genotoxicity and mutagenicity of DCPD. The data demonstrate that DCPD is negative for
genotoxic activity.
Table 4. Summary of DCPD Genotoxicity and Mutagenicity
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without
Activation
With
Activation
Genotoxicity studies in prokaryotic organisms
Reverse mutation
Ames assay;
Salmonella typhimurium strains
TA 98, 100, 1535, 1537 and/or
1538 in the presence or absence of
S9.
5.0 |iL/platc
Study was conducted in
duplicate with strains derived
from the same parental strain;
same results observed on both
occasions.
Hart (1980)
333 ng/plate
DCPD tested negative in all
tests; highest ineffective dose
level tested without clearing of
the background colonies in a
Salmonella test strain was
100 ng/plate.
Zeiger et al.
(1987)
SOS repair induction
ND
Genotoxicity studies in nonmammalian eukaryotic organisms
Mutation
Saccharomyces cerevisiae
strain D4 in the presence or
absence of S9.
5.0 |iL/platc
Study was conducted in
duplicate with strains derived
from the same parental strain;
same results observed on both
occasions.
Hart and Dacre
(1978)
Recombination induction
ND
Chromosomal abberation
ND
Chromosomal malsegregation
ND
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Table 4. Summary of DCPD Genotoxicity and Mutagenicity
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without
Activation
With
Activation
Mitotic arrest
ND
Genotoxicity studies in mammalian cells—in vitro
Mutation
ND
Chromosomal aberrations
Chinese hamster lung cells
(CHL/IU)
0.057 mg/mL
(continuous
treatment)
DCPD marginally induced
chromosomal aberrations at
the highest concentration
(0.057 mg/mL) after 24-hr
continuous treatment;
however, these aberrations
were confirmed to be negative
in the in vitro micronucleus
test.
OECD (2002)
0.057 mg/mL
(short-term
treatment)
—
—
Cytogenetic effects not
reported under the conditions
of this test.
OECD (2002)
0.1 mg/mL
(short-term
treatment)
—
—
Cytogenetic effects not
reported under the conditions
of this test.
OECD (2002)
Sister chromatid exchange
(SCE)
ND
DNA damage
ND
DNA adducts
ND
Genotoxicity studies in mammals—in vivo
Chromosomal aberrations
ND
SCE
ND
DNA damage
ND
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Table 4. Summary of DCPD Genotoxicity and Mutagenicity
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without With
Activation Activation
DNA adducts
ND
Mouse biochemical or visible
specific locus test
ND
Dominant lethal
ND
Genotoxicity studies in subcellular systems
DNA binding
ND
aLowest effective dose for positive results, highest dose tested for negative results.
b - = negative; ND = no data.
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Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity
All of the genotoxicity and mutagenicity studies for DCPD were negative or equivocal
(see Table 4). DCPD was negative for mutagenicity in both bacteria {Salmonella typhimurium)
(Hart, 1980; Zeiger et al., 1987) and yeast (Saccharomyces cerevisiae) (Hart and Dacre, 1978).
DCPD also tested negative in the chromosomal aberration test using Chinese hamster lung
(CHL/IU) cells. Both short-term and continuous treatments were administered in the presence
and absence of metabolic activation with no cytogenic effects. DCPD marginally induced
structural chromosomal aberrations at the highest concentration tested (0.057 mg/mL) following
24 hours of continuous treatment but was later confirmed to be negative in the in vitro
micronucleus test (OECD, 2002).
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DERIVATION OF PROVISIONAL VALUES
Tables 5 and 6 present a summary of noncancer and cancer reference values, respectively. IRIS data are indicated in the table, if
available.
Table 5. Summary of Noncancer Reference Values for DCPD (CASRN 77-73-6)
Toxicity Type (units)
Species/Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFC
Principal Study
Subchronic p-RfD
(mg/kg-d)
Mink/M+F
Reduced kit weight (absolute) following 4 wk
of nursing.
2 x KT1
NOAEL
23.6
100
Aulerich et al. (1979)
Chronic p-RfD
(mg/kg-d)
Mink/M+F
Reduced kit weight (absolute) following 4 wk
of nursing.
8 x 1(T2
NO A F.I.
23.6
300
Aulerich et al. (1979)
Screening Subchronic p-RfC
(mg/m3)a
Rat/M
Increased formation of hyaline droplets in
proximal convoluted tubules in male rat
kidneys.
3 x 1(T3
NOAEL
0.97
300
Exxon (1980);
Dodd et al. (1982);
Bevanetal. (1992)
Screening Chronic p-RfC
(mg/in3)"
Rat/M
Increased formation of hyaline droplets in
proximal convoluted tubules in male rat
kidneys.
3 x 1(T4
NOAEL
0.97
3,000
Exxon (1980);
Dodd et al. (1982);
Bevanetal. (1992)
aA screening value is provided in Appendix A to this document.
Table 6. Summary of Cancer Values for DCPD (CASRN 77-73-6)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF
NDr
p-IUR
NDr
NDr = not determined.
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DERIVATION OF ORAL REFERENCE DOSES
The database for DCPD oral toxicity studies includes three subchronic-duration studies,
conducted on rats, mice, and dogs (Hart, 1976 [rat and mouse]; Hart 1980 [dog]), one
developmental study on rats (Hart, 1980), and three reproductive studies, conducted on rats
(Hart, 1980 and Jamieson et al., 1995) and mink (Aulerich et al., 1979). The
subchronic-duration studies examined a variety of hematology, hemocytology, serum
biochemistry, clinical chemistry, histopathology, and ophthalmologic effects. The results of the
three studies showed no clear biologically significant effects at the tested doses (ranging from
2.7 to 68.4 mg/kg-day). The studies by Hart (1979 and 1980) and Aulerich et al. (1979) were
previously evaluated by IRIS for the assessment of DIMP (U.S. EPA, 1993) and are therefore
considered adequate for the derivation of p-RfDs. Also, each study utilized an appropriate
number of animals and was conducted under sound experimental guidelines.
Among two rat reproductive studies, the dietary study by Hart (1980) identified NOAELs
of 34.2 and 48.1 mg/kg-day for males and females, respectively, based on no observed
toxicological effects at the highest dose. The gavage study (Jamieson et al., 1995) reported a
NOAEL of 10 mg/kg-day and a LOAEL of 30 mg/kg-day based on the reduction in pup survival
and weight at birth. However, the utility of the Jamieson et al. (1995) study is limited because it
is only available as a meeting abstract, and the specific details of observations could not be
reviewed. The reproductive study in minks by Aulerich et al. (1979) identified a NOAEL of
23.6 mg/kg-day and a LOAEL of 42.4 mg/kg-day based on reduction in kit weight following
nursing from females exposed to 42.4 mg/kg-day (LOAEL) DCPD in the diet, indicating either a
toxicological effect on neonates through direct ingestion of DCPD in milk or indirectly through a
perturbation in the maternal metabolism that affects lactation. The developmental study by Hart
(1980) reported no treatment-related effects up to 63 mg/kg-day (the highest dose tested).
From the available database of oral exposure to DCPD, Aulerich et al. (1979) is the only
study that is reported in sufficient detail that exhibits a toxicological effect (i.e. reduced kit
weight) in animals exposed to DCPD. A lower NOAEL from this study compared to the
NOAELs >28.2 mg/kg-day from subchronic-duration studies by Hart (1980) also suggests that
reproductive toxicity in minks is more sensitive than any potential subchronic systemic toxicity.
Furthermore, findings by Aulerich et al. (1979) are supported by the Jamieson et al. (1995) study
(although available only as a meeting abstract). Therefore, Aulerich et al. (1979) is selected as
the principal study for derivation of the p-RfD. Based on this study, a NOAEL of
23.6 mg/kg-day is identified as the point of departure (POD). Benchmark dose (BMD) analysis
is not possible because the original report only provided mean and standard error without the
sample size, and individual kit response data were not provided (see Table B.18).
The U.S. EPA endorses a hierarchy of approaches to derive human equivalent oral
exposures from laboratory animal data, including body-weight scaling to the 3/4 power
(i.e., BW3 4) (U.S. EPA, 201 lc). The use of BW3 4 scaling for deriving an RfD is specifically
recommended when the observed effects are systemic and associated with the parent compound
or a stable metabolite. In the present case, however, BW3 4 scaling is not recommended because
there are developmental/neonatal effects (i.e., reduced kit weight following 4 weeks of nursing)
in which neonatal animals are directly exposed to DCPD, and empirical data are currently
lacking on whether BW3'4 scaling is appropriate for extrapolating from neonates or juveniles
across species (i.e., minks to humans).
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Derivation of Subchronic Provisional RfD (Subchronic p-RfD)
The subchronic p-RfD for DCPD, based on the NOAELadj of 23.6 mg/kg-day
(Aulerich et al., 1979), is derived as follows:
Subchronic p-RfD = NOAELadj UFC
= 23.6 mg/kg-day -MOO
= 2 x 10_1 mg/kg-day
The composite uncertainty factor (UFC) for the subchronic p-RfD is 100, as explained in
Table 7.
Table 7. UFs for Subchronic p-RfD of DCPD
UF
Value
Justification
ufa
10
A UFa of 10 has been applied for interspecies extrapolation to account for uncertainty in
extrapolating from laboratory animals to humans (i.e., interspecies variability) because information
was unavailable to quantitatively assess toxicokinetic or toxicodynamic differences between
animals and humans for DCPD.
ufd
1
A UFd of 1 has been applied because the database includes two acceptable multi-generation
reproductive toxicity studies in rats and minks (Hart, 1980; Aulerich et al., 1979), and one
acceptable developmental toxicity study in rats (Hart, 1980) via the oral route.
UFh
10
A UFh of 10 has been applied for inter-individual variability to account for human-to-human
variability in susceptibility in the absence of quantitative information to assess the toxicokinetics
and toxicodynamics of DCPD in humans.
ufl
1
A UFl of 1 has been applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
1
A UFS of 1 has been applied because developmental/neonatal toxicity was used as the critical effect
(i.e., reduced kit weight). The developmental/neonatal period is recognized as a susceptible life
stage when exposure during a time window of development is more relevant to the induction of
effects than lifetime exposure (U.S. EPA, 1991).
UFC
100
The confidence of the subchronic p-RfD for DCPD is medium as explained in Table 8
below.
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Table 8. Confidence Descriptors for Subchronic p-RfD for DCPD
Confidence Categories
Designation"
Discussion
Confidence in study
M
Confidence in the key study is medium. The Aulerich et al. (1979)
study has a sound experimental design for a reproductive study in
minks. Although this study (Aulerich et al., 1979) is not peer reviewed,
it was previously evaluated by IRIS and considered adequate for the
derivation of a p-RfD. Also, experiments were performed according to
GLP guidelines. The reported effects were also supported by a rat
gavage study (Jamieson et al., 1995).
Confidence in database
M
The database includes subchronic-duration studies on rats, mice, and
dogs (Hart, 1976 [rat and mouse]; Hart, 1980 [dog]) and reproductive
studies on rats and mink (Hart, 1980; Jamieson, 1995; Aulerich et al.,
1979). Of the available studies on oral exposure, all three
subchronic-duration oral studies (Hart, 1976 [rat and mouse]; Hart,
1980 [dog]), and three reproductive studies (Hart, 1980; Jamieson et al.,
1995; Aulerich et al., 1979) reported similar effects following treatment
with DCPD, which increases the confidence in the database.
Confidence in subchronic
p-RfDb
M
The overall confidence in the subchronic p-RfD is medium.
aL = low, M = medium, H = high.
bThe overall confidence cannot be greater than lowest entry in table.
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Derivation of Chronic Provisional RfD (Chronic p-RfD)
Based on the same database and similar considerations, the chronic p-RfD for DCPD,
based on the NOAELadj of 23.6 mg/kg-day (Aulerich et al., 1979), is derived as follows:
Chronic p-RfD = NOAELadj ^ UFC
= 23.6 mg/kg-day -^300
= 8 x 10~2 mg/kg-day
The UFC for the chronic p-RfD is 300, as explained in Table 9.
Table 9. UFs for Chronic p-RfD of DCPD
UF
Value
Justification
ufa
10
A UFa of 10 has been applied for interspecies extrapolation to account for uncertainty in
extrapolating from laboratory animals to humans (i.e., interspecies variability) because
information was unavailable to quantitatively assess toxicokinetic or toxicodynamic differences
between animals and humans for DCPD.
ufd
1
A UFd of 1 has been applied because the database includes two acceptable multi-generation
reproductive toxicity studies in rats and minks (Hart, 1980; Aulerich et al., 1979), and one
acceptable developmental toxicity study in rats (Hart, 1980) via the oral route.
UFh
10
A UFh of 10 has been applied for inter-individual variability to account for human-to-human
variability in susceptibility in the absence of quantitative information to assess the toxicokinetics
and toxicodynamics of DCPD in humans.
ufl
1
A UFl of 1 has been applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
3
A UFS of 3 is applied to account for duration extrapolation. The study by Aulerich et al. (1979) on
minks is a reproductive study but also contains a chronic-duration portion on adult animals.
However, this study does not comprehensively evaluate chronic systemic toxicity endpoints (e.g.,
no detailed biochemistry measurements). Therefore, a partial UFS of 3 is warranted.
UFC
300
The confidence of the chronic p-RfD for DCPD is medium as explained in Table 10
below.
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Table 10. Confidence Descriptors for Chronic p-RfD for DCPD
Confidence Categories
Designation"
Discussion
Confidence in study
M
Confidence in the key study is medium. The Aulerich et al. (1979)
study has a sound experimental design for a reproductive study in
minks. Although this study (Aulerich et al., 1979) is not peer
reviewed, it was previously evaluated by IRIS and considered
adequate for the derivation of a p-RfD. Also, experiments were
performed according to GLP guidelines. The reported effects were
also supported by a rat gavage study (Jamieson, 1995).
Confidence in database
M
The database includes subchronic-duration studies on rats, mice,
and dogs (Hart, 1976 [rat and mouse]; Hart, 1980 [dog]) and
reproductive studies on rats and minks (Hart, 1980; Jamieson,
1995; Aulerich et al., 1979). Of the available studies on oral
exposure, all three subchronic-duration oral studies (Hart, 1976 [rat
and mouse]; Hart, 1980 [dog]), and three reproductive studies
(Hart, 1980; Jamieson et al., 1995; Aulerich et al., 1979) reported
similar effects following treatment with DCPD, which increases
the confidence in the database. However, the database lacks
chronic toxicity studies.
Confidence in chronic p-RfDb
M
The overall confidence in the chronic p-RfD is medium.
aL = low, M = medium, H = high.
bThe overall confidence cannot be greater than lowest entry in table.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
One human case study (Okubo et al., 2000) reported a statistically significant increase in
female births among the workers in a plastic products and DCPD recovery facility; however, the
study is limited by the small sample size and exposure to a mixture of chemicals including
DCPD. There are four sub chronic-duration inhalation animal studies (Exxon, 1980 [rat and
mouse]; Kinkead et al., 1971 [rat and dog]) available for the development of subchronic and
chronic p-RfCs. Two of these studies were conducted in two different strains of rats (F344 and
Harlan Wistar strains), and the other two studies were conducted in mice and dogs. Each of
these studies examined a variety of serum chemical, clinical chemical, histopathologic, and
ophthalmologic parameters. Kidney lesions (e.g., tubule degeneration, the presence of epithelial
cells and casts, and increased formation of hyaline droplets in proximal convoluted tubules) were
reported at many of the exposure concentrations in both male and female rats. The study in
F344 rats (Exxon, 1980) reported kidney lesions only in males, but a similar study in
Harlan-Wistar rats (Kinkead et al., 1971) reported these responses in both males and females.
However, the kidney lesions in males were more severe than those in females. Although these
rat studies did not confirm the presence of alpha 2u-globulin in the kidneys of male rats exposed
to DCPD, an additional study by Hamamura et al. (2006) showed accumulation of
alpha 2u-globulin in the kidneys of male rats following exposure to DCPD, but only through the
oral route. However, the Hamamura et al. (2006) study is limited by its short duration (10 days),
small sample size (4/sex), and conflicting findings when compared to a larger oral study by Hart
(1976), which did not find any kidney effects in rats of the same strain exposed to DCPD.
Hence, the lack of clear evidence directly associating alpha 2u-globulin with renal lesions
following DCPD inhalation precludes ruling out the relevance of these rat kidney lesions to
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humans. Furthermore, kidney effects were also observed in the dog study by Kinkead et al.
(1971), which showed concentration-dependent increases in kidney weight that reached 10% at
concentrations >26.5 mg/m3.
In addition to kidney effects, Exxon (1980) reported reduced serum albumin
accompanied by increased absolute and relative liver weights in female mice after exposure to
4.9 mg/m3. However, these liver changes were not concentration dependent. In rats, liver
weights were increased but did not consistently reach 10% when compared to controls. Liver
weights in dogs increased by more than 10% but occurred at concentrations higher than the
kidney effects (Kinkead et al., 1971; Exxon, 1980).
The increased formation of hyaline droplets in proximal convoluted tubules in the
kidneys of male F344 rats (Exxon, 1980) is supported by concentration-related histologic kidney
lesions (i.e., round cell accumulations, dilated tubules, casts, and tubular degeneration) in both
sexes of Harlan-Wistar rats (Kinkead et al., 1971) at concentrations >39.7 mg/m3 (35.2 ppm).
Additional kidney effects such as concentration-dependent increases in kidney weight were also
observed in dogs at >26.5 mg/m3 (Kinkead et al., 1971). Because rats are more sensitive than
mice and beagle dogs (Kinkead et al., 1971; Exxon, 1980), the Exxon (1980) report on rats is
selected as the principal study with increased formation of hyaline droplets in the proximal
convoluted tubules of the kidneys in male rats as the critical effect. The Exxon (1980) study is
considered inadequate for p-RfC derivation because it is not peer reviewed nor does it indicate
the use of GLP guidelines. However, this study is suitable for the derivation of screening p-RfCs
in accordance with U.S. EPA practice (see Appendix A).
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
Table 11 identifies the cancer WOE descriptor for DCPD.
Table 11. Cancer WOE Descriptor for DCPD
Possible WOE Descriptor
Designation
Route of Entry
(oral, inhalation,
or both)
Comments
"Carcinogenic to
Humans "
NS
NA
No human carcinogenicity data were
identified.
"Likely to Be Carcinogenic
to Humans "
NS
NA
No animal carcinogenicity studies were
identified.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
No animal carcinogenicity studies were
identified.
"Inadequate Information
to Assess Carcinogenic
Potential"
Selected
Both
Selected due to the lack of any information
on carcinogenicity.
"Not Likely to Be
Carcinogenic to Humans "
NS
NA
There are no data to indicate that DCPD is not
carcinogenic.
NA = not applicable; NS = not selected.
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DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
The lack of any data on the carcinogenicity of DCPD precludes the derivation of
quantitative estimates for either oral (p-OSF) or inhalation (p-IUR) exposure.
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APPENDIX A. PROVISIONAL SCREENING VALUES
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
subchronic and chronic RfCs for DCPD. However, information is available for this chemical
which, although insufficient to support derivation of a provisional toxicity value, under current
guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health Risk
Technical Support Center summarizes available information in an appendix and develops a
"screening value." Appendices receive the same level of internal and external scientific peer
review as the PPRTV documents to ensure their appropriateness within the limitations detailed in
the document. Users of screening toxicity values in an appendix to a PPRTV assessment should
understand that there is considerably more uncertainty associated with the derivation of an
appendix screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of screening values should be directed to the
Superfund Health Risk Technical Support Center.
DERIVATION OF SCREENING PROVISIONAL INHALATION REFERENCE
CONCENTRATIONS
Derivation of Screening Subchronic Provisional RfC (Screening Subchronic p-RfC)
One human study (Okubo et al., 2000) examining the effects of chronic inhalation of
DCPD is available in the literature. However, the small number of cases assessed and the
exposure to a mixture of chemicals prevents the use of this study for the derivation of p-RfCs.
No animal studies examining the effects of chronic inhalation of DCPD are available in the
literature; therefore, sub chronic-duration studies are used for the development of the screening
chronic p-RfC value. The principal study (Exxon, 1980) identified a NOAEL of 0.97 mg/m3
with increased formation of hyaline droplets in the proximal convoluted tubules of the kidneys in
male rats selected as the critical effect. Kidney effects were also seen at higher exposure levels
in rats and beagle dogs (Kinkead et al., 1971). Because the data on formation of hyaline droplets
in renal tubules of male rats (see Table B.22, epithelial cell casts) are considered
semiquantitative measurements and are presented as median and quantile deviation without a
sample size, they are not amenable to benchmark dose (BMD) modeling. Therefore, the
NOAEL of 0.97 mg/m3 is used as the POD for derivation of screening subchronic and chronic
p-RfCs.
To determine the POD for derivation of the screening subchronic p-RfC, exposure
concentrations are first adjusted for continuous exposure (ConcADj) followed by HEC
conversions (ConcHEc) based on ConcADj (calculated for extrarespiratory effects - increased
formation of hyaline droplets in proximal convoluted tubules in the kidneys of male rats) as
specified in the RfC guidelines (U.S. EPA, 1994b). Example calculations are presented below.
The Exxon (1980) study did not observe any portal of entry/respiratory effects.
Exposure concentration adjustment for continuous exposure:
ConcADj = ConcExxon (1980) x (MW ^ 24.45) x (hours exposed ^ 24) x
(days exposed ^ 7 days per week)
= 1 x (132.2 ^ 24.45) x (6 hours ^ 24 hours) x (5 days ^ 7 days)
= 0.97 mg/m3
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HEC conversion for extrarespiratory effects:
Coiichec = Coiicadj x DAF;
DAF (dosimetric adjustment factor for the specific site of effects
such as respiratory and extrarespiratory tract regions).
The DAFr for gases/vapors with toxicity effects at sites remote of
the respiratory tract (extrarespiratory effects) is based on on the
ratio of the animal blood:gas partition coefficient (Hb/g -animal) and
the human blood:gas partition coefficient (Hb/g-human). See below:
DAF = ([Hb/g]A^ [Hb/g]H) = the ratio of the blood:gas (air) partition
coefficient of the chemical for the rat to the human. The value of
1.0 is used for the ratio of (Hb/g)A ^ (Hb/g)H or as a default gas
partition coefficient of 1.0 when one or both of the partition
coefficients are not available, as recommended by U.S. EPA
(1994b).
= 1.0
ConcnEc = ConcADj x DAF
= 0.97 x 1.0
= 0.97 mg/m3
The screening subchronic p-RfC for DCPD is derived as follows:
Screening Subchronic p-RfC = NOAELrec ^ UFC
= 0.97 mg/m3 - 300
= 3 x 10 3 mg/m3
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The UFC for the subchronic p-RfD is 300, as explained in Table A.l.
Table A.l. UFs for Screening Subchronic p-RfC of DCPD
UF
Value
Justification
ufa
3
A UFa of 3 (10°5) has been applied to account for uncertainty in characterizing the toxicodynamic
differences between rats and humans following inhalation exposure to DCPD. The toxicokinetic
uncertainty has been accounted for by calculation of a human equivalent concentration (HEC) as
described in the RfC methodology (U.S. EPA, 1994b).
ufd
10
A UFd of 10 has been applied because there are no acceptable two-generation reproductive toxicity
or developmental toxicity studies via the inhalation route.
UFh
10
A UFh of 10 has been applied for inter-individual variability to account for human-to-human
variability in susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of DCPD in humans.
ufl
1
A UFl of 1 has been applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
1
A UFS of 1 is applied because a subchronic-duration study was selected as the principal study.
UFC
300
Derivation of Screening Chronic Provisional RfC (Screening Chronic p-RfC)
The screening chronic p-RfC is derived based on the same principal study (Exxon, 1980)
and POD (0.97 mg/m3) as used to derive the screening subchronic RfC.
The screening chronic p-RfC for DCPD is derived as follows:
Screening Chronic p-RfC = NOAELHec + UFC
= 0.97 mg/m3 - 3,000
= 3 x 10 4 mg/m3
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The UFC for the chronic p-RfD is 3,000, as explained in Table A.2.
Table A.2. UFs for Screening Chronic p-RfC of DCPD
UF
Value
Justification
ufa
3
A UFa of 3 (10°5) has been applied to account for uncertainty in characterizing the toxicodynamic
differences between rats and humans following inhalation exposure to DCPD. The toxicokinetic
uncertainty has been accounted for by calculation of a human equivalent concentration (HEC) as
described in the RfC methodology (U.S. EPA, 1994b).
ufd
10
A UFd of 10 has been applied because there are no acceptable two-generation reproductive toxicity
or developmental toxicity studies via the inhalation route.
UFh
10
A UFh of 10 has been applied for inter-individual variability to account for human-to-human
variability in susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of DCPD in humans.
ufl
1
A UFl of 1 has been applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
10
A UFS of 10 is applied to account for the extrapolation from less than chronic exposure.
UFC
3,000
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APPENDIX B. DATA TABLES
Table B.l. Average Absolute Body and Organ Weights (g) in Male S-D Rats Exposed to
DCPD in Food for 13 Weeksa b
Body
Weight
Brain
Thyroid
Heart
Liver
Spleen
Kidneys
Adrenals
Testes
Controls
Mean
351.8
1.7038
0.0200
1.3098
15.7852
0.6630
3.2419
0.0548
4.7420
SD
42.4
0.0925
0.0053
0.1673
2.5732
0.0990
0.4082
0.0083
0.7157
SE
8.3
0.0185
0.0011
0.0328
0.5046
0.0198
0.0801
0.0017
0.1404
N
26
25
25
26
26
25
26
24
26
6.3 mg/kg-d
Mean
371.4
1.7005
0.0240*
1.3004
15.9446
0.6559
3.3816
0.0590
4.8376
SD
40.6
0.1634
0.0056
0.1858
2.8713
0.0800
0.4277
0.0104
0.5220
SE
7.8
0.0320
0.0011
0.0358
0.5526
0.0157
0.0823
0.0021
0.1005
N
27
26
27
27
27
26
27
25
27
19.2 mg/kg-d
Mean
361.1
1.7098
0.0266*
1.3177
15.2345
0.6965*
3.4018
0.0647*
4.8663
SD
52.5
0.0690
0.0057
0.1892
3.6048
0.1155
0.3887
0.0089
0.5082
SE
10.9
0.0147
0.0012
0.0394
0.7516
0.0241
0.0811
0.0019
0.1060
N
23
22
22
23
23
23
23
22
23
57.4 mg/kg-d
Mean
347.3
1.6562
0.0226
1.2093*
14.6744
0.6403
3.3712
0.0589
4.6509
SD
55.4
0.1086
0.0036
0.1727
3.2639
0.1087
0.4972
0.0079
0.7680
SE
10.9
0.0213
0.0007
0.0339
0.6401
0.0213
0.0975
0.0017
0.1506
N
26
26
24
26
26
26
26
22
26
aSource: Hart (1976).
Statistical analysis and significance data not presented by study author.
* Statistically significant by Student's /-test, p< 0.05, conducted independently fortius review.
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Table B.2. Average Absolute Organ and Body Weights (g) of Female S-D Rats Exposed to
DCPD in Food for 13 Weeksa b
Body
Weight
Brain
Thyroid
Heart
Liver
Spleen
Kidneys
Adrenals
Ovaries
Controls
Mean
227.2
1.6212
0.0204
0.9114
9.0666
0.5195
2.0271
0.0723
0.1134
SD
26.1
0.1024
0.0052
0.1320
1.5696
0.1228
0.2280
0.0112
0.0339
SE
4.9
0.0194
0.0010
0.0249
0.2966
0.0232
0.0431
0.0023
0.0064
N
28
28
27
28
28
28
28
24
28
7.2 mg/kg-d
Mean
230.9
1.5343
0.0202*
0.8713
9.2143
0.5108
2.0120
0.0737
0.1071
SD
17.5
0.1443
0.0071
0.0746
0.9725
0.0845
0.1235
0.0123
0.0331
SE
3.2
0.0268
0.0014
0.0138
0.1806
0.0157
0.0229
0.0025
0.0061
N
29
29
28
29
29
29
29
25
29
22.6 mg/kg-d
Mean
230.4
1.5834
0.0198
0.8838
8.7616
0.5128
2.0054
0.0725
0.1162
SD
24.4
0.1291
0.0034
0.1306
1.2906
0.0748
0.2216
0.0090
0.0323
SE
4.6
0.0248
0.0006
0.0247
0.2439
0.0141
0.0419
0.0018
0.0061
N
28
27
28
28
28
28
28
25
28
68.1 mg/kg-d
Mean
233.4
1.5877
0.0205
0.8768
8.5947
0.5042
1.9281
0.0732
0.1238
SD
14.5
0.1335
0.0045
0.1804
1.5838
0.0758
0.3560
0.0093
0.0374
SEC
(2.6)
NR
(0.02)
NR
(0.0008)
NR
(0.03)
NR
(0.29)
NR
(0.01)
NR
(0.06)
NR
(0.002)
NR
(0.007)
NR
N
30
29
30
30
30
30
30
30
30
aSource: Hart (1976).
Statistical analysis and significance data not presented by study author.
°Values in parentheses independently calculated for this review based on reported SD and N.
* Statistically significant by Student's /-test. p< 0.05, conducted independently fortius review.
NR = not reported.
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Table B.3. Average Relative Organ/Body-Weight Percentages of Male S-D Rats Exposed to
DCPD in Food for 13 Weeksa b
Brain
Thyroid
Heart
Liver
Spleen
Kidneys
Adrenals
Testes
Controls
Mean
0.4892
0.0057
0.3744
4.4932
0.1902
0.9236
0.0157
1.3520
SD
0.0560
0.0014
0.0442
0.5863
0.0270
0.0694
0.0029
0.1700
SE
0.0112
0.0003
0.0087
0.1150
0.0054
0.0136
0.0006
0.0333
N
25
25
26
26
25
26
24
26
6.3 mg/kg-d
Mean
0.4627
0.0065
0.3522
4.3061
0.1793
0.9122
0.0161
1.3091
SD
0.0633
0.0016
0.0526
0.7433
0.0302
0.0764
0.0030
0.1324
SE
0.0124
0.0003
0.0101
0.1431
0.0059
0.0147
0.0006
0.0255
N
26
27
27
27
26
27
25
27
19.2 mg/kg-d
Mean
0.4876
0.0077*
0.3682
4.1992
0.1946
0.9488
0.0183*
1.3616
SD
0.0910
0.0030
0.0473
0.7536
0.0307
0.0695
0.0045
0.1333
SE
0.0194
0.0006
0.0099
0.1571
0.0064
0.0145
0.0010
0.0278
N
22
22
23
23
23
23
22
23
57.4 mg/kg-d
Mean
0.4929
0.0068*
0.3517
4.2057
0.1864
0.9768*
0.0176
1.3405
SD
0.1131
0.0017
0.0569
0.5494
0.0329
0.0826
0.0053
0.1187
SE
0.0222
0.0008
0.0112
0.1077
0.0064
0.0162
0.0011
0.0233
N
26
24
26
26
26
26
22
26
aSource: Hart (1976).
Statistical analysis and significance data not presented by study author.
* Statistically significant by Student's /-test, p< 0.05, conducted independently for this review.
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Table B.4. Average Relative Organ Weight Percentages of Female S-D Rats Exposed to
DCPD in Food for 13 Weeksa b
Brain
Thyroid
Heart
Liver
Spleen
Kidneys
Adrenals
Ovaries
Controls
Mean
0.7240
0.0088
0.4079
3.9851
0.2282
0.8952
0.0329
0.0502
SD
0.1117
0.0034
0.0928
0.5587
0.0494
0.0657
0.0081
0.0142
SE
0.0211
0.0007
0.0172
0.1056
0.0093
0.0124
0.0017
0.0027
N
28
27
28
28
28
28
24
28
7.2 mg/kg-d
Mean
0.6681*
0.0088
0.3788
3.9941
0.2221
0.8742
0.0320
0.0466
SD
0.0800
0.0032
0.0384
0.3414
0.0376
0.0607
0.0048
0.0144
SE
0.0149
0.0006
0.0071
0.0634
0.0070
0.0113
0.0010
0.0027
N
29
28
29
29
29
29
25
29
22.6 mg/kg-d
Mean
0.6952
0.0087
0.3844
3.8021
0.2230
0.8730
0.0317
0.0503
SD
0.0841
0.0018
0.0428
0.3940
0.0263
0.0747
0.0033
0.0126
SE
0.0162
0.0003
0.0081
0.0745
0.0050
0.0141
0.0007
0.0024
N
27
28
28
28
28
28
25
28
57.4 mg/kg-d
Mean
0.6831
0.0088
0.3767
3.6890
0.2165
0.8266*
0.0314
0.0535
SD
0.0688
0.0019
0.0775
0.6555
0.0329
0.1432
0.0036
0.0176
SE
Illegible
Illegible
Illegible
Illegible
0.0060
0.0261
0.0007
0.0032
N
29
30
30
30
30
30
30
30
aSource: Hart (1976).
Statistical analysis and significance data not presented by study author.
* Statistically significant by Student's /-test, p< 0.05, conducted independently for this review.
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Table B.5. Average Absolute Organ Weights (g) of Female Swiss Albino Mice
Exposed to DCPD in Food for 13 Weeksa'b
Body
Weight
Thyroid
Heart
Liver
Spleen
Kidneys
Adrenals
Ovaries
Controls
Mean
28.9
0.0056
0.2013
1.8839
0.1345
0.4676
0.0104
0.0458
SD
2.7
0.0033
0.0773
0.3554
0.0774
0.1054
0.0032
0.0612
SE
0.5
0.0007
0.0139
0.0638
0.0139
0.0189
0.0006
0.0110
N
31
26
31
31
31
31
26
31
8.1 mg/kg-d
Mean
28.9
0.0054
0.2122
1.8816
0.1448
0.4808
0.0111
0.0438
SD
3.5
0.0014
0.0990
0.3415
0.0818
0.1031
0.0015
0.515
SE
0.6
0.0003
0.0178
0.0613
0.0147
0.0185
0.0003
0.0092
N
31
24
31
31
31
31
22
31
22.7 mg/kg-d
Mean
28.8
0.0036*
0.1907
1.7801
0.1241
0.4524
0.0098
0.0326
SD
2.3
0.0010
0.0310
0.2553
0.0350
0.0569
0.0017
0.0178
SE
0.4
0.0002
0.0055
0.0451
0.0062
0.0101
0.0003
0.0031
N
32
26
32
32
32
32
28
32
68.4 mg/kg-d
Mean
29.5
0.0049
0.1886
1.8644
0.1333
0.4778
0.0111
0.0391
SD
2.1
0.0025
0.0573
0.2426
0.0654
0.0695
0.0041
0.0570
SE
0.4
0.0005
0.0101
0.0429
0.0116
0.0123
0.0008
0.0101
N
32
30
32
32
32
32
27
32
aSource: Hart (1976).
Statistical analysis and significance data not presented by study author.
* Statistically significant by Student's /-test, p< 0.05 compared to control, conducted independently for this review.
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Table B.6. Average Absolute Organ Weights (g) of Male Swiss Albino Mice
Exposed to DCPD in Food for 13 Weeksa'b
Body
Weight
Thyroid
Heart
Liver
Spleen
Kidneys
Adrenals
Testes
Controls
Mean
36.0
0.0048
0.2481
2.5269
0.1560
0.7341
0.0073
0.5130
SD
4.0
0.0024
0.0869
0.4153
0.0937
0.1274
0.0023
0.2474
SE
0.7
0.0006
0.0154
0.0734
0.0166
0.0225
0.0005
0.0459
N
32
18
32
32
32
32
21
29
5.6 mg/kg-d
Mean
37.7*
0.0040
0.2706
2.5562
0.1221
0.7232
0.0078
0.4311
SD
3.8
0.0011
0.0607
0.4303
0.0279
0.1068
0.0021
0.0601
SE
0.7
0.0002
0.0107
0.0761
0.0049
0.0189
0.0006
0.0106
N
32
23
32
32
32
32
14
32
17.0 mg/kg-d
Mean
37.4
0.0051
0.2747
2.3727
0.1208*
0.6671*
0.0072
0.4216*
SD
7.5
0.0013
0.0463
0.3711
0.0318
0.1218
0.0022
0.0565
SE
1.3
0.0003
0.0082
0.0656
0.0056
0.0215
0.0005
0.0100
N
32
25
32
32
32
32
19
32
49.5 mg/kg-d
Mean
36.7
0.0057
0.2413
2.3936
0.1362
0.6922
0.0075
0.4205
SD
3.5
0.0037
0.0473
0.3625
0.0490
0.1097
0.0035
0.0655
SE
0.5
0.0008
0.0086
0.0662
0.0091
0.0200
0.0007
0.0120
N
30
23
30
30
29
30
26
30
aSource: Hart (1976).
Statistical analysis and significance data not presented by study author.
* Statistically significant by Student's /-test, p< 0.05, conducted independently for this review.
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Table B.7. Average Relative Organ/Body-Weight Percentages of Female Swiss Albino
Mice Exposed to DCPD in Food for 13 Weeksa'b
Thyroid
Heart
Liver
Spleen
Kidneys
Adrenals
Ovaries
Controls
Mean
0.0190
0.6929
6.4711
0.4566
1.6074
0.0361
0.1510
SD
0.0114
0.2264
0.7119
0.2267
0.2533
0.0110
0.1824
SE
0.0022
0.0407
0.1279
0.0407
0.0455
0.0022
0.0328
N
26
31
31
31
31
26
31
8.1 mg/kg-d
Mean
0.0190
0.7332
6.5076
0.4983
1.6635
0.0392
0.1527
SD
0.0050
0.3253
0.8117
0.2723
0.2884
0.0055
0.1776
SE
0.0010
0.0584
0.1458
0.0489
0.0518
0.0012
0.0319
N
24
31
31
31
31
22
31
22.7 mg/kg-d
Mean
0.0128*
0.6644
6.1703
0.4280
1.5713
0.0340
0.1132
SD
0.0037
0.1064
0.5692
0.1056
0.1430
0.0058
0.0602
SE
0.0007
0.0188
0.1006
0.0187
0.0253
0.0011
0.0106
N
25
32
32
32
32
28
32
68.4 mg/kg-d
Mean
0.0170
0.6421
6.3346
0.4515
1.6202
0.0376
0.1330
SD
0.0097
0.2025
0.7743
0.2152
0.2073
0.0134
0.1908
SE
0.0018
0.0358
0.1369
0.0380
0.0366
0.0026
0.0337
N
30
32
32
32
32
27
32
aSource: Hart (1976).
Statistical analysis and significance data not presented by study author.
* Statistically significant by Student's /-test, p< 0.05 compared to control, conducted independently for this review.
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Table B.8. Average Relative Organ/Body-Weight Percentages of Male Swiss Albino Mice
Exposed to DCPD in Food for 13 Weeksa'b
Thyroid
Heart
Liver
Spleen
Kidneys
Adrenals
Testes
Controls
Mean
0.0130
0.6935
7.0208
0.4315
2.0435
0.0201
1.4114
SD
0.0060
0.2397
0.7822
0.2548
0.2871
0.0056
0.6606
SE
0.0014
0.0424
0.1383
0.0450
0.0507
0.0012
0.1227
N
18
32
32
32
32
21
29
5.6 mg/kg-d
Mean
0.0107
0.7168
6.4650*
0.3264*
1.9191*
0.0203
1.1537*
SD
0.0029
0.1313
0.7544
0.0814
0.2031
0.0048
0.1865
SE
0.0006
0.0232
0.1334
0.0144
0.0359
0.0013
0.0330
N
23
32
32
32
32
14
32
17.0 mg/kg-d
Mean
0.0138
0.7529
6.4595*
0.3302*
1.8171*
0.0189
1.1538*
SD
0.0042
0.1517
1.0829
0.0969
0.3361
0.0062
0.2124
SE
0.0008
0.0268
0.1914
0.0171
0.0594
0.0014
0.0375
N
25
32
32
32
32
19
32
49.5 mg/kg-d
Mean
0.0157
0.6608
6.5150*
0.3660
1.8807*
0.0212
1.1499*
SD
0.0109
0.1289
0.6649
0.1050
0.1949
0.0112
0.1625
SE
0.0023
0.0235
0.1214
0.0195
0.0356
0.0022
0.0297
N
23
30
30
29
30
26
30
aSource: Hart (1976).
Statistical analysis and significance data not presented by study author.
* Statistically significant by Student's /-test, p < 0.05, conducted independently fortius review.
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Table B.9. Summary of Reproductive Performance in Female Rats
(CRLrCOBS CD [SD] BR) Dosed with DCPD in Food on GDs 6-15ab
Dose (ppm)
Pregnancy ratio (Pregnant/bred)
19/21
20/20
19/20
19/20
Live litter
19/19 (100%)
20/20 (100%)
19/19 (100%)
19/19 (100%)
Implantation sites (left horn/right
horn)
154/159
132/168
132/160
134/158
Resorptions
18
22
19
13
Litters with resorptions
14 (74%)
8 (40%)
11 (58%)
8 (42%)
Dead fetuses
0
0
0
0
Litters with dead fetuses
0
0
0
0
Live fetuses/implantation site
295/313 (94%)
278/300 (93%)
273/292 (93%)
279/292 (96%)
Mean live litter size (fetuses)
15.5
13.9
14.4
14.7
Average fetal weight (g)
2.3
2.3
2.4
2.4
Average fetal length (cm)
2.7
2.6
2.7
2.7
aSource: Hart (1980).
Statistical analysis conducted by study author using the litter as the basic statistical unit.
Table B.10. Number and Sex of Fetuses From Female Rats Dosed with
DCPD in Food on GDs 6-15a b
Dose (ppm)
Males
Females
0 (Control)
48
46
80
40
46
250
47
39
750
40
47
aSource: Hart (1980).
Statistical analysis conducted by study author using the litter is the basic statistical unit.
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Table B.ll. Skeletal Abnormalities in Fetuses from Female Rats Dosed with
DCPD in Food on GDs 6-15a b c
Dose (ppm)
Number Fetuses
Examined
Number Fetuses
Normal
Fetuses with Commonly
Encountered Changes
Only
Fetuses with
Unusual Skeletal
Variations
0 (Control)
199(19)
106
91 (17)
2(2)
80
192 (20)
85
103 (19)
4(3)
250
187(19)
92
95 (13)
0(0)
750
192(19)
91
98 (17)
3(2)
aSource: Hart (1980).
bNumber of litters in parentheses.
Statistical analysis conducted by study author using the litter as the basic statistical unit.
Table B.12. Summary of Fib Generation—First Mating (F2a)a
Parameter
Exposure Groupb
Control
Low
High
Indices0
Male fertility (males producing litter/mated)
10/10 (100)
10/10 (100)
9/10 (90)
Female fertility (females producing litter/mated)
19/20 (95)
18/20 (90)
14/20 (70)
Gestation (females live litter/pregnant)
19/19 (100)
18/18 (100)
14/14 (100)
Newborn viability (live pups/total pups)
241/242 (100)
209/216 (97)
162/162 (100)
Pup viability (pups Day 4/pups Day 0)
237/241 (98)
196/209 (94)*
159/162 (98)
Lactation (pups Day 21/pups Day 4)
147/150 (98)
135/139 (97)
107/109 (98)
Pup weight (g)d
Day 0 Males
6 ±0.90 (100)
6 ±0.84 (100)
6 ±0.83 (100)
Day 0 Females
6 ±0.79 (100)
6 ±0.92 (100)
6 ±0.95 (100)
Day 21 Males
44 ±5.9 (100)
46 ±6.4 (105)
44 ±5.5 (100)
Day 21 Females
41 ±5.3
43 ±6.6 (105)
42 ±5.3 (102)
Sex ratio offspring (M/F) Day 0e
111/131 (46)f
94/122 (44)f
84/78 (52)f
Live pups per litter (Mean ± SD)d
13 ±2.6
12 ± 2.7 (92)
12 ± 2.7 (92)
"Source: Hart (1980); subscripts a and b distinguish the results in pups from the first (a) or second (b) mating of the
Fib generation.
bAverage daily doses were calculated for each generation and sex by the study author; for the Fib generation
males, doses were 0, 4.3, or 39.9 mg/kg-d and for females doses were 0, 7.8, or 60.7 mg/kg-d; for the F2b
generation, male doses were 0, 4.6, or 44.1 mg/kg-d and female doses were 0, 8.1, or 73.1 mg/kg-d.
°Index data presented as ratio (percent).
dData presented as mean ± SD (% of controls); % calculated for this review.
"Data presented as number of males/number of females (% males).
fSome pups missexed.
* Statistically significant (p < 0.05). Calculated independently for this review.
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Table B.13. Summary of Fib Generation—Second Mating (F2b)a
Parameter
Exposure Groupb
Control
Low
High
Indices0
Male fertility (males producing litter/mated)
10/10 (100)
10/10 (100)
9/10 (90)
Female fertility (females producing litter/mated)
19/20 (95)
19/20 (95)
17/20 (85)
Gestation (females live litter/pregnant)
19/19 (100)
19/19 (100)
17/17 (100)
Newborn viability (live pups/total pups)
263/263 (99)
286/287 (100)
230/235 (98)
Pup viability (pups Day 4/pups Day 0)
250/263 (95)
280/286 (98)
214/230 (93)
Lactation (pups Day 21/pups Day 4)
149/151 (99)
149/152 (98)
127/128 (99)
Pup weight (g)d
Day 0 Males
6 ±0.84
6 ±0.63 (100)
6 ±0.54 (100)
Day 0 Females
6 ±0.75
6 ±0.52 (100)
6 ±0.66 (100)
Day 21 Males
45 ±6.8
48 ±7.2 (107)
51 ±6.6 (113)
Day 21 Females
43 ± 7.4
46 ±6.6 (107)
48 ±6.6 (112)
Sex ratio offspring (M/F) Day 0e
121/145 (45)
146/141 (51)
119/116(51)
Live pups per litter (Mean ± SD)
14 ±2.5
15 ± 1.6(107)
14 ± 1.4(100)
"Source: Hart (1980); subscripts a and b distinguish the results in pups from the first (a) or second (b) mating of the
Fib generation.
bAverage daily doses were calculated for each generation and sex by the author; for the Fib generation males doses
were 0, 4.3, or 39.9 mg/kg-d and for females doses were 0, 7.8, or 60.7 mg/kg-d; for the F2b generation, male
doses were 0, 4.6, or 44.1 mg/kg-d and female doses were 0, 8.1, or 73.1 mg/kg-d.
°Index data presented as ratio (percent).
dData presented as mean ± SD (% of controls); % calculated for this review.
"Data presented as number of males/number of females (% males).
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Table B.14. Summary of F2b Generation—Second Mating (F3b)a
Parameter
Exposure Groupb
Control
Low
High
Indices0
Male fertility (males producing litter/mated)
9/10 (90)
10/10 (100)
9/9 (100)
Female fertility (females producing
litter/mated)
17/20 (85)
16/20 (80)
15/18 (83)
Gestation (females live litter/pregnant)
17/17 (100)
16/16 (100)
15/15 (100)
Newborn viability (live pups/total pups)
211/215 (98)
206/213 (97)
188/191 (98)
Pup viability (pups Day 4/pups Day 0)
207/211 (98)
206/206 (100)
185/188 (98)
Lactation (pups Day 21/pups Day 4)
134/135 (99)
127/128 (99)
114/117(97)
Pup weight (g)d
Day 0 Males
6 ±0.79
7 ±0.98 (117)
7 ±0.83 (117)
Day 0 Females
6 ± 0.64
6 ±0.87 (100)
6 ±0.83 (100)
Day 21 Males
49 ± 10
44 ± 11 (90)
43 ± 11 (88)
Day 21 Females
48 ±9.3
41 ± 12 (85)
41 ±9.5* (85)
Sex ratio offspring (M/F) Day 0e
93/122 (43)
107/106 (50)
93/98 (49)
Live pups per litterd
12 ±2.7
13 ±2.5
13 ±2.8
"Source: Hart (1980); subscripts a and b distinguish the results in pups from the first (a) or second (b) mating of the
F2b generation.
bAverage daily doses were calculated for each generation and sex by the author; for the F2b generation, male doses
were 0, 4.6, or 44.1 mg/kg-d, and female doses were 0, 8.1, or 73.1 mg/kg-d; author did not calculate F3 doses.
°Index data presented as ratio (percent).
dData presented as mean ± SD (% of controls); % calculated for this review.
"Data presented as number of males/number of females (% males).
* Statistically significant at p< 0.05 compared to control; Student's /-test.
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Table B.15. Summary of F2b Generation—First Mating (F3a)a
Parameter
Exposure Groupb
Control
Low
High
Indices0
Male fertility (males producing litter/mated)
9/10 (90)
10/10 (100)
8/9 (89)
Female fertility (females producing
litter/mated)
13/20 (65)
16/20 (80)
15/18 (83)
Gestation (females live litter/pregnant)
13/13 (100)
16/16 (100)
15/15 (100)
Newborn viability (live pups/total pups)
162/163 (99)
195/196 (99)
204/206 (99)
Pup viability (pups Day 4/pups Day 0)
156/162 (96)
187/195 (96)
201/204 (99)
Lactation (pups Day 21/pups Day 4)
92/100 (92)
118/118(100)
117/120 (98)
Pup Weight (g)d
Day 0 Males
6 ± 0.77
6 ± 1.3 (100)
7 ±0.82 (117)
Day 0 Females
7 ±0.80
5 ± 1.2 (71)
6 ± 0.80 (86)
Day 21 Males
46 ±5.8
46 ±4.7 (100)
48 ±6.1 (104)
Day 21 Females
45 ±7.6
42 ± 4.2 (93)
45 ± 5.7 (100)
Sex ratio offspring (M/F) Day 0e
81/82 (50)
103/93 (53)
108/98 (52)
Live pups per litter (Mean ± SD)d
12 ±3.3
12 ±3.9
14 ±2.0
"Source: Hart (1980); subscripts a and b distinguish the results in pups from the first (a) or second (b) mating of the
F2b generation.
bAverage daily doses were calculated for each generation and sex by the author; for the F2b generation, male doses
were 0, 4.6, or 44.1 mg/kg-d, and female doses were 0, 8.1, or 73.1 mg/kg-d; author did not calculate F3 doses.
°Index data presented as ratio (percent).
dData presented as mean ± SD (% of controls); % calculated for this review.
"Data presented as number of males/number of females (% males).
Table B.16. Calculation of Estimated Daily Intake by Minks Fed DCPD at Various Dose
Levels for 12 Months"
DCPD Level in Diet
(ppm)
Mean Daily Feed
Consumption (g)b
Mg DCPD
Ingested/d
Mean Body
Weight (g)c
Daily Ingested Dose
(mg/kg-d)
0
230
0
1,071
0
100
245
24.5
1,038
23.6
200
222
44.4
1,047
42.4
400
217
86.8
1,021
85.0
800
210
168.0
989
169.9
aSource: Aulerich et al. (1979).
Represents mean feed consumption for eight measurements taken over 4 months.
Represents mean body weight for 18 measurements taken over 12 months.
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Table B.17. Summary of Body-Weight Changes in Minks fed DCPD at Three Doses for
12 Months3
DCPD Level in Diet, ppm
(ADDb, mg/kg-d)
N
Body Weight at Study
Initiation, 07/22/1977
N
Body Weight at Study
Termination, 06/30/1978
Change in Body
Weight (%)
Males
0
(0)
6
1,083 ± 56
6
1,640 ± 62
51.4
100
(23.6)
6
1,133 ±47
5
1,573 ± 69
38.8
200
(42.4)
6
1,029 ±55
5
1,508 ±92*
46.6
400
(85.0)
6
1,150 ±40*
6
1,722 ± 70
49.7
800
(169.9)
6
1,054 ± 42
6
1,538 ±43*
45.9
Females
0
(0)
24
760 ± 16
19
811 ± 26
6.7
100
(23.6)
24
739 ±14*
21
746 ± 25*
0.9
200
(42.4)
24
739±16*
21
837 ±27*
13.3
400
(85.0)
24
731±18*
23
837 ±25*
14.5
800
(169.9)
24
731±18*
21
771 ±20*
5.5
Combined Males and Females
0
(0)
30
825 ± 29
25
1,010 ±75
22.4
100
(23.6)
30
818 ±32
26
905 ± 68*
10.6
200
(42.4)
30
796 ± 27*
26
966 ± 59*
21.4
400
(85.0)
30
815 ±35
29
1020 ±71
25.2
800
(169.9)
30
796 ± 29*
27
941 ±64*
18.2
aSource: Aulerich et al. (1979).
bAdjusted daily dose.
* Statistically significant (p < 0.05, Fisher's Exact test). Calculated independently for this review.
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Table B.18. Performance of Nursing Offspring and Dams fed DCPDa
DCPD Level,
ppm
(ADDb,
mg/kg-d)
Whelping
Females
Lactating at
4 Wk (%)
Kit
Mortality
to 4 Wk
(%)
Number of
Kits per
Lactating
Female
(±SE)
Average
Absolute
Weight of
Kits at
4 Wk
(g±SE)
Kit
Bio mass'
Average
Weight of
Whelping
Dam
(g±SE)
Average
Weight of
Lactating
Females
4 Wk
Postpartum
(g ± SE)
0.0
(0.0)
79
21.7
4.91 ±0.51
165 ±2.6
810.2
978 ± 27.4
878 ± 38.2
100
(23.6)
89
22.9
4.63 ±0.51
158 ±2.7
732.5
1,000 ± 27.6
867 ±23.1
200
(42.4)
93
33.8
3.92 ±0.54
146 ±5.2*
571.9
981 ±42.4
900 ± 44.4
400
(85.0)
100
14.7
4.76 ±0.38
147 ±2.6*
701.1
995 ±25.1
913 ±29.1
800
(169.9)
100
15.6
4.50 ±0.41
128 ±3.1*
576.0
939 ±20.2
843 ± 20.5
"Source: Aulerich et al. (1979).
bAdjusted Daily Dose.
°Biomass = average kit body-weight gain between birth and 4 wk of age x the average number of kits raised per
lactating female.
* Statistically significant (p < 0.05; Dunnett's /- test); calculated by study authors.
56
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Table B.19. Effect of Chronic Administration of DCPD to Minks on Mean Organ Weights
(g ± SE) at Necropsy"
Organs
DCPD Treatment, ppm
(Adjusted Daily Dose, mg/kg-d)b
0
(0.0)
100
(23.6)
200
(42.4)
400
(85.0)
800
(169.9)
Liver
27 ± 1.5
24 ± 1.4
26 ± 1.0
28 ± 1.6
32 ±2.0
Spleen
3.3 ±0.29
2.5 ±0.20
2.6 ±0.21
2.4 ±0.16*
2.5 ±0.24
Kidney
4.8 ±0.22
4.5 ±0.22
4.4 ±0.18
4.7 ±0.21
4.7 ±0.23
Lungs
7.8 ±0.42
7.0 ±0.35
7.6 ±0.41
8.1 ±0.43
7.3 ±0.31
Adrenals
0.10 ±0.015
0.11 ±0.007
0.10±0.011
0.12 ± 0.011
0.13 ±0.012
Heart
6.0 ±0.30
5.8 ±0.28
5.5 ±0.27
5.9 ±0.26
5.6 ±0.24
Testes
1.8 ±0.1
1.6 ±0.3
1.8 ±0.2
1.8 ±0.2
1.1 ± 0.1*
Ovaries
0.10 ±0.01
0.11 ±0.01
0.11 ±0.01
0.11 ±0.01
0.11±0.01
Brain
8.1 ±0.18
7.8 ±0.15
7.9 ±0.20
7.9 ±0.13
7.9 ±0.13
aSource: Aulerich et al. (1979).
bCalculated from average body weights and food consumption provided in study using the following equation
DoseADi = Doseppm x Food Consumption per Day x (l -f- Body Weight) x (Days Dosed Total Days).
* Statistically significant (p < 0.05; Dunnett's /-test): calculated by study authors.
57
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Table B.20. Mean Food Consumption of Male and Female Fischer 344 Rats Exposed to
DCPD Vapor During a 90-Day Inhalation Study3
Completed Exposures (days)
Mean Chamber Concentration, ppm
(HECs, mg/m3)
Group
Control
(0.0)
1.0
(0.97)
5.1
(4.9)
51.0
(49)
Male Rats
4
B
30.7 ± 6.9b
35.0 ±6.6
36.1 ±5.1
31.8 ± 3.0
8
B
27.4 ±2.0
28.0 ± 1.8
32.0 ±3.0**
27.8 ±2.8
10
A
28.6 ±2.5
25.6 ±3.8
29.9 ±6.2
26.9 ±2.1
13
B
27.5 ±3.4
26.7 ±2.9
27.8 ±2.3
28.6 ±2.9
19
B
22.7 ± 1.7
23.4 ±2.0
22.1 ±2.0
24.6 ± 1.4
30
B
27.4 ±2.2
26.9 ±2.6
26.5 ±2.4
28.1 ±2.8
65
C
22.6 ±3.9
22.9 ±2.1
25.0 ±2.6
25.6 ±3.0
64 (29)°
D
17.5 ±5.6
21.3 ± 1.7
17.2 ±6.0
20.9 ±3.7
64 (92)
E
20.6 ±2.2
20.1 ±4.4
19.5 ±3.4
22.8 ±2.5
Female Rats
4
B
17.3 ± 2.3b
16.5 ± 1.4
17.0 ±0.9
18.3 ±4.6
8
B
19.3 ±2.4
19.2 ±2.7
19.7 ±3.2
19.4 ±1.3
10
A
17.4 ± 1.7
17.4 ±3.9
16.8 ±2.2
18.2 ± 1.9
13
B
18.0 ±2.5
19.7 ± 1.9
18.9 ± 1.8
20.4 ± 1.5
19
B
17.0 ± 1.7
15.4 ±2.5
16.7 ±3.8
19.0 ± 1.4
30
B
17.6 ±3.0
18.4 ±2.1
18.6 ±3.2
19.2 ± 1.9
65
C
17.8 ±1.6
16.7 ± 1.8
18.0 ± 1.9
18.4 ± 1.2
64 (29)°
D
15.2 ± 1.3
16.2 ± 1.6
15.4 ±1.1
17.2 ±2.2*
64 (92)
E
19.0 ±2.4
16.6 ± 1.5*
13.9 ±5.8*
16.9 ± 1.8*
aSource: Exxon (1980).
bValues represent mean ± SD for N = 7-9 animals; units are mg/rat/24 hr.
°() Indicates the number of postexposure days for Groups D and E.
* Statistically significant (p < 0.05, analysis of variance [ANOVA]) compared to control.
**Statistically significant (p < 0.01, ANOVA) compared to control.
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Table B.21. Mean Water Consumption of Male and Female Fischer 344 Rats Exposed to
DCPD Vapor During a 90-Day Inhalation Study3
Completed
Exposures (days)
Mean Chamber Concentration, ppm
(HECs, mg/m3)
Group
Control
(0.0)
1.0
(0.97)
5.1
(4.9)
51.0
(49)
Male Rats
4
B
37.1 ±4.4b
43.2 ±4.4*
40.4 ±5.1
46.0 ±5.5***
8
B
42.7 ±5.2
42.4 ±3.0
43.1 ±2.0
46.2 ±2.9
10
A
37.3 ±3.0
34.2 ±6.6
38.8 ±4.3
42.9 ±5.3*
13
B
43.2 ±3.8
43.1 ±4.0
42.3 ±4.5
49.0 ±5.2**
19
B
38.1 ±3.5
39.4 ±3.7
38.2 ±3.6
43.9 ±4.6**
30
B
41.0 ±4.1
42.9 ±4.0
38.9 ±5.2
50.0 ±4.5***
65
C
35.2 ±3.6
42.9 ±3.0***
30.2 ±5.1*
33.1 ± 3.5
64 (29)°
D
26.1 ±9.5
28.7 ±3.9
23.5 ± 10.9
34.1 ±5.0*
64 (92)
E
29.7 ±3.0
27.1 ± 10.4
26.8 ±8.5
33.1 ± 4.8
Female Rats
4
B
31.3 ±5.5b
28.3 ±3.8
29.1 ±3.0
32.6 ±3.6
8
B
32.4 ±6.9
29.3 ±3.3
29.6 ±5.6
32.9 ±4.3
10
A
27.8 ±2.7
30.6 ±2.7
30.0 ±5.2
30.1 ±3.8
13
B
34.5 ±4.4
34.8 ±5.7
32.9 ±2.4
40.5 ±4.5*
19
B
32.0 ±2.3
30.2 ±4.5
28.1 ± 10.3
37.0 ±4.3*
30
B
32.2 ±4.4
33.8 ±6.8
31.6 ±4.4
37.5 ±5.0
65
C
29.9 ±3.2
30.7 ±3.1
34.2 ±4.4*
32.8 ±2.6
64 (29)°
D
28.5 ±2.0
28.5 ±3.4
31.3 ±4.7
26.7 ±2.0
64 (92)
E
27.6 ±4.7
24.9 ±5.5
21.8 ±8.7
26.1 ±4.9
"Source: Exxon (1980).
bValues represent mean ± SD for N = 7-9 animals; units are ml/rat/24 hr.
°() Indicates the number of postexposure days for Groups D and E.
Statistically significant by ANOVA, atp< 0.05*, p < 0.01**, andp < 0.001*** compared to control.
59
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Table B.22. Mean and Median Results of Urinary Determinations from Male Fischer 344
Rats Exposed to DCPD Vapor During a 90-Day Inhalation Study3
Exposure
Concentration,
ppm
(HECs, mg/m3)
Urine Volume
(ml)b
Specific Gravity
(g/ml)b
Osmolality
(mOsm/kg)b
Urine Sediment Examination"1
Epithelial Cells0
Epithelial Cell
Casts0
Group Be—4 completed exposures'
Control (0.0)
7.3 ± 1.3
1.056 ±0.004
2118± 178
0±0
0±0
1.0 (0.97)
7.6 ± 1.1
1.053 ±0.004
2130±172
0±0
0±0
5.1 (4.9)
6.9 ± 1.3
1.055 ±0.004
2155±183
0 ± 0.2
0±0
51.0 (49)
8.0 ± 1.6
1.047 ±0.007**
1811 ±268**
0±0
0±0
Group Be—8 completed exposures'
Control (0.0)
7.3 ± 1.5
1.054 ±0.005
1998± 194
0 ± 0.2
0±0
1.0 (0.97)
7.6 ± 1.2
1.055 ±0.004
2055 ±165
1 ± 0.3
0±0
5.1 (4.9)
6.9 ± 1.9
1.056 ±0.004
2074±191
2 ± o***
0 ± 0.5
51.0 (49)
7.9 ± 1.5
1.048 ±0.005*
1762±182*
3 ± 0***
1 ±0.5**
Group Ae—10 completed exposures'
Control (0.0)
6.6 ±0.7
1.055 ±0.004
2143± 157
0±0
0±0
1.0 (0.97)
6.0 ± 1.6
1.056 ±0.005
2213 ±242
1 ± 0.8*
0±0
5.1 (4.9)
7.0 ±0.8
1.053 ±0.003
2108±150
1 ± 0.5
0±0
51.0 (49)
8.3 ± 1.6*
1.045 ±0.004***
1753 ±220***
1 ±0**
0 ± 0.2
Group Be—13 completed exposures'
Control (0.0)
7.8 ± 1.3
1.055 ±0.005
2082 ± 195
0 ± 0.5
0±0
1.0 (0.97)
7.2 ± 1.8
1.055 ±0.007
2097 ± 294
1 ± 0.5
0±0
5.1 (4.9)
7.5 ± 1.5
1.055 ±0.003
2103±113
1 ± 0.5
0 ± 0.5
51.0 (49)
8.6 ±2.3
1.046 ±0.005**
1754 ± 254
2 ±0.2**
0 ± 0.5
Group Be—19 completed exposures'
Control (0.0)
7.2 ± 1.1
1.058 ±0.004
2269 ±217
0 ± 0.4
0±0
1.0 (0.97)
6.6 ± 1.2
1.058 ±0.004
2257 ± 203
1 ± 0.2
1 ± 0.5
5.1 (4.9)
6.2 ±2.1
1.056 ±0.005
2159±188
2 ±0.5**
1 ± 0.8
51.0 (49)
7.5 ± 1.5
1.050 ±0.004**
1966 ± 240*
3 ± 0***
2 ±1**
Group Be—30 completed exposures'
Control (0.0)
6.8 ± 1.6
1.060 ±0.004
2350 ± 147
0±0
0±0
1.0 (0.97)
7.3 ± 1.7
1.059 ±0.004
2290±154
1 ± 0.5
0 ± 0.2
5.1 (4.9)
6.9 ±0.9
1.056 ±0.003
2156±120**
2 ±0.5**
1±0*
51.0 (49)
9.0 ± 1.9**
1.047 ±0.005***
1768 ±208***
3 ± 0***
1± 1
60
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Table B.22. Mean and Median Results of Urinary Determinations from Male Fischer 344
Rats Exposed to DCPD Vapor During a 90-Day Inhalation Study3
Exposure
Concentration,
ppm
(HECs, mg/m3)
Urine Volume
(ml)b
Specific Gravity
(g/ml)b
Osmolality
(mOsm/kg)b
Urine Sediment Examination"1
Epithelial Cells0
Epithelial Cell
Casts0
Group Ce—64 completed exposures'
Control (0.0)
4.6 ± 1.1
1.064 ±0.002
2447 ± 160
0 ±0.5
0±0
1.0 (0.97)
4.1 ±0.8
1.062 ±0.002
2328 ± 87
1± 1
0±0
5.1 (4.9)
5.1 ± 1.5
1.057 ±0.004***
2099±155***
2 ±0.5
0±0
51.0 (49)
6.8 ± 1.5**
1.046 ±0.002***
1656±106***
3 ±0.5***
0 ± 0.5
Group De—64 completed exposures/29 postexposure days'
Control (0.0)
4.2 ±2.0
1.064 ±0.005
2379 ± 270
0±0
0±0
1.0 (0.97)
4.2 ±0.6
1.066 ±0.002
2497 ± 65
1 ± 0.5
0±0
5.1 (4.9)
4.6 ± 1.7
1.060 ±0.008
2202 ±362
1 ± 0.2
0±0
51.0 (49)
6.7 ±1.1
1.054 ±0.003***
1994±191**
2 ±0.5***
0±0
Group Ee—64 completed exposures/92 postexposure days'
Control (0.0)
5.2 ± 1.6
1.064 ±0.006
2389 ±253
0 ± 0.2
0±0
1.0 (0.97)
4.5 ± 1.1
1.065 ±0.004
2405 ±142
0 ± 0.2
0±0
5.1 (4.9)
4.9 ± 1.0
1.065 ±0.003
2399± 139
0 ± 0.5
0±0
51.0 (49)
6.5 ± 1.0*
1.056 ±0.003***
2056±115***
0 ± 0.5
0±0
aSource: Exxon (1980).
bValues represent mean ± SD.
°Values represent median ± quartile deviation.
dUrine sediment examination results; 0 = negative; 1+ = a few; 2+ = moderate amount; 3+ = numerous.
eGroups A, B, C, D, and E correspond to sacrifice weeks 3, 7, 14, 18, and 27, respectively. Exposure started at the
end of Week 1 for each group,
interim data collection time.
* Statistically significant (< 0.05
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Table B.23. Mean Absolute and Relative Liver and Kidney Weights for Male Fischer 344
Rats Exposed to DCPD Vapor During a 90-Day Inhalation Study3
Parameter
Mean Chamber Concentration, ppm
(HECs, mg/m3)
Control
(0.0)
1.0
(0.97)
5.1
(4.9)
51.0
(49)
Male Rats—Group A
Body weight (g) at sacrifice
237.4 ± 13.lb
241.7 ± 12.8
238.0 ± 11.4
241.8 ± 10.3
Liver weight, absolute, g
9.502 ±0.730
9.939 ±0.918
9.990 ±0.896
10.675 ±0.976
Liver weight, % body weight
4.002 ±0.197
4.107 ±0.206
4.189 ±0.240
4.408 ±0.248***
Right kidney weight, absolute, g
0.883 ±0.068
0.907 ±0.051
0.911 ±0.071
0.977 ±0.049**
Right kidney weight, % body
weight
0.372 ±0.023
0.376 ±0.018
0.383 ±0.024
0.405 ±0.018**
Left kidney weight, absolute, g
0.887 ±0.073
0.901 ±0.078
0.907 ± 0.044
1.010 ±0.079**
Left kidney weight, % body weight
0.374 ±0.020
0.373 ±0.023
0.382 ±0.015
0.418 ±0.026***
Male Rats—Group B
Body weight (g) at sacrifice
289.5 ± 10.0b
305.5 ± 17.7
288.8 ± 10.2
290.9 ± 12.9
Liver weight, absolute, g
10.668 ±0.558
11.477 ±0.918*
10.583 ±0.757
11.258 ±0.660
Liver weight, % body weight
3.684 ±0.112
3.754 ±0.154
3.662 ±0.177
3.869 ±0.107*
Right kidney weight, absolute, g
1.041 ±0.061
1.151 ±0.065**
1.068± 0.083
1.180 ±0.078***
Right kidney weight, % body
weight
0.359 ±0.012
0.377 ±0.023
0.370 ±0.024
0.406 ±0.021***
Left kidney weight, absolute, g
1.042 ±0.063
1.144 ±0.066**
1.085 ±0.064
1.155 ±0.077**
Left kidney weight, % body weight
0.360 ±0.019
0.375 ±0.020
0.376 ±0.019
0.397 ±0.021***
Male Rats—Group C
Body weight (g) at sacrifice
340.0 ±15.8b
341.2 ±24.8
341.7 ± 15.1
343.0 ± 16.9
Liver weight, absolute, g
11.171 ±0.617
11.243 ± 1.004
11.228 ±0.839
12.059 ±0.685
Liver weight, % body weight
3.287 ±0.124
3.294 ±0.144
3.284 ±0.134
3.517 ±0.134***
Right kidney weight, absolute, g
1.291 ±0.195
1.249 ±0.211
1.148 ±0.074
1.311 ±0.081
Right kidney weight, % body
weight
0.381 ±0.062
0.366 ±0.056
0.336 ±0.020
0.383 ±0.019
Left kidney weight, absolute, g
1.196 ±0.111
1.243 ±0.184
1.149 ±0.053
1.319 ±0.088*
Left kidney weight, % body weight
0.352 ±0.027
0.365 ±0.049
0.337 ±0.016
0.385 ±0.022*
62
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Table B.23. Mean Absolute and Relative Liver and Kidney Weights for Male Fischer 344
Rats Exposed to DCPD Vapor During a 90-Day Inhalation Study3
Parameter
Mean Chamber Concentration, ppm
(HECs, mg/m3)
Control
(0.0)
1.0
(0.97)
5.1
(4.9)
51.0
(49)
Male Rats—Group D
Body weight (g) at sacrifice
355.0 ±23.7b
359.5 ± 12.4
374.0 ±27.5
376.2 ± 12.9
Liver weight, absolute, g
11.271 ±0.965
11.668 ±0.583
11.712 ± 1.425
12.444 ± 0.870
Liver weight, % body weight
3.173 ± 0.115
3.246 ±0.124
3.125 ±0.214
3.306 ±0.157
Right kidney weight, absolute, g
1.237 ±0.144
1.224 ±0.061
1.279 ±0.109
1.281 ±0.062
Right kidney weight, % body
weight
0.348 ±0.022
0.341 ±0.014
0.342 ±0.018
0.341 ±0.015
Left kidney weight, absolute, g
1.228 ±0.112
1.222 ±0.079
1.252 ±0.082
1.290 ±0.061
Left kidney weight, % body weight
0.346 ±0.015
0.340 ±0.018
0.335 ±0.017
0.343 ±0.014
Male Rats—Group E
Body weight (g) at sacrifice
403.5 ± 17.0b
394.9 ±24.0
397.9 ± 14.5
407.8 ± 19.1
Liver weight, absolute, g
13.058 ± 1.433
11.905 ± 1.247
12.137 ± 1.040
12.825 ±0.889
Liver weight, % body weight
3.238 ±0.347
3.009 ±0.192
3.049 ±0.219
3.144 ±0.152
Right kidney weight, absolute, g
1.409 ±0.097
1.441 ±0.231
1.402 ±0.205
1.367 ±0.127
Right kidney weight, % body
weight
0.350 ±0.028
0.364 ±0.038
0.353 ±0.054
0.335 ±0.023
Left kidney weight, absolute, g
1.401 ±0.080
1.431 ±0.135
1.431 ±0.167
1.397 ± 0.115
Left kidney weight, % body weight
0.347 ±0.018
0.363 ±0.028
0.360 ±0.042
0.342 ±0.016
aSource: Exxon (1980).
bValues represent mean ± SD for Y = 9 animals.
* Statistically significant (p < 0.05, ANOVA) compared to control.
**Statistically significant (p < 0.01, ANOVA) compared to control.
***Statistically significant (p < 0.001, ANOVA) compared to control.
63
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Table B.24. Incidence and Severity of Hyaline Droplets in Proximal Tubules of Male Rats
Exposed to DCPD for 13 Weeks"
Severityb
Week 6 Exposure Group, ppm
(Human Equivalency Concentration, mg/m3)c
Control
(0)
1.0
(0.97)
5.1
(4.9)
51.0
(49)
Mild
0/9 (0)
5/9 (55.6)
4/9 (44.4)
0/9 (0)
Moderate
0/9 (0)
2/9 (22.2)
1/9(11.1)
6/9 (66.7)
Marked
0/9 (0)
0/9 (0)
0/9 (0)
1/9(11.1)
Severityb
Week 13 Exposure Group, ppm
(Human Equivalency Concentration, mg/m3)c
Control
(0)
1.0
(0.97)
5.1
(4.9)
51.0
(49)
Mild
0/9 (0)
0/9 (0)
8/9 (88.9)
0/9 (0)
Moderate
0/9 (0)
0/9 (0)
0/9 (0)
3/9 (33.3)
Marked
0/9 (0)
0/9 (0)
0/9 (0)
6/9 (66.7)
aSource: Bevan et al. (1992).
bValues represent the incidence of the structural change at the respective degree of severity.
°Number of animals with endpoint/number of animals exposed, () = percent of total.
64
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Table B.25. Incidence and Severity of Regenerative Epithelium in Proximal Tubules of
Male Rats Exposed to DCPD for 13 Weeks with a 13-Week Recovery Period"
Severityb
Week 6 Exposure Group, ppm
(Human Equivalency Concentration, mg/m3)c
Control
(0)
1.0
(0.97)
5.1
(4.9)
51.0
(49)
Males
Minimal
1/8 (12.5)
2/9 (22.2)
3/9 (33.3)
0/9 (0)
Mild
2/8 (25)
3/9 (33.3)
4/9 (44.4)
7/9 (77.8)
Moderate
0/8 (0)
0/9 (0)
2/9 (22.2)
2/9 (22.2)
Severe
0/8 (0)
0/9 (0)
0/9 (0)
0/9 (0)
Females
Mild only
0/9 (0)
0/9 (0)
0/9 (0)
0/9 (0)
Severityb
Week 13 Exposure Group, ppm
(Human Equivalency Concentration, mg/m3)c
Control
(0)
1.0
(0.97)
5.1
(4.9)
51.0
(49)
Males
Minimal
0/9 (0)
1/9(11.1)
0/9 (0)
0/9 (0)
Mild
9/9 (100)
7/9 (77.8)
0/9 (0)
0/9 (0)
Moderate
0/9 (0)
1/9(11.1)
8/9 (88.9)
1/9(11.1)
Severe
0/9 (0)
0/9 (0)
1/9(11.1)
8/9 (88.9)
Females
Mild only
1/9(11.1)
1/9(11.1)
0/9 (0.0)
0/9 (0.0)
Severityb
Week 13 Recovery Group, ppm
(Human Equivalency Concentration, mg/m3)c'd
Control
(0)
1.0
(0.97)
5.1
(4.9)
51.0
(49)
Males
Minimal
3/9 (33.3)
2/9 (22.2)
2/9 (22.2)
1/9(11.1)
Mild
6/9 (66.7)
7/9 (77.8)
6/9 (66.7)
6/9 (66.7)
Moderate
0/9 (0)
0/9 (0)
0/9 (0)
2/9 (22.2)
Severe
0/9 (0)
0/9 (0)
0/9 (0)
0/9 (0)
Females
Mild only
2/9 (22.2)
3/9 (33.3)
3/9 (33.3)
1/9(11.1)
"Source: Bevan et al. (1992)
bValues represent the incidence of the structural change at the respective degree of severity. Animals having a grade
of <1 are not listed.
°Number of animals with endpoint/number of animals exposed, () = percent of total,
following 13 weeks of exposure, animals were maintained 13 weeks without exposure.
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Table B.26. Summary of Responses of Groups of 12 Rats of Each Sex that Inhaled DCPD
Vapor for 89 Days3
Parameter
Males
Females
Mean concentration, ppm
(mg/m3)
0.0
(0.0)
19.7
(22.2)
35.2
(39.7)
73.8
(83.1)
0.0
(0.0)
19.7
(22.2)
35.2
(39.7)
73.8
(83.1)
Initial body weight (g)
219.6
232.8
217.3
225.1
175.3
177.9
178.7
176.8
Final body weight (g)
526.8
568.7
569.6
559.6
355.3
348.9
356.5
345.7
Mean body weight gain (g)
307.3
335.8
352.3
333.9b
179.9
169.9
177.8
168.1
Mean liver weight (g)
16.54
19.57**
18.82*
19.83**
11.10
10.86
12.33
11.60
Mean liver weight
(% of body weight)
3.13
3.45**
3.30
3.55***
3.16
3.12
3.48
3.36
Mean kidney weight (g)
3.23
3 39***
4.05***
3 95***
2.21
2.14
2.26
2.19
Mean kidney weight
(% of body weight)
0.62
0.68***
0 7^***
0 70***
0.62
0.62
0.64
0.63
Number of sets of tissues
examined microscopically
12
12
12
12
12
11
12
12
aSource: Kinkead et al. (1971).
bOne male rat given 73.8 ppm did not gain weight normally due to an unnoticed excessive incisor growth, which
prevented the obtainment of a normal food intake. Therefore, the remaining 11 rats were used for statistical
analysis.
* Statistically significant (< 0.05
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Table B.27. Mean Body Weight in B6C3Fi Mice Exposed to DCPD
Vapor During a 90-Day Inhalation Study3
Group
Identification
Mean Chamber Concentration (ppm) (HEC equivalent, mg/m3)
Control
1.0 (0.97)
5.1 (4.9)
51.0 (49)
Body weight (g)b
Male
A
25.8 ±2.1
25.1 ±2.1
27.0 ±2.6
26.7 ± 1.4
B
28.4 ±2.2
28.6 ±2.8
29.4 ±2.1
29.3 ±2.3
C
31.8 ± 3.1
31.3 ± 2.2
30.4 ±2.6
32.0 ±2.5
D
30.0 ±2.0
30.5 ± 1.8
30.9 ±2.3
31.8 ±3.0
E
32.8 ±4.6
32.7 ± 1.7
31.3 ±2.0
34.3 ±3.2
Female
A
22.9 ±0.9
21.3 ± 1.4
22.0 ± 1.1
21.9 ± 1.0
B
25.0 ±0.8
24.2 ±0.9
25.0 ± 1.8
25.4 ± 1.7
C
26.2 ± 1.5
25.6 ± 1.6
28.2 ± 1.4*
28.1 ±2.2*
D
26.9 ± 1.3
27.2 ± 1.7
27.6 ± 1.9
28.1 ±2.3
E
32.0 ±2.8
29.5 ± 1.0*
27.6 ± 1.5*
29.7 ±2.3*
aSource: Exxon (1980).
bValues represent mean ± SD, units are in grams.
* Statistically significant (p < 0.05, ANOVA) compared to control.
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Table B.28. Mean Serum Glucose Concentrations for Male B6C3Fi Mice Exposed to
DCPD Vapor During a 90-Day Inhalation Study3
Chamber concentration (ppm) (HEC equivalent, mg/m3)
Glucose (g/L)b
Group A—10 completed exposures
Control (0.0)
1.96 ±0.20
1.0 (0.97)
1.97 ±0.23
5.1 (4.9)
2.02 ±0.16
51.0 (49)
2.19 ±0.27
Group B—30 completed exposures
Control (0.0)
2.41 ±0.50
1.0 (0.97)
2.22 ±0.37
5.1 (4.9)
2.20 ±0.16
51.0 (49)
2.41 ±0.42
Group C—64 completed exposures
Control (0.0)
2.27 ±0.34
1.0 (0.97)
2.56 ±0.37
5.1 (4.9)
2.53 ±0.27
51.0 (49)
2.92 ±0.34*
aSource: Exxon (1980).
bValues represent mean ± SD.
* Statistically significant (< 0.01< p < 0.001, Bartlett's test for the homogeneity of variance).
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Table B.29. Mean Serum Albumin Concentrations for Female B6C3Fi Mice Exposed to
DCPD Vapor During a 90-Day Inhalation Study3
Chamber concentration (ppm) (HEC equivalent, mg/m3)
Albumin (g/L)c
Group A—10 completed exposuresb
Control (0.0)
1.0 (0.97)
5.1 (4.9)
51.0 (49)
Group B—30 completed exposures
Control (0.0)
34.9 ±2.4
1.0 (0.97)
36.7 ± 1.3
5.1 (4.9)
35.1 ±2.3
51.0 (49)
33.5 ±2.1
Group C—64 completed exposures
Control (0.0)
31.5 ± 1.0
1.0 (0.97)
30.8 ± 1.5
5.1 (4.9)
29.2 ± 1.0*
51.0 (49)
29.3 ±0.9*
aSource: Exxon (1980).
insufficient sample collected.
°Values represent mean ± SD.
* Statistically significant (0.01< p < 0.001, Bartlett's test for the homogeneity of variance).
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Table B.30. Mean Absolute Liver and Kidney Weights in B6C3Fi Mice Exposed to DCPD
Vapor During a 90-Day Inhalation Study3
Group
Identification
Mean Chamber Concentration (ppm) (HEC equivalent, mg/m3)
Control
1.0 (0.97)
5.1 (4.9)
51.0 (49)
Absolute Liver weight (g)b
Male
A
1.506 ±0.101
1.512 ±0.140
1.665 ±0.182
1.597 ±0.197
B
1.605 ±0.087
1.602 ±0.187
1.628 ±0.167
1.717 ±0.301
C
1.642 ±0.265
1.775 ±0.108
1.688 ±0.194
1.745 ±0.169
D
1.553 ±0.118
1.594 ±0.083
1.633 ±0.136
1.648 ±0.113
E
1.770 ±0.196
1.735 ±0.140
1.634 ±0.158
1.809 ±0.126
Female
A
1.413 ±0.091
1.256 ±0.088*
1.341 ±0.095
1.340 ±0.139
B
1.427 ±0.108
1.410 ±0.099
1.613 ±0.493
1.454 ±0.138
C
1.537 ±0.184
1.464 ±0.184
1.795 ±0.147*
1.644 ±0.122
D
1.530 ± 0.114
1.632 ±0.107
1.650 ±0.126
1.652 ±0.134
E
1.743 ±0.143
1.676 ±0.073
1.490 ±0.135*
1.652 ±0.121
Absolute Right Kidney weight (g)b
Male
A
0.266 ± 0.042
0.248 ± 0.027
0.274 ±0.033
0.257 ±0.028
B
0.292 ± 0.025
0.298 ±0.048
0.291 ±0.037
0.290 ± 0.044
C
0.345 ±0.029
0.349 ±0.035
0.331 ±0.034
0.335 ±0.031
D
0.338 ±0.032
0.328 ±0.047
0.339 ±0.026
0.336 ±0.044
E
0.365 ±0.058
0.353 ±0.044
0.355 ±0.036
0.358 ±0.049
Female
A
0.190 ±0.019
0.167 ±0.021
0.174 ±0.016
0.183 ±0.015
B
0.188 ±0.015
0.185 ±0.028
0.203 ± 0.028
0.210 ±0.027
C
0.233 ±0.021
0.235 ±0.012
0.265 ±0.033*
0.250 ±0.023
D
0.255 ±0.017
0.254 ± 0.024
0.244 ± 0.024
0.272 ±0.018
E
0.274 ±0.034
0.262 ± 0.026
0.259 ±0.022
0.273 ± 0.027
aSource: Exxon (1980).
bValues represent mean ± SD, units are in grams.
* Statistically significant (p < 0.05, ANOVA) compared to control.
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Table B.31. Summary of Responses of Groups of Three Male Beagles that Inhaled DCPD
Vapor for 89 Days3
Parameter
Mean concentration (ppm)
(Human Equivalency Concentration, mg/m3)b
0
(0)
8.9
(10.0)
23.5
(26.5)
32.4
(36.5)
Mean body weight at end (kg)
11.2
10.0
11.2
10.9
Mean body weight gain at end (kg)
1.60
1.23
1.93
2.67
Mean liver weight (g)
317.0
328.7 (104)
339.0 (107)
393.3 (124)
Mean liver weight (% of body weight)
2.85
3.35 (116)
3.04 (107)
3.61 (127)
Mean kidney weight (g)
42.7
46.0 (108)
51.0(119)
53.3 (125)
Mean kidney weight (% of body weight)
0.38
0.47 (124)
0.45 (118)
0.49 (129)
aSource: Kinkead et al. (1971).
b(): % of control.
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APPENDIX C. BMD MODELING OUTPUTS FOR DCPD
There are no BMD modeling outputs for DCPD.
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