United States
Environmental Protection
1=1 m m Agency
EPA/690/R-09/039F
Final
9-08-2009
Provisional Peer-Reviewed Toxicity Values for
Nitrocellulose
(CASRN 9004-70-0)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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COMMONLY USED ABBREVIATIONS
BMD
Benchmark Dose
IRIS
Integrated Risk Information System
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
NOAELhec
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
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
animal to human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete to complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL to NOAEL uncertainty factor
UFS
subchronic to chronic uncertainty factor
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
NITROCELLULOSE (CASRN 9004-70-0)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (U.S. EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1)	U.S. EPA's Integrated Risk Information System (IRIS).
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in U.S. EPA's Superfund
Program.
3)	Other (peer-reviewed) toxicity values, including
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in U.S. EPA's IRIS. PPRTVs are developed according to a
Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific
literature using the same methods, sources of data, and Agency guidance for value derivation
generally used by the U.S. EPA IRIS Program. All provisional toxicity values receive internal
review by two U.S. EPA scientists and external peer review by three independently selected
scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multiprogram consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all U.S. EPA programs, while PPRTVs are developed
specifically for the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. EPA programs or
external parties who may choose of their own initiative to use these PPRTVs are advised that
Superfund resources will not generally be used to respond to challenges of PPRTVs used in a
context outside of the Superfund Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) 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), or OSRTI.
INTRODUCTION
No RfD, RfC, or carcinogenicity assessment for nitrocellulose is available on IRIS
(U.S. EPA, 2008) or the Health and Environmental Assessment Summary Tables
(HEAST; U.S. EPA, 1997). Nitrocellulose is not included in the Chemical Assessments and
Related Activities (CARA) list (U.S. EPA, 1991, 1994). The Drinking Water Standards and
Health Advisories list (U.S. EPA, 2006) does include nitrocellulose, but it notes that the Health
Advisory Document (HA) for nitrocellulose (U.S. EPA, 1987) does not include HA values and
describes this compound as relatively nontoxic. The HA was developed under a cooperative
agreement between U.S. EPA and the U.S. Army (Roberts, 1985) and is also presented by
Hartley et al. (1992). The U.S. Army also developed a Water Quality Criteria for Nitrocellulose
(Ryon, 1986). The Agency for Toxic Substances and Disease Registry (ATSDR, 2008) has not
produced a Toxicological Profile for nitrocellulose, and no Environmental Health Criteria
Document is available from the World Health Organization (WHO, 2008). The American
Conference of Governmental Industrial Hygienists (ACGIH, 2007), the Occupational Safety and
Health Administration (OSHA, 2008), and the National Institute for Occupational Safety and
Health (NIOSH, 2008) have not established occupational health standards for nitrocellulose. The
carcinogenicity of nitrocellulose has not been assessed by the International Agency for Research
on Cancer (IARC, 2008) or the National Toxicology Program (NTP, 2005, 2008).
Literature searches were conducted from the 1960s through May 2009 for studies
relevant to the derivation of provisional toxicity values for nitrocellulose. Databases searched
include DTIC, MEDLINE, TOXLINE (Special), BIOSIS, TSCATS/TSCATS 2, CCRIS,
DART/ETIC, GENETOX, HSDB, RTECS, and Current Contents.
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REVIEW OF PERTINENT DATA
Human Studies
A retrospective cohort study examined mortality among 2490 males who worked in a
Massachusetts plastics producing plant for at least 1 year during 1949-1966 (Marsh, 1983).
Chemicals produced in this plant included nitrocellulose (cellulose nitrate), cellulose acetate,
styrene polymers, polyvinyl chloride, polyvinyl butyral and phenolic and melamine resins. Vital
status was determined as of December 31, 1976, for 99.7% of the cohort, and death certificates
were obtained for 98.0% of 603 observed deaths. Comparison with local county white males
revealed a slight excess in mortality from digestive-system cancer (standardized mortality ratio
[SMR] = 101.8, CI not reported) and a statistically significant excess (p < 0.05) in genitourinary
cancer (SMR = 153.6, CI not reported). A secondary (nested) matched case-control study was
conducted to determine if particular jobs or work areas were related to the excesses found in the
primary study. For nitrocellulose processing, the odds ratios for all digestive-system cancers
combined were 1.07, 1.91, and 2.85 for exposures greater than 1 month, 5 years, and 10 years,
respectively; none of these odd ratios were statistically significant. For specific digestive system
cancers, a statistically significant (p < 0.05) odds ratio of 8.90 was found based on four cases of
rectal cancer among workers employed in cellulose nitrate production for periods greater than
5 years. These findings are only weakly suggestive of a possible association between cellulose
nitrate production and rectal cancer due to concurrent multiple chemical exposures, small
number of deaths and other study limitations.
Animal Studies
Oral Exposure, Subchronic Duration
Ellis et al. (1976) conducted 13-week oral toxicity studies of nitrocellulose in rats, mice,
and dogs. These studies used a common exposure protocol with three treatment groups and two
control groups for each species. The treatment groups received 1, 3, or 10% nitrocellulose in the
feed calculated on a dry-weight basis. There were two control groups receiving either untreated
feed (normal controls), or feed containing 10% cotton linters ([cotton controls] cellulose linters
[short-fibered cotton hairs], the material that was nitrated to produce the nitrocellulose) to
determine if any observed effects were due to the passage of nonnutritive bulk through the
gastrointestinal tract.
The 13-week study with young CD rats used groups containing eight males and eight
females (Ellis et al., 1976). Using average feed intake data over Weeks 1-13 and average body
weights from Weeks 0, 4, 8, and 13, U.S. EPA (1987) calculated that doses for the 1 and
3% nitrocellulose groups were approximately 667 and 2366 mg/kg-day for males and 820 and
2673 mg/kg-day for females. Measured intakes for the rats fed 10% nitrocellulose or 10% cotton
linters in the diet were more than double those of the untreated control rats. At
10%) nitrocellulose or 10% cotton linters in the diet, enormous mounds (unquantified) of white
fluffy material were scattered all around the cages. Therefore, actual intake of nitrocellulose or
cotton linters at 10% in the diet cannot be calculated with any degree of accuracy
(U.S. EPA, 1987).
Evaluations in all groups of rats included behavioral changes and toxic signs (daily),
body weight (weekly), hematology (Weeks 4, 8, and 13) and clinical chemistry (Week 13)
(Ellis et al., 1976). Hematological endpoints included erythrocyte, leukocyte, reticulocyte, and
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platelet counts, hemoglobin parameters, and mean corpuscular volume among other standard
measures. Clinical chemistry endpoints included blood glucose, aspartate aminotransferase,
alanine aminotransferase, alkaline phosphatase, blood urea nitrogen, creatinine, lactate
dehydrogenase, a-hydroxybutyrate dehydrogenase, and creatine phosphokinase. Rats fed
10% nitrocellulose or 10% cotton linters for 13 weeks were also evaluated for serum
immunoglobulin E (IgE) concentration and chromosomal aberrations in lymphocytes and kidney
cells. After 13 weeks, four males and four females from each group were necropsied for
evaluation of organ weights (liver, kidneys, spleen, testes, ovaries, and brain), gross pathology,
and histopathology (comprehensive; rats fed 1% or 3% nitrocellulose or 1% or 3% cotton linters
not examined). Treatment for the remaining animals in each group was discontinued, and they
were maintained for an additional 4 weeks to evaluate the reversibility of any adverse effects.
These animals were not necropsied or evaluated for hematology and clinical chemistry because
there were no adverse effects on these endpoints in the animals evaluated at 13 weeks. Specific
results for animals fed 1% or 3% cotton linters were not reported.
Body-weight gain was reduced in the male rats fed 10% nitrocellulose or 10% cotton
linters (body weight after 13 weeks of exposure was 14—17% and 21 —22% less than unexposed
controls, respectively) (Ellis et al., 1976). Food consumption was slightly increased in both
sexes at 1 and 3% nitrocellulose. Male and female rats fed 10% nitrocellulose or 10% cotton
linters consumed large amounts of feed, but they scattered much of it around the cages. These
rats apparently tried to discard the fiber while trying to get at the feed. The authors concluded
that the reduced weight gain in the male rats occurred because they did not absorb enough of the
nutritive portion of the feed. There was no apparent increase in feed scattering in the groups fed
the lower dietary concentrations of nitrocellulose, indicating that these rats ate more feed to
compensate for the nonnutritive fiber in their diet; the rats apparently received enough nutritional
intake from their increased intake because they gained weight comparably to the untreated
controls. Nitrocellulose administration did not cause any significant hematology or clinical
chemistry changes or any gross or microscopic lesions. The male rats fed 10% nitrocellulose or
cotton linters had absolute liver, kidney, and/or spleen weights that were significantly lower than
the untreated control males. The authors attributed these changes to the depressed body-weight
gain because the relative weights of these organs based on body weight and brain weight were
comparable to those of the untreated controls. Based on the lack of systemic effects, this study
identified a NOAEL of 3% nitrocellulose (2366 mg/kg-day). The decrease in body weight at the
high dose of 10% nitrocellulose is not relevant for humans because of the lack of relevance of
the mode of action (MOA; decreased nutritional intake by physical interference).
The 13-week study with young albino Swiss mice had groups containing eight males and
eight females (Ellis et al., 1976). Using average feed intake data over Weeks 1-13 and average
body weights from Weeks 0, 4, 8, and 13, U.S. EPA (1987) calculated that doses for the 1 and
3% nitrocellulose groups were approximately 1690 and 5062 mg/kg-day for males and 1741 and
7000 mg/kg-day for females. As in the rat study, the actual intake of 10% nitrocellulose or
10%) cotton linters in the diet cannot be calculated with any degree of accuracy due to excessive
scattering of the fibers (U.S. EPA, 1987). Evaluations were similar to those described for the
rats except that clinical chemistry, serum IgE, and cytogenicity were not assessed in the mice.
After 13 weeks, four males and four females from each group were necropsied for evaluation of
organ weights (liver, kidneys, spleen, testes, ovaries, and brain), gross pathology, and
histopathology (comprehensive; mice fed 1% or 3% nitrocellulose not examined). Treatment for
the remaining animals in each group was discontinued, and they were maintained for an
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additional 4 weeks to evaluate the reversibility of any adverse effects. These animals were not
necropsied or evaluated for hematological changes because there were no adverse effects on
these endpoints in the animals evaluated at 13 weeks.
The main effects in the mice were weight loss and deaths during the first few weeks of
the study in males and females fed 10% nitrocellulose or cotton linters (Ellis et al., 1976). The
deaths were apparently due to intestinal impaction from the fibrous physical nature of the
substances as the lower part of the intestinal tract was blocked by masses of fibers. (The authors
noted that the rats did not experience these deaths because their intestines were probably
sufficiently large, relative to fiber length, to allow continued passage of fiber.) Additional mice
from a chronic study (same shipment and identical levels of nitrocellulose) were added to this
study to compensate for the early losses. The surviving 10% nitrocellulose mice gained weight;
some had come close to the normal control weight by Week 13. The body weights of the mice
fed 1 or 3% nitrocellulose were similar to those of the normal controls. The mice fed 1 or
3% nitrocellulose consumed slightly more feed than the controls. Feed consumption in the mice
fed 10%) nitrocellulose or 10%> cotton linters was considerably higher; as in the rats, this reflected
scattering of fibers and feed about the cages. There were no consistent or toxicologically
significant hematological changes in any of the groups. Absolute and/or relative spleen weights
of mice fed 10%> nitrocellulose or cotton linters were significantly smaller than those of the
normal control mice. No treatment-related gross or histopathologic changes were observed in
the surviving mice. This study identified a NOAEL of 3% nitrocellulose (5062 mg/kg-day in
males and 7000 mg/kg-day in females). The mortality and weight loss at the high concentration
of 10%o nitrocellulose is discounted as a concern for humans because of the nature of the physical
blockage of the intestinal tract. The effects were similar to those found in the cotton controls.
The 13-week study with young beagle dogs used groups containing two males and two
females (Ellis et al., 1976). There were three treated groups that were fed nitrocellulose at 1, 3,
or 10%o in the feed as dry weight. Using average feed intake data for Weeks 1-4 (data for
Weeks 5-13 not reported) and data for body weight at Week 4, U.S. EPA (1987) calculated that
the doses for the 1, 3, and 10%> nitrocellulose groups were approximately 518, 1900, and
6890 mg/kg-day for males and 610, 2976, and 8485 mg/kg-day for females. The doses for the
10%o cotton-cellulose linters group were similarly calculated to be approximately
6181 mg/kg-day in males and 8627 mg/kg-day in females. The evaluations were similar to those
of the rats except that the clotting time and bromsulfophthalein (BSP) retention tests were also
performed and cytogenicity was not assessed. After 13 weeks, one male and one female from
each group was necropsied for evaluation of organ weights (liver, kidneys, spleen, testes,
ovaries, and brain), gross pathology and histopathology (comprehensive; dogs fed 1%> or
3% nitrocellulose not examined). No adverse effects were observed in the dogs fed
nitrocellulose or cotton linters. Food consumption was increased in all treated dogs and was
approximately 15%> higher than the normal controls in those fed 10%> nitrocellulose or cotton
linters. The authors indicated that the net food consumption by all dogs was similar if it is
assumed that the nitrocellulose and cotton linters were nonnutritive bulk. All dogs, including the
untreated controls, showed some variations in body weight and hematology and clinical
chemistry indices, but the changes were within normal limits. No treatment-related changes in
organ weight, gross pathology or histopathology were observed. This study identified a NOAEL
of 10%o nitrocellulose (6890 mg/kg-day in males and 8485 mg/kg-day in females); no LOAEL
was identified.
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Oral Exposure, Chronic Duration
Ellis et al. (1980) conducted 24-month oral toxicity studies of nitrocellulose in rats, mice,
and dogs. These studies used a common exposure protocol with three treatment groups and two
control groups for each species. The treatment groups received 1, 3, or 10% nitrocellulose in the
diet calculated on a dry basis. Control groups were similar to those in the Ellis et al. (1976)
study (normal and cotton controls).
The 24-month study with CD rats used groups of 32 males and 32 females supplemented
with additional groups of 8 males and 8 females exposed for 12 months (Ellis et al., 1980).
Using average feed intake over 24 months (mean of 23 monthly measurements) and average
terminal body weight at 24 months, U.S. EPA (1987) calculated that doses for the 1 and
3% nitrocellulose groups were approximately 350 and 1280 mg/kg-day for males and 373 and
1422 mg/kg-day for females. Dietary intake of nitrocellulose or cotton linters at 10% in the diet
could not be estimated because of extensive food and fiber scatterings around the cages.
Evaluations included clinical observations (daily), body weight (weekly for first 6 months and
then biweekly), food consumption (first 4 weeks then during last week of each month),
hematology (4/sex/group after 6, 12, 18, and 24 months), and clinical chemistry (4/sex/group
after 12 and 24 months). Evaluated endpoints were the same as in the subchronic study
(Ellis et al., 1976). Necropsies were conducted after 12 months (4/sex/group) and 24 months, as
well as on rats dying at unscheduled times, for evaluation of organ weights (liver, kidneys,
spleen, testes, ovaries and brain), gross pathology and histopathology (comprehensive). After
24 months of treatment, 4 rats/sex/group were given the untreated control diet for 28 days to
evaluate the reversibility of any effects.
Average body weights in the rats fed 1 or 3% nitrocellulose were similar to those in the
unexposed controls (Ellis et al., 1980). Rats in the 10% nitrocellulose and 10% cotton linters
groups failed to gain weight or lost weight in the first week and, thereafter, gained weight more
slowly than the unexposed controls, reaching plateaus after 1 year of 575-600 g in males and
325-350 g in females compared to 775 g in male controls and 375 g in female controls; the
deficits from controls were reduced somewhat at the end of the study, as the high-dose rats
gained weight slightly faster than controls over the second year of the study. Rats fed the
10%) nitrocellulose or 10% cotton linters diets had a somewhat better survival rate than
unexposed controls; the authors concluded that this was probably associated with their lower
body weight, which was apparently due to decreased obesity (i.e., decreased body fat rather than
decreased lean body mass). Treated rats had a dose-related increase in apparent feed
consumption consistent with the fact that nitrocellulose acts as a nonnutritive bulk. Apparent
feed consumption for rats given 10% nitrocellulose or 10% cotton linters was approximately
twice that of untreated controls, but some of this increase was due to scattering of diet around the
cages, which accounted for part of the loss of weight in the feeders (the measured parameter); the
rats wasted large quantities of diet apparently attempting to remove fiber from feed. The
hematology, clinical chemistry, organ weight, histopathology, and other evaluations showed
normal biological variations—but no exposure-related effects. Based on a lack of systemic
effects, this study identified a NOAEL of 3% nitrocellulose (1280 mg/kg-day for males and
1422 mg/kg-day for females).
The 24-month study with CD-I mice used groups of 58 males and 58 females
(Ellis et al., 1980). Based on average feed intake over 24 months (mean of 18 monthly
measurements) and average terminal body weight at 24 months, U.S. EPA (1987) calculated that
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doses for the 1 and 3% nitrocellulose groups were approximately 1814 and 4866 mg/kg-day for
males and 1767 and 6056 mg/kg-day for females. As in the rat study, the actual intake of
10% nitrocellulose or 10% cotton linters in the diet could not be calculated with any degree of
accuracy due to excessive scattering of the fibers (U.S. EPA, 1987). Evaluations were similar to
those in the rat study except that blood glucose, serum alkaline phosphatase, serum IgE, and
cytogenicity were not assessed in the mice. After 24 months of treatment, 4 mice/sex/group
were given the untreated control diet for 28 days to evaluate the reversibility of any effects;
evaluations of these mice did not include clinical chemistry or histopathology.
Effects in the mice included some early deaths during the first 3 weeks of the study in the
10%) nitrocellulose and 10%> cotton linters groups due to intestinal impaction by the fiber content
of the feed (Ellis et al., 1980). Gross necropsy found emboli of white fibrous material blocking
the intestines at various sites from the jejunum downward. Additional mice, fed the same diets
from the start of the study, were substituted for the dead mice. The high fiber content of the
10%o nitrocellulose and cotton linters diets was also the probable cause of an apparent physical
irritation effect that first occurred in Week 18 and decreased by the end of Month 10. This effect
was characterized by hyperemia of the ears and eyelids; subsequent edema of the genitalia, feet,
and tail; and continued scratching (an action that implies irritation). The irritation was most
common in the 10%> cotton-linters group, less common in the 10%> nitrocellulose group, and
almost nonexistent in the other groups; it was not correlated with any other toxic sign. A large
number of deaths in the 10%> nitrocellulose group (approximately 25%> mortality in both sexes)
and a smaller number of deaths in 10%> cotton-linters group occurred at approximately Month 9.
Histopathological examinations were not conducted on these mice. A physical fiber effect was
considered as a possible cause for the deaths because they occurred in mice fed both types of
fibers, but a compound effect of unknown mechanism could not be dismissed because there were
approximately three times more deaths among the 10%> nitrocellulose mice than among the 10%>
cotton linters mice. Average body weight and apparent feed consumption in the mice fed 1 or
3% nitrocellulose were similar to those in the unexposed controls. Mice fed 10%> nitrocellulose
or 10%o cotton linters lost weight during the first week but then began to gain; the gains leveled
off after 4 months and, during the second year, the average weight of all control and treated
groups converged. Apparent feed consumption for mice given 10%> nitrocellulose or 10%> cotton
linters was approximately 2-3 times higher than that of untreated controls (consistent with the
presence of nonnutritive bulk in the diet), but part of this increase was due to excessive scattering
of fiber around the cages. The hematology, clinical chemistry, organ weight, histopathology and
other evaluations showed no exposure-related effects. This study identified a NOAEL of
3% nitrocellulose (4866 mg/kg-day in males and 6056 mg/kg-day in females). The mortality at
the high concentration of 10%> is discounted as a concern for humans due to the physical nature
of the effect (blockage of the intestinal tract).
The 24-month study with beagle dogs used groups of six males and six females
(Ellis et al., 1980). Based on average feed intake over 24 months (mean of 22 monthly
measurements) and average terminal body weight of 2 dogs/sex at 24 months, doses for the 1, 3,
and 10%o nitrocellulose groups were approximately 311, 1013, and 4070 mg/kg-day for males
and 344, 1034, and 4576 mg/kg-day for females as calculated by U.S. EPA (1987) methodology.
The approximate doses for the 10%> cotton linters groups were similarly calculated to be 2888
and 3874 mg/kg-day. Evaluations included clinical observations (daily), body weight (weekly),
food consumption (1 week each month), hematology (4-6/sex/group after 3,9, 12, 18, and
24 months), clinical chemistry (same schedule as hematology), and serum IgE (same schedule as
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hematology). Hematology and clinical chemistry endpoints were essentially the same as in the
chronic rat study. Necropsies were conducted after 12 months (1/sex/group; 1 and
3% nitrocellulose groups not examined) and 24 months (2/sex/group) for evaluation of organ
weights (same organs as in rats, as well as adrenals, thyroids and pituitary), gross pathology, and
histopathology (comprehensive).
No toxic signs were observed in any of the dogs at any time (Ellis et al., 1980). There
were no consistent effects on body weight although feed consumption showed a dose-related
increase; the dogs fed 10% nitrocellulose or 10% cotton linters ate considerably more than the
unexposed controls (average feed consumption was 28—38% and 20-22% higher, respectively).
The hematology, clinical chemistry, organ weight, histopathology and other evaluations showed
no exposure-related effects. This study identified a NOAEL of 10% nitrocellulose
(4070 mg/kg-day in males and 4576 mg/kg-day in females); no LOAEL was identified.
Reproductive Toxicity Studies
A three-generation reproduction study of nitrocellulose was conducted in CD rats
(Ellis et al., 1980). The initial groups of rats used as the parental generation (F0) were started at
the same time as the previously described 24-month chronic toxicity study in rats. Rats of each
group, parents and offspring of each generation, received the same control or nitrocellulose diets
as in the chronic study (i.e., 0, 1, 3, or 10% nitrocellulose or 10% cotton linters). Dose
estimation is precluded by insufficient feed consumption measurements (limited to the control,
10%) nitrocellulose, and 10% cotton linters groups during lactation of the F2b and F3b
generations) and lack of information on feed scattering. For the F0 generation, 10 males and
20 females from each group were mated after receiving the test diets for 6 months. Each male
was housed with two females from the same group for 14 days. Offspring from these matings
(Fla, first litters) were discarded at weaning. The F0 rats were mated a second time and
20-24 offspring of each sex from this mating (Fib, second litters) were selected from each group
at weaning. The F0 females and surplus pups were discarded and the F0 males were retained in
the chronic study. Each Fib male was mated with one female within the same group for 14 days
at 3 months of age. The F2a generation was discarded at weaning and the Fib rats were
terminated at weaning of the F2b pups. The F2b rats were then selected and mated at 3 months
of age according to the same procedure used for the Fib. The study was terminated upon
weaning of the F3b rats. The general health of each parental generation (F0, Fl, and F2) was
assessed by body weight at the first mating. At birth, all offspring were examined for gross
physical abnormalities and numbers of live and dead pups in each litter were recorded. Survival
and body weights were recorded at 0, 4, and 21 days. Reproductive performance for each
parental generation was assessed by mating ratio (the number of copulations to number of
male-female pairings), pregnancy ratio (the number of pregnancies to the number of
copulations), fertility ratios for each sex (the number of males or females with offspring to the
number of that sex mated) and duration of gestation. Litter indices included the litter size, the
live-born index (the percentage of the total number of pups live-born), the body weight of
live-born pups at birth, the viability index (the percentage of live-born pups surviving to 4 days),
the lactation index (the percentage of pups alive at Day 4 surviving to weaning), the body weight
of pups at weaning, and the sex ratio (the number of males to the total number of offspring).
The mean body weights at the time of first matings for males of all parental generations
given 10%) nitrocellulose and for males and females of all parental generations given 10%> cotton
linters were significantly reduced when compared to untreated controls (Ellis et al., 1980). There
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were no indications that the treatments adversely affected male or female reproductive
performance. Significant reductions were observed in the mean lactation index and the body
weight of pups at weaning in Fib, F2a, and/or F2b litters exposed to 10% nitrocellulose and
10% cotton linters. For example, mean lactation index in the 10% nitrocellulose F2a and
F2b litters was 48 and 44% lower than the respective unexposed litters. The body weights at
weaning in the 10% nitrocellulose Fib, F2a, and F2b litters were 41, 45, and 32% lower than the
respective unexposed litters. As in the chronic toxicity study, rats given diets containing
10%) fiber (nitrocellulose or cotton linters) ate more than the other rats, presumably to
compensate for the inert fiber content of the feed. The authors attributed the reductions in
lactation index and pup body weight at weaning to increased fiber consumption and consequent
lower maternal weight, indicating no specific nitrocellulose toxicity. This study identified a
NOAEL of 3% nitrocellulose.
Other Studies
Oral absorption was studied in two CD rats that were administered four daily doses of
14C-nitrocellulose by gavage (Ellis et al., 1976). The 14C-nitrocellulose fibers were cut and
ground small enough to fit through an 18-gauge dosing needle. One rat received the compound
as a suspension in water, and the other rat received the compound as a suspension in
0.2% methyl cellulose-0.4% Tween 80 (MC-TW80). Each rat was dosed with 1 mL/100 g of
either the aqueous or MC-TW80 suspension. Samples of expired CO2, blood, urine, feces, liver,
spleen, kidneys, lungs, muscle, and the gastrointestinal tract plus its contents (stomach, small
intestine, cecum, and large intestine) were collected 24 hours after the last dose for analysis of
radioactivity. Radioactivity was recovered only in the various parts of the gastrointestinal tract,
plus its contents, and in the feces; no detectable radioactivity was found in any other tissue, body
fluid, or expired CO2. From these results, the authors concluded that nitrocellulose was not
absorbed by the rat.
Nitrocellulose was not mutagenic in Salmonella typhimurium strains TA98, TA100,
TA1535, TA1537, or TA1538 when tested at concentrations as high as 5000 g/plate with or
without S-9 metabolic activation (Ellis et al., 1978).
DERIVATION OF PROVISIONAL ORAL RfD
VALUES FOR NITROCELLULOSE
Although the intestinal absorption study (Ellis et al., 1976) was limited, by analogy to
cellulose, nitrocellulose is unlikely to be absorbed from the gut in mammals, except ruminants.
The portal-of-entry effects observed in rats and mice are likely the result of either the
compaction of nitrocellulose (or cellulose in general) in the intestinal tract causing a physical
blockage or a reduction of the nutritive content of feed. These effects are considered not relevant
to humans because of the larger diameter of the human intestinal tract and the implausibility of
consumption of such high levels of nitrocellulose by humans. In addition, nitrocellulose will not
likely be taken up by plants or animals, nor is it soluble in water, so there is little potential for
exposure to humans in food or water from contaminated sites. As a result, the p-RfD for
nitrocellulose can be set to the highest exposure level tested in mammalian species that did not
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result in physical impairment of nutrition. This level is 8485 mg/kg-day in the 13-week dietary
study in dogs (Ellis et al., 1976). The p-RfD for both subchronic and chronic exposure is derived
as follows:
Subchronic and Chronic p-RfD = NOAEL UF
= 8485 mg/kg-day ^ 3
= 3000 (3 x 103) mg/kg-day
The chronic dog study (Ellis et al., 1980), with a lower NOAEL than the subchronic
study, is not used as the basis for the chronic p-RfD because it is not plausible that continued
exposure will lower the effect level (there being none). The composite uncertainty factor (UF) of
3 accounts for potentially sensitive humans who might experience gastrointestinal distress at
high exposures. Specifically, the factor of 3 is for the dynamic component of UFh. As exposure
will be limited physically and there is virtually no likelihood of systemic effects in humans, all
other uncertainty factors are set to 1. Systemic toxicokinetic and toxicodynamic differences
within humans and across species are not relevant. In addition, there does not seem to be a need
for additional interspecies uncertainty because the data suggest that the only limiting factors
across species are the size of the intestinal lumen (leading to blockage in smaller animals) and
dietary insufficiency, both of which will not be factors for humans. The lack of developmental
toxicity studies, too, is not a concern because of the lack of systemic distribution of
nitrocellulose.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR NITROCELLULOSE
No information is available on the subchronic or chronic inhalation toxicity of
nitrocellulose, which precludes derivation of RfC values for this chemical.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR NITROCELLULOSE
Weight-of-Evidence Descriptor
Information on the carcinogenicity of nitrocellulose in humans is available from an
epidemiological study of a plastics plant that produced nitrocellulose (cellulose nitrate) and a
variety of other chemicals, including cellulose acetate, styrene polymers, polyvinyl chloride,
polyvinyl butyral, and phenolic and melamine resins (Marsh, 1983). Mortality among workers
was investigated using a matched case-control study nested within a retrospective cohort design.
Analysis of job and work location variables suggested a possible association between rectal
cancer and cellulose nitrate production. The odds ratios for all digestive system cancers
combined showed an increase with length of exposure to cellulose nitrate production, although
not at statistically significant levels (p > 0.05). For specific digestive system cancers, a
statistically significant odds ratio of 8.90 was found based on four cases for rectal cancer among
workers employed in cellulose nitrate production for periods greater than 5 years. These
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findings are only suggestive of a possible association between cellulose nitrate production and
rectal cancer due to the concurrent multiple chemical exposures, small number of deaths, and
other study limitations.
Information on the carcinogenicity of nitrocellulose in animals is available from the
24-month oral studies in rats, mice, and dogs (Ellis et al., 1980). Comprehensive
histopathological evaluations showed no increases in neoplastic lesions in any of the species at
dietary concentrations as high as 3% (1280-1422, 4866-6056, and 1013-1034 mg/kg-day in
rats, mice and dogs, respectively) and 10% (4076-4576 mg/kg-day in dogs, doses not available
in rats and mice due to excessive feed scattering).
Nitrocellulose was not mutagenic in Salmonella typhimurium strains TA98, TA100,
TA1535, TA1537, or TA1538 when tested with or without S-9 metabolic activation
(Ellis et al., 1978). In vivo testing in rats showed 10% nitrocellulose in the diet did not induce
chromosomal aberrations in peripheral blood lymphocytes or kidney cells after 13 weeks of
exposure (Ellis et al., 1976) or bone marrow or kidney cells after 24 months of exposure
(Ellis et al., 1980). Excessive scattering of feed precludes an accurate estimation of dose.
As summarized above, the chronic oral studies of nitrocellulose in animals demonstrate a
lack of carcinogenic effect in three species (rats, mice, and dogs) (Ellis et al., 1980). These
findings are consistent with the expectation that the treated animals, like humans, cannot digest
cellulose and passed the fibers through the digestive tract unabsorbed. This nondigestion of
nitrocellulose was confirmed in an oral absorption study (Ellis et al., 1976). After repeated
gavage doses (once daily for 4 days) of 14C-nitrocellulose to rats, radioactivity was recovered
only in various parts of the gastrointestinal tract plus its contents and in the feces; no detectable
radioactivity was found in any other tissue, body fluid or expired CO2. Additionally, there is no
indication that nitrocellulose is genotoxic (Ellis et al., 1976, 1978, 1980). In accordance with
current U.S. EPA cancer guidelines (U.S. EPA, 2005), the available data inadequate for an
assessment of human carcinogenic potential of nitrocellulose following oral exposure.
For inhalation exposure, the occupational epidemiology study (Marsh, 1983) is only
suggestive of a possible association between nitrocellulose production and rectal cancer in
humans. There is no additional information regarding the carcinogenicity of nitrocellulose by
the inhalation route of exposure. In accordance with current EPA cancer guidelines
(U.S. EPA, 2005), the available data are inadequate for an assessment of human carcinogenic
potential of nitrocellulose following inhalation exposure.
Quantitative Estimates of Carcinogenic Risk
Due to the lack of data in support of carcinogenicity, it is neither possible nor appropriate
to derive quantitative estimates of carcinogenic risk for nitrocellulose for either oral (p-OSF) or
inhalation (p-IUR) exposures.
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REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2007. 2007 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
ACGIH, Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2008. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service.
Online, http://www.atsdr.cdc.gov/toxprofiles/index.asp.
Ellis, H.V., J.J. Kowalski, J.R. Hodgson et al. 1976. Mammalian toxicity of munitions
compounds. Phase II: Effects of multiple doses. Part IV: Nitrocellulose. Progress Report No. 5.
Midwest Research Institute, Kansas City, MO, Contract No. DAMD-17-74C-4073. NTIS No.
ADA062016.
Ellis, H.V., J.R. Hodgson, S.W. Hwang et al. 1978. Mammalian toxicity of munitions
compounds. Phase I: Acute oral toxicity, primary skin and eye irritation, dermal sensitization,
disposition and metabolism, and Ames tests of additional compounds Midwest Research
Institute, Kansas City, MO, Contract No. DAMD-17-74C-4073. NTIS No. ADA069333.
(Summarized in Ryon, 1986).
Ellis, H.V., J.H. Hagensen, J.R. Hodgson et al. 1980. Mammalian toxicity of munitions
compounds. Phase III: Effects of lifetime exposure. Part III: Nitrocellulose. Progress Report
No. 9. Midwest Research Institute, Kansas City, MO, Contract No. DAMD-17-74C-4073. NTIS
No. ADA079353.
Hartley, W.R., J. Glennon, L. Gordon et al. 1992. Nitrocellulose (NC). In: Drinking Water
Health Advisory: Munitions. U.S. Environmental Protection Agency, Office of Drinking Water
Health Advisories. W.C. Roberts and W.R. Hartley, ed. Lewis Publishers, Ann Arbor, pp.
181-199. (Also presented by U.S. EPA, 1987).
IARC (International Agency for Research on Cancer). 2008. Search IARC Monographs.
Online, http://monographs.iarc.fr/index.php.
Marsh, G.M. 1983. Mortality among workers from a plastics producing plant: A matched
case-control study nested in a retrospective cohort study. J. Occup. Med. 25:219-230.
NIOSH (National Institute for Occupational Safety and Health). 2008. NIOSH Pocket Guide to
Chemical Hazards. Index by CASRN.
NTP (National Toxicology Program). 2005. 11th Report on Carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Online, http://ntp-server.niehs.nih.gov.
NTP (National Toxicology Program). 2008. Management Status Report. Online.
http://ntp. niehs.nih.gov/index.cfm? obi ectid=78CC7E4C-FlF6-975E-72940974DE301C3F.
12

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FINAL
9-8-2009
OSHA (Occupational Safety and Health Administration). 2008. OSHA Standard 1910.1000
Table Z-l. Part Z, Toxic and Hazardous Substances. Online.
http://www.osha.gov/pls/oshaweb/owadisp.show document?!) tabie=STANDARDS&p id=999
2.
Roberts, W.C. 1985. Data Summary for Nitrocellulose. U.S. Army Medical Bioengineering
Research and Development Laboratory, Fort Detrick, MD. Technical Report 8609. NTIS No.
ADA186413.
Ryon, M.G. 1986. Water Quality Criteria for Nitrocellulose. Final Report. Chemical Effects
Information Task Group. Biology Division. Oak Ridge National Laboratory, Oak Ridge, TN for
U.S. Army Medical Research and Development Command, Fort Detrick, MD. NTIS No.
ADA169348.
U.S. EPA. 1987. Nitrocellulose Health Advisory. Office of Drinking Water, Washington, DC.
NTIS PB90-273541. (Also presented by Hartley et al., 1992).
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA/540/R-97/036. NTIS PB97-921199.
U.S. EPA. 2005. Guidelines for Carcinogen Risk Assessment and Supplemental Guidance for
Assessing Susceptibility from Early-Life Exposure to Carcinogens. Risk Assessment Forum,
Washington, DC. EPA/630/P-03/001F. Online, http://www.epa.gov/cancerguideiines/.
U.S. EPA. 2006. 2006 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. EPA 822-R-06-013. Washington, DC. Online.
http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf.
U.S. EPA. 2008. Integrated Risk Information System (IRIS). Online. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http ://www. epa. gov/iri s/.
WHO (World Health Organization). 2008. Online catalogs for the Environmental Health
Criteria Series. Online.
http://www.who.int/ipcs/publications/ehc/ehc alphabetical/en/index.html.
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