-------
TABLE 6-6
Incidence of Tumors 1n Female BALB/c Mice Treated by Gavage with
Hydrazlne Sulfate 1n Water for ISO Days3
Sex
c
F
(virgin)
F
(breeder)
F
(gonadectomlzed)
Ooseb
(mg/day)
1.13
(170 mg total)
(38 mg/kg/day)
0
1.13
(38 mg/kg/day)
0
1.13
(38 mg/kg/day)
0
Target
Organ
lung
lung
lung
liver
ovary
lung
liver
ovary
lung
lung
Tumor Type
(p value)
adenoma or carcinoma
adenoma or carcinoma
adenoma or carcinoma
carcinoma
carcinoma
adenoma or carcinoma
carcinoma
carcinoma
adenoma or carcinoma
adenoma or carcinoma
Tumor
Incidence
20/22
(<0.0001)
1/25
(NA)
25/25
(<0.0001)
7/25
(<0.004)
6/25
2/25
(NA)
0/25
(NA)
0/25
(NA)
15/25
(<0.017)
7/26
(NA)
0327d
6-18
07/26/90
-------
TABLE 6-6 (cont.)
QUALITY OF EVIDENCE
Strengths of Study: The Influence of ovarian hormones on the Induction of
pulmonary tumors was demonstrated. Mice were treated
until moribund. Appropriate controls were tested.
Weaknesses of Study: Only one dose was tested.
Overall Adequacy: Adequate for quantitative risk assessment
aSource: Blanclflorl, 1970c
bDoses were reported 1n mg hydrazlne sulfate/day. They were converted to
mg hydrazlne sulfate/kg bw/day, assuming the body weight of mice to be 0.03
kg (U.S. EPA, 1966b).
cF1sher Exact Test performed
NA = Not applicable
0327d 6-19 07/26/90
-------
TABLE 6-7
Incidence of Liver Carcinoma 1n CBA/Cb/Se Mice Treated
by Gavage with Hydrazlne Sulfate In Hater for
25 Weeks, 6 Days/Week*
Sex
M
F
Dose or Exposure13
(mg/day)
1.13 (38 mg/kg/day)
0.56 (19 mg/kg/day)
0.28 (9 mg/kg/day)
0.14 (4.7 mg/kg/day)
0
1.13 (38 mg/kg/day)
0.56 (19 mg/kg/day)
0.28 (9 mg/kg/day)
0.14 (4.7 mg/kg/day)
0
Duration
of Study
(weeks)
87
78
76
98
100
87
78
76
98
100
Tumor Incidence0
(p- value)
15/25 (<0.0001)
12/25 (<0.0001)
7/25 (<0.085)
1/26 (<0.362)
3/30 (NA)
15/24 (<0.0001)
16/24 (<0.0001)
2/25 (<0.443)
0/25 (<0.55)
1/29 (NA)
Strengths of Study:
Weaknesses of Study:
Overall Adequacy:
QUALITY OF EVIDENCE
The Induction of hepatocarclnoma by hydrazlne was
demonstrated. Nice were observed during the appro-
priate latency period; several dose levels were used.
Purity of test compound not reported.
Adequate for quantitative risk assessment
aSource: B1anc1f1or1, 1970a
bDoses were converted to mg hydrazlne sulfate/kg bw/day, assuming mice
weigh 0.03 kg (U.S. EPA, 1986b).
cF1sher Exact Test performed
NA . Not applicable
0327d
6-20
07/26/90
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TABLE 6-8
Incidence of Hepatocellular Carcinomas In Livers of Hale
Syrian Golden Hamsters Treated with Hydrazlne Sulfate (>99%)
in Drinking Hater for 2 Years3
Doseb
(mg/kg/day)
0.0
4.6
8.3
10.3
Tumor Incidence0
(p value)
0/31
0/31
4/34
11/34
(NA)
(NA)
(0.068)
(0.0003)
Strengths of Study:
Weaknesses of Study:
Overall Adequacy:
Comment:
QUALITY OF EVIDENCE
The durations of treatment and study were long.
Appropriate controls were reported. Methylatlon of
DNA guanlne during the induction of liver cancer was
measured. Multiple doses were used.
Only males were tested.
Adequate for quantitative risk assessment
Hamsters were given hydrazlne sulfate In drinking
water at concentrations of 170, 340 or 510 ppm. The
authors calculated the doses of hydrazlne 1n mg/kg/day.
aSource: Bosan et al., 1987
bDose expressed as hydrazlne (free base)
cF!sher Exact Test performed
NA = Not applicable
0327d
6-21
07/26/90
-------
produced pulmonary adenomas and adenocarclnomas \n 46-50% of the treated
Swiss mice, compared with 9-1IX In the controls. The average dally hydra-
zlne sulfate consumption per Swiss mouse was reportedly 0.74 mg (0.18 mg
hydrazlne) for the males and 0.65 mg (0.16 mg hydrazlne) for the females.
Based upon body weights provided by the author, the transformed animal doses
were for males and females 26 and 23 mg hydrazlne sulfate/kg/day, respec-
tively. Hydrazlne sulfate treatment did not Induce a significantly
Increased Incidence of tumors at other sites In the Swiss mice or at any
site In the C3H or AKR mice, but the treatment substantially decreased the
Incidence of mammary gland adenomas In the C3H females.
Similar results were obtained In a similarly designed study 1n which
0.001X hydrazlne 1n the drinking water was administered continuously for the
Hfespan of 50 male and 50 female Swiss mice, which were 6 weeks old at the
beginning of treatment (Toth, 1972a). The average dally consumption of
hydrazme/mouse was 0.069 mg for males and 0.056 mg for females. Assuming
the average weight of mice to be 0.03 kg (U.S. EPA, 1986b), the transformed
animal doses were calculated to be 2.3 and 1.9 mg hydrazIne/kg/day for males
and females, respectively. The hydrazlne treatment reportedly Induced
pulmonary adenomas and adenocarclnomas In 48-54% of the mice, but elevated
Incidences of tumors at other sites were not reported. However, concurrent
controls were not used In this study; the Incidences of tumors In untreated
control Swiss mice from the earlier Toth (1969) study served as a reference.
BlandfloM (1970a) conducted a multiple-dose study 1n which hydrazlne
*
sulfate was administered by gavage to groups of 24-30 eight-week-old
CBA/Cb/Se mice of each sex at doses of 0, 0.14, 0.28, 0.56 or 1.13 mg/day, 6
days/week for 25 weeks. Assuming that the mice weighed 0.03 kg (U.S. EPA,
1986b), the corresponding doses were 0, 4, 8, 16 or 32 mg/kg/day. Hlsto-
0327d 6-22 07/26/90
-------
logical examination of the livers, lungs, unspecified endocrine glands and
other tissues suspected of having lesions were conducted on all mice when
moribund or at the time of natural death. Multiple pulmonary tumors were
reportedly present In "many" of the treated mice, but Incidences were not
reported because the purpose of this study was to describe hepatic tumors.
Hepatic tumors, classified as very vascularlzed hepatocardnomas, were
Induced 1n a dose-related manner In both sexes (see Table 6-6); lung
metastases were observed 1n some of the high-dose (37.7 mg/kg) mice. A
multiple-dose study that was not available for Independent review showed
that similar gavage administration of hydrazlne sulfate also resulted in
dose-dependent Induction of pulmonary tumors In the same strain of mice
(B1anc1f1or1, 1970b).
Sever 1 and Blanclflorl (1968) administered dally doses of hydrazlne
sulfate at it and 12 mg/day to 14 male and 18 female Cb/Se rats, respec-
tively, by gavage from the age of 8 weeks for 68 weeks. Assuming an average
body weight of 0.35 kg for rats (U.S. EPA, 1986b), these doses correspond to
51 and 34 mg hydrazlne sulfate/kg/day for males and females, respectively.
Untreated groups of 28 male and 22 female rats were used as controls. The
liver, lungs and other organs that showed macroscopic lesions were examined
hlstolog1ca11y at the time of natural death. Lung tumors (adenomas or
adenocarclnomas) were found In 3/14 males and 1n 5/18 females after 109
weeks but in none of the untreated controls. Liver tumors (hepatic cell
carcinomas or spindle cell carcinomas) occurred In 4/13 treated male rats,
0/13 treated females and In none of the untreated controls. Spontaneous
liver tumors had never been observed in Cb rats maintained In the same
laboratory during the previous 14 years. Stelnhoff and Nohr (1968), how-
ever, reported only a weak carcinogenic effect of hydrazlne In Ulstar rats.
0327d 6-23 07/26/90
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Hydrazlne was administered in drinking water In concentrations of 0, 2, 10
and 50 mg/i until the spontaneous death of the rats. Using U.S. EPA
values for the body weights of rats (0.35 kg) and dally water consumption
(0.049 i/day), these doses are approximately equivalent to 0, 0.26, 1.4
and 7.0 mg hydrazlne/kg/day. Each group consisted of 50 males and 50
females. Hostly benign liver cell tumors were found with the highest
concentration used.
Administration of hydrazlne sulfate to Syrian golden hamsters In the
drinking water at a concentration of 0.012% (average dose, 2.3 mg/day) for
life (Toth, 1972b) or by gavage at doses of 2.8 mg/day (10 applications In
20 weeks) or 3.0 mg/day (60 applications 1n 15 weeks) (B1anc1f1or1, 1970c)
did not produce significant Increases In the Incidence of tumors after
lifetime observation. Assuming the average body weight of hamsters to be
0.14 kg (U.S. EPA. 1986b), these three doses correspond to 16, 14 or 12 mg
hydrazlne sulfate/kg/day. Bosan et al. (1987) reported an Increased Inci-
dence of hepatocellular carcinomas In Syrian golden hamsters after treatment
with 170, 340 or 510 pom hydrazlne sulfate 1n drinking water [4.6, 8.3 or
10.3 mg hydrazlne (free base)/kg/day, as calculated by the authors] for 2
years.
6.2.3. Other Relevant Information. A single Intraperltoneal dose of
hydrazlne sulfate to male CBA mice, together with [14C]fornate or
l-[methy1-"C]meth1on1ne as a source of 14C, produced [l4C]7-methyl-
guanlne in liver DNA and RNA (Qulntero-Rulz et al., 1981). No methylguanlne
was observed In controls treated only with the source of "C. The alkyla-
tlon of nucleic acids suggests a possible mechanism of hydrazlne carclno-
genldty. The methylatlon of DNA guanlne In the liver, kidney and lung of
hamsters after oral treatment with hydrazlne was also reported by Bosan et
al. (1987). The study 1s described 1n Section 6.2.2.
0327d
6-24
07/26/90
-------
No Indication of a carcinogenic effect of hydrazlne was found after
subcutaneous Injection of 0.25-5 mg/kg of hydrazlne once a week for 2.5
years Into groups of 50 male and 50 female Sprague-Dawley rats (Stelnhoff
and Hohr, 1988). Negative results were also found after Intratracheal
administration of 0.25-5 mg/kg of hydrazlne 1n Sprague-Dawley rats once a
week for 2.5 years.
6.3. GENOTOXICITY
Hydrazlne was generally positive In reverse mutation tests In Salmonella
typ_h_Hnur_1um (Herbold and Buselmaler, 1976; Rowland and Severn, 1981; Wade et
al.. 1981) and Escherlchla coll (von Wright, 1981; Noda et al., 1986) with
or without activation, and In phage tests and a ONA damage test 1n £.. coll
(Helnemann, 1971; Green, 1981; von Wright, 1981). Results were also
positive in a forward mutation test In several strains of Saccharomyces
cerevlslae (Lemontt, 1978; NcDougall and lemontt, 1979; Lemontt and Lair,
1982). Results 1n Drosophlla melanogaster were positive for somatic
mutations and mixed In the sex-linked recessive lethal test (Shukla. 1972;
Vljaykumar and Lain, 1979; Yoon et al., 1985).
Results of Jni vUro tests In mammalian sytems were generally positive,
Including sister chromatld exchanges 1n Chinese hamster ovary cells (HacRae
and Stlch, 1979; Perry and Thomson, 1981), DNA damage 1n rat hepatocytes
(S1na et al., 1983), and unscheduled DNA synthesis 1n HeLa cells (Martin and
McDermld, 1981} and human flbroblasts (Agrelo and Amos, 1981). Negative
results were reported j£ vivo 1n the mlcronucleus test (Tsuchlmoto and
Natter, 1981) and dominant lethal test (Epstein et al.. 1972) In mice.
6.4. DEVELOPMENTAL TOXICITY
Pertinent data regarding the teratogenlclty of hydrazlne In animals are
few, and no human studies were located. No Inhalation studies regarding
0327d 6-25 07/26/90
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6-28
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-------
teratogenU effects from hydrazlne exposure were located 1n the available
literature cited In Appendix A.
Schiller et al. (1979) examined the effect of a single 260 mg/kg gavage
dose of hydrazlne on day 12 of gestation on the development of Intestinal
brush border enzymes 1n Syrian golden hamsters. Exposure to hydrazlne
significantly (p<0.05) reduced neonatal (3- to 4-day-old) lactase activity,
Increased neonatal and postnatal (24- to 25-day-old) alkaline phosphatase
activity, and elevated postnatal but decreased young adult (53- to 60-day-
old) sucrase activity. The number of offspring assayed was not specified,
but the treatment and control groups consisted of 24 mated hamsters each.
Head examinations of the treated neonates revealed normal palate develop-
ment, but these data were not reported quantitatively.
Lee and Aleyasslne (1970) Injected hydrazlne subcutaneously Into 12
pregnant Wlstar rats at a dose of 6 mg/kg/day on days 11-21 of gestation. A
group of 15 pregnant rats served as vehicle (saline) controls. Maternal
deaths occurred In two of the treated and none of the control rats, but
additional indices of maternal toxUlty were not evaluated. Fetotoxlclty In
the treated group was Indicated by a reduced ratio of fetal survivors to
Implantation sites (37% In treated vs. 79% 1n controls) and significantly
(p<0.001) reduced fetal weight. Gross malformations were not observed In
the fetuses of the hydrazlne-treated rats, but generalized edema and,
occasionally, petechlal hemorrhages were present. Neonatal survival was
determined In additional groups of 12 treated and 15 control rats; none of
the hydrazlne-treated rats gave birth to newborns that survived the first 24
hours, but newborns from 12 of the control rats survived.
The results of embryotox1c1ty/teratogen1dty studies conducted by the
Air Force Aerospace Medical Research Laboratory are available In abstract
0327d
6-29
07/26/90
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form (Lyng et al., 1980; Keller et al., 1982). In a study with F344 rats
(Keller et al., 1982), hydrazlne was Intraperltoneally Injected at unspeci-
fied doses <10 ing/kg on days 6-15 of gestation. Dose-related embryo-
lethality and maternal toxlclty (not described) were observed at the two
highest doses. Injection of 10 rag/kg hydrazlne on gestation days 7-9, 10-12
or 13-15 Indicated that the most susceptible prenatal period was on days
7-9; embryolethalUy and an Increased Incidence of anomalies (not detailed).
but no major malformations, were observed In this group. Increased
perinatal mortality was also noted 1n the offspring of rats Injected with 10
mg/kg hydrazlne on gestation days 7-9, but neonatal developmental parameters
(I.e., weight gain, ear detachment, Incisor eruption, eye opening, surface
righting, cliff avoidance, forward motion or swimming ability) were not
adversely affected. Percutaneous treatment with 50 mg/kg hydrazlne on day 9
of gestation reportedly produced a high Incidence of embryolethalUy 1n F344
rats, but similar treatment with 5 mg/kg was not embryolethal; additional
data regarding this experiment were not reported 1n the abstract.
Intraperltoneal Injection of hydrazlne at doses of 4, 12 or 20 mg/kg/day
on days 6-9 of gestation had no significant effect on the number of Implan-
tations per female, mean number of viable fetuses per Utter or mean number
of resorptlons per Utter 1n ICR mice, but similar treatment with 30 or 40
mg/kg hydraz1ne/day was fetotoxlc {Lyng et al., 1980). Maternal toxlclty
was Indicated at doses >4 mg/kg/day by reduced weight gain during the Injec-
tion period (12 and 20 mg/kg/day) and mortality (4/21 died at 40 mg/kg/day).
Fetal soft tissue (e.g., exencephaly and hydronephrosls) and skeletal (e.g.,
supernumerary Mbs) anomalies occurred 1n all groups treated with <40 mg/kg/
day. Additional data regarding this study were not reported In the abstract.
0327d 6-30 07/26/90
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6.5. OTHER REPRODUCTIVE EFFECTS
Seller (1977} evaluated several chemical mutagens and carcinogens
Including hydrazlne for their effects on testlcular DMA synthesis. Hale
mice weighing between 23 and 28 g received a single oral dose of 200 mg
hydrazlne/kg. Hydrazlne administration Inhibited mouse testlcular ONA
synthesis, similarly to other mutagens and carcinogens; [*H]thym1d1ne
Incorporation was 72.4X of control (p<0.05).
Sotomayor et al. (1982) measured the occurrence of unscheduled DNA
synthesis In melotlc and postmelotlc germ-cell stages of male (101xC3H)F1
mice after IntrapeMtoneal Injection of 10, 20, 40, 80 or 120 mg hydra-
zlne/kg. Sixteen days after Injection, sperm heads from the caudal and
caput epldldymls were collected. The sperm heads were then assayed for
unscheduled DNA synthesis by Incorporation of [»H]thym1d1ne, Hydrazlne
did not significantly increase unscheduled DNA synthesis at any dose.
Because hydrazlae** known to damage DNA, thus stimulating DNA repair mecha-
nisms, Sotomayor et al. (1982) concluded that either very little hydrazlne
reached the spermatogenlc cells, or that the DNA repair enzymes do not
recognize hydrazlne-lnduced damage.
Uyrobek et al. (1981) evaluated the capacity of hydrazlne to Induce
morphologically abnormal sperm In male B6C3F1/CRL mice at doses between 0.9
and 400 mg/kg. No Increase In the number of abnormal sperm was observed In
hydrazlne-treated mice at any dose compared with control mice treated with
the distilled water vehicle only.
6.6. SUMMARY
Hydrazlne lethality was dose-related 1n female mice exposed by Inhala-
tion continuously to 0.26 or 1.3 mg/ma, or Intermittently to 1.3 or 6.5
mg/m>, for 6 months; the percentages of mortality were 2.5. 7.5, 35 and
0327d 6-31 07/26/90
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55%, respectively (Haun and Klnkead, 1973). Hepatotoxldty may have been
the cause of death. Comstock et al. (1954) reported high levels of mortal-
ity 1n rats, mice, guinea pigs and dogs exposed to 18 mg/m3 for <6 months.
Jacobson et al. (1955) reported 4-hour Inhalation LC. values for mice
(330 mg/m9) and rats (747 mg/m3).
The carcinogenic potential of hydrazlne was assessed In an extensive
study of Inhalation exposure in F344 male and female rats, male Syrian
golden hamsters, male and female C578B1/6 mice, and male and female beagle
dogs (Carter et al., 1981; MacEwen et al., 1981; Vernot et al.. 1985). The
animals were exposed to hydrazlne vapor at concentrations of 0.07. 0.33, 1.3
and 6.5 mg/m3 for rats and hamsters, 0.07, 0.33 and 1.3 mg/m3 for mice.
and 0.33 and 1.3 mg/m* for dogs over a 12-month period. At $.5 mg/m3.
the Incidence of nasal benign (adenomatous polyps) and malignant (squamous
cell carcinoma) tumors Increased 1n rats, and the Incidence of nasal polyps
and thyroid adenocardnomas increased In hamsters. A significant Increase
1n pulmonary adenomas was observed In mice exposed to 1.3 mg/m3. No
carcinogenic effect was found in the dogs.
Oral exposure to hydrazlne Increased the Incidence of pulmonary tumors
in different strains of mice (IARC, 1973; Blandflorl, 1969, 1970b,c,d,
1971; BlanclfloM and Seven. 1966; Blandflorl and Rlbacchl, 1962a,b;
Blandflorl et al.. 1963a.b, 1964; Hllla, 1965; Roe et al., 1967; Toth,
1969, 1971; Kelly et al.. 1969; Yamamoto and HeIsburger, 1970; Bhlde et al.,
1976). Nice generally developed multiple adenomas and adenocardnomas.
Three strains of mice also developed hepatomas and hepatocardnomas (IARC,
1973). In contrast, a decreased Incidence of mammary gland adenomas was
observed 1n female C3H mice that received 0.65 mg hydrazlne dally In the
drinking water (Toth. 1969). Blandflorl (1970c) administered hydrazlne
0327d
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07/26/90
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sulfate by gavage to 8-week-old CBA/Cb/Se mice at doses of 0, 0.14. 0.28,
0.56 or 1.13 nig/day. A dose-related Increase In vascularlzed hepatocard-
nomas was observed In both sexes. Lung metastases were also found at the
highest dose tested.
Sever! and Blandflorl (1968) reported that lung tumors (adenomas and
adenocardnomas) were found In 3/14 male and 5/18 female Cb/Se rats exposed
from the age of 8 weeks for 68 weeks to dally oral hydrazlne doses of 18 mg
for males and 12 mg for females. Hepatic carcinomas were also observed In
4/13 males and 1n 0/18 females. No spontaneous hepatic carcinomas had been
observed previously In the Cb rat colony maintained In this laboratory.
Stelnhoff and Mohr (1988) concluded that hydrazlne was a weak carcinogen In
Wlstar rats that received 0, 2, 10 or 50 mg hydrazlne/t until spontaneous
death. Benign liver cell tumors were obwrvwd only at the highest concen-
tration tested.
Significant Increases In tumor incident* were not found 1n two studies
of Syrian golden hamsters that received 2.3 mg/day in drinking water for
life (Toth, 1972b) or gavage doses of 2.8-3.0 mg/day for 15-20 weeks
{Blandflorl, 1970c). Bosan et al. (1987), however, reported an Increased
Incidence of hepatocellular carcinomas In Syrian golden hamsters that
received 4.6, 8.3 or 10.3 mg hydrazlne/kg/day for 2 years.
Subcutaneous Injection or Intratracheal instillation of 0.25-5 mg
hydraz1ne/kg once/week for 2.5 years had no carcinogenic effect In male or
female Sprague-Oawley rats (Stelnhoff and Mohr, 1988).
Hydrazlne Is genotoxlc In prokaryotes, lower eukaryotes, insects and
mammals. Hydrazlne caused DMA damage In phage and E.. coll (Helnemann, 1971;
Von Wright, 1981; Green, 1981) and 1n animal cells in vitro (S1na et al.,
1983), as well as unscheduled DNA synthesis In human flbroblasts and HeLa
0327
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cells in vitro (Agrelo and Amos, 1981; Martin and McDermld, 1981). Gene
mutations were observed 1n Salmonella (Wade et al.. 1981; Anderson and
Styles. 1978; HerboId and Buselmaler, 1976; Rowland and Severn, 1981), E..
coll and yeasts (Noda et al., 1986; Von Wright, 1981; Lemontt, 1978;
NcDougall and Lemontt, 1979). Hydrazlne Induced somatic mutations In
Drosophlla (Shukla, 1972; Vljaykumar and Oa1n, 1979) and mouse L5178Y cells
hi vitro (Rogers and Back, 1981). No effect of hydrazlne was observed in
the In vivo mlcronucleus test or the dominant lethal assay In mice
(Tsuchlmoto and Hatter, 1981; Epstein et al., 1972).
Hydrazlne-lnduced systemic toxklty after Inhalation exposure 1s
observed primarily In the liver, lungs and blood. Dogs exposed to 6.6
mg/m* Intermittently or 1.3 mg/m' continuously for 6 months suffered
decreased red blood cell counts, hemoglobin concentration and hematocrlts,
and increased erythrocyte fragility (Haun and Klnkead, 1973). Under the
same exposure protocol, fatty liver changes In mice and moderate fat accumu-
lation In the "liver of rhesus monkeys were observed. Similarly, Cornstock et
al. (1954) found fatty liver changes 1n beagle dogs exposed to 18 mg
hydrazlne/m9 for <6 months. Cornstock et al. (1952) reported emphysema and
Interstitial pneumonltls 1n rats and emphysema and atelectasls 1n dogs
exposed to 6 mg hydrazlne/m* for 31 weeks. Chronic Inflammation, atelec-
tasls and lymphold hyperplasla were observed 1n guinea pigs exposed to 3-6
mg/m» for 2 weeks followed by 8 weeks at 4-8 mg/m* (Weatherby and Yard,
1955). In the sane study, pathological changes noted In mongrel dogs
exposed to 3-6 ing/a* Included central-zone fatty degeneration and necrosis
of the livers and accumulation of bile pigment. Capillary damage In the
kidney and lung atelectasls were also observed (Weatherby and Yard, 1955).
0327d 6-34 07/26/90
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MacEwen et al. (1981) reported that hydrazlne exposure caused aspermato-
genests or hypospermatogenesls in Syrian golden hamsters. MacEwen et al.
(1981) also found that female rats suffered lesions Including ovary atrophy,
salplngHls and endometrltis when exposed to 6.6 mg hydrazlne/m3 for 1
year.
Systemic toxlclty after oral exposure to hydrazlne 1s similar to Inhala-
tion exposure. B1anc1f1or1 (1970a) administered hydrazlne by gavage to
Syrian golden hamsters (2.8-3.0 mg/hamster for 15-20 weeks; assuming a body
weight of 0.14 kg, this Is equivalent to -20 mg/kg) and observed severe
liver lesions Including cirrhosis, bile duct proliferation, pressure atrophy
and hepatocyte degeneration. In contrast, male albino rats that received
between 15 and 25 mg hydrazlne/kg/day for 3 or 4 weeks suffered no patho-
logical changes of heart, lung, liver, spleen, stomach, small Vnte$t1n<,
kidney, adrenal, pancreas or testes (Weatherby and Yard, 1955).
Occupational exposures to hydrazlne In gold-plating (Wrarvgsjo and
Martensson, 1986) and soldering work (Frost and HJorth, 1959) resulted In
contact dermatitis and eczema, respectively. Workers recovered completely
after exposure was discontinued.
Hydrazlne does not appear to be teratogenlc, although U 1s clearly
embryo- and fetotoxlc at levels associated with maternal toxlclty. Lee and
Aleyasslne (1970) Injected pregnant rats with 8 mg hydraz1ne/kg/day subcuta-
neously on gestation days 11-21. None of the hydrazlne-treated rats gave
birth to newborns that survived the first 24 hours, while newborns from
untreated control rats survived. Keller et al. (1982) determined that the
most susceptible prenatal period regarding embryolethality 1n rats was
gestation days 7-9. Lyng et al. (1980) administered IntraperHoneal
0327d
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07/26/90
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Injections of 4, 12. 20, 30 or 40 mg hydrazlne/kg and found that maternal
toxldty was also Indicated by reduced weight gain (at 12 and 20 mg/lcg) and
maternal death (4/21 rats died 1n the 40 rag/kg group).
0327d 6-36 07/26/90
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUNAN
The ACGIH (1989) has set a TLV-TWA for hydrazlne at 0.1 ppm (0.13
mg/m3} for occupational exposure during an 8-hour workday and 40-hour
workweek. ACGIH has not recommended a TLV-STEL for hydrazlne (ACGIH, 1989)
but has designated hydrazlne as a "suspected human carcinogen" and given It
a "skin" notation, Indicating that cutaneous absorption may contribute
significantly to total absorption. ACGIH (1989) Is considering a reduction
In the TLV-THA to 0.01 ppm. NIOSH (1978) recommended that occupational
exposure to hydrazlne be limited to a 2-hour celling level of 0.03 ppm (0.04
mg/m3). OSHA (1989) has directed that the final-rule PEL for exposure to
hydrazlne be set at a TWA concentration of 0.1 ppm (0.13 mg/m3). Further-
more, OSHA (1989) has given hydrazlne a "skin designation," Indicating that
dermal absorption of hydrazlne may contribute significantly to total
exposure.
7.2. AQUATIC
Guidelines and standards to protect aquatic life from exposure to
hydrazlne were not located In the available literature cited In Appendix A.
0328d 7-1 03/28/90
-------
-------
8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. MacEwen et al. (1981) Investigated the oncogen1c
effects of a 12-roonth Inhalation exposure to hydrazlne sulfate In mice,
rats, hamsters and dogs. Statistically significant Increases In tumor
Incidence were observed In female mice exposed to 1 ppm (lung adenoma), male
and female rats exposed to 1 or 5 ppm (nasal cavity adenoma/adenocardnoma),
male rats exposed to 5 ppm (thyroid adenocardnoma) and Syrian Golden
hamsters exposed to 5 ppm (nasal cavity polyp) (see Table 6-1). The
Increases In tumor Incidence and polyp formation were dose-related In all
cases. No Increase In tumor Incidence was observed In dogs.
This study was well designed and comprehensive; several species were
exposed to hydrazlne sulfate at <4 dose levels, hlstopathologUal examina-
tion of the animals Included 44 tissues and organs, the exposure period was
long, the follow-up observation period was 24-50 months, and appropriate
controls and statistics were reported.
8.1.2. Oral. B1anc1f1or1 (1970a) administered hydrazlne sulfate by
gavage to mice for 76-98 weeks and observed a dose-related Increase In the
Incidence of liver carcinomas (see Table 6-7). An adequate exposure and
observation period was used In this study, several dose levels of hydrazlne
sulfate were administered, a dose-related Increase In tumor Incidence was
demonstrated and both male and female mice were tested. The only weaknesses
of the study were that a single species was examined and statistical
analysis was not reported.
Bosan et al. (1987) reported a dose-related Increase In hepatocarclnomas
after oral exposure of Syrian Golden hamsters to hydrazlne sulfate for 2
years (see Table 6-8). An Increase In DNA methylatlon 1n the liver was also
0329d
8-1
01/22/90
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observed. This was a well conducted chronic study; however, statistical
analysis was not reported, and only one species was examined.
Several other studies of oral exposure to hydrazlne sulfate In mice
demonstrated an Increase In tumor Incidence, primarily lung or liver adenoma
or carcinoma. Although these studies Indicate that, at least In mice, the
lung Is equally sensitive as the liver to the carclnogenlclty of hydrazlne,
they are of limited value for quantitative risk assessment because only one
dose level was tested and statistical analysis of the results was not
reported (Toth 1969, 1972; Roe et al.. 1967; Seven and B1anc1f1or1, 1966}
(see Tables 6-2 to 6-6).
8.1.3. Other Routes. No Indication of carclnogenlclty was found after
administration of hydrazlne by subcutaneous Injection In rats once/week for
2.5 years (Stelnhoff and Nohr, 1988). Negative results were also reported
for rats given hydrazlne by Intratracheal Instillation for 2.5 years
(Stelnhoff and Nohr, 1988).
8.1.4. Height of Evidence. Hydrazlne caused a dose-related Increase 1n
the incidence of tumor formation 1n mice (lung adenoma) and rats
(alveolalgenlc carcinoma, lymphosarcoma of spleen) after Inhalation exposure
(NacEwen et al., 1981). Oral exposure to hydrazlne caused a dose-related
Increase In the Incidence of hepatic carcinomas In mice (B1anc1f1or1, 1970d;
Bosan et al., 1987). Other studies also documented Increased lung and liver
tumor Incidence after oral exposure In mice (Blandflorl, 1970c; Toth, 1969,
1972; Roe et al., 1967; Seven and B1anc1f1or1. 1968). Bosan et al. (1987)
observed an Increased Incidence of liver tumors 1n hamsters treated orally
with hydrazlne.
Toth (1969) reported an Increased Incidence of pulmonary adenoma or
adenocarclnoma In mice exposed orally to hydrazlne, but observed a decrease
In the Incidence of mammary gland carcinomas In hydrazlne-treated female
0329d 8-2 07/26/90
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mice. Toth (1972) and BlandfloM (1970c) reported that oral exposure to
hydrazlne did not significantly Increase tumor formation In hamsters.
Hydrazlne 1s genotoxlc 1n prokaryotes, lower eukaryotes, Insects and 1n
animal and human cells jhn vitro, although no effect was observed 1n the In
vivo mlcronucleus test or the dominant lethal assay In mice (see Table 6-9).
Data regarding the cardnogenlcUy of hydrazlne 1n humans were
Inadequate. On the basis of these data and the U.S. EPA (1986c)
classification scheme, hydrazlne has been classified In EPA we1ght-of-
evldence Group B2: probable human carcinogen (U.S. EPA, 1988, 1989).
8.1.5. Quantitative Risk Estimates.
8.1.5.1. INHALATION The Inhalation q^ for hydrazlne, 17.1
(mg/kg/day T1. was calculated from data reported 1n MacEwen et al. (1981),
which documented a dose-related Increase 1n the Incidence of nasal cavity
adenoma or adenocardnoma 1n male F344 rats. The corresponding unit risk Is
4.9xlQ~3 Ug/mT1. The Inhalation q^ and unit risk for
hydrazlne has been reviewed and verified by the U.S. EPA (1989). The dose
associated with a risk level of IxltT5 1s 5.9xlO"7 mg/kg/day. Multiply-
ing this value by the reference human body weight (70 kg) and then dividing
It by the reference human Inhalation rate (20 m'/day) yields a correspond-
ing air concentration of 2xlO~* mg/m3. Air concentrations associated
with risk levels of lx!0~« and lxlO~7 are 2xlO"7 mg/m" and 2x10~«
mg/ma, respectively.
8.1.5.2. ORAL The oral q^ for hydrazlne, 3.0 (mg/kg/day)"1,
was calculated from data reported by Blanclfforl (1970a) that documented a
dose-related Increase 1n the Incidence of hepatoma formation 1n male mice
exposed to hydrazlne sulfate. The corresponding unit risk 1s 8.5x10~s
0329d
8-3
08/02/90
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4. The q-j* based on the data for hydrazlne sulfate was
adopted for hydrazlne without adjustment for differences In the molecular
weights of the two compounds. The oral q * and unit risk for hydrazlne
have been reviewed and verified by the U.S. EPA (1989). The dose associated
with a risk level of IxltT' Is 3.3xlO~« mg/kg/day. Multiplying this
value by the reference human body weight (70 kg) and then dividing It by the
reference human water consumption rate (2 i/day) yields a corresponding
water concentration of l.ZxlCT4 mg/l. Water concentrations associated
with risk levels of lxlO'« and lx!0~7 are 1.2xlO~5 and 1.2x10"*
mg/l, respectively.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME (SUBCHRONIC) Hydrazlne-lnduced
systemic tox1c1ty after Inhalation exposure 1s observed primarily In the
liver, lungs and blood. Dogs exposed to 6.6 mg/m» Intermittently (Rec.
#3, Appendix C.2.1.) or 1.3 mg/m9 continuously for 6 months suffered
decreased red blood cell counts, hemoglobin concentration and hematocrlts.
and Increased erythrocyte fragility (Haun and Klnkead, 1973}. Under a
similar exposure protocol, death and fatty liver changes In mice at 0.26
mg/m3 (Rec. #1, Appendix C.2.1.) and moderate fat accumulation 1n the
liver of rhesus monkeys at 1.3 mg/m» Intermittently (Rec. #5, Appendix
C.2.1.) were observed. Similarly, Comstock et al. (1954) found fatty liver
changes and death 1n beagle dogs exposed Intermittently to 18 mg hydrazlne/
3
m3 for <6 nonths (Rec. #11. Appendix C.2.1.). Comstock and Oberst (1952)
reported death, emphysema and interstitial pneumonHls In rats (Rec. #7,
Appendix C.2.1.), and emphysema and atelectasls 1n dogs (Rec. #6, Appendix
C.2.1.) exposed to 6 mg hydrazlne/m1 for 31 weeks. Chronic Inflammation,
0329d
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03/28/90
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atelectasls and lymphold hyperplasla were observed In guinea pigs exposed to
3-6 mg/m3 for 2 weeks followed by 8 weeks at 4-8 mg/m» (Weatherby and
Yard, 1955) (Rec. #12, Appendix C.2.I.). In the same study, pathological
changes noted 1n mongrel dogs exposed to 3-6 mg/m3 Included central-zone
fatty degeneration and necrosis of the liver and accumulation of bile
pigment (Rec. #13, Appendix C.2.I.). Capillary damage In the kidney and
lung atelectasls were also observed (Weatherby and Yard, 1955).
The subchronlc Inhalation data, however, cannot be used for derivation
of an RfD. Haun and Klnkead (1973) reported significant mortality 1n mice
exposed continuously at 0.2 ppm (HEC = 0.26 mg/m*), which represents a
PEL. Calculation of HECs for all NOAEL and LOAEL values from the exposure
concentrations used In other subchronlc Inhalation studies (Comstock and
Oberst, 1952; Heatherby and Yard, 1955) were not lower than 0.26 mg/m*,
the HEC for the PEL In mice.
8.2.1.2. CHRONIC Chronic Inhalation data regarding hydrazlne are
also not appropriate for derivation of a chronic Inhalation RfD. NacEwen et
al. (1981) observed respiratory tract Inflammation and nasal/lung hyper-
plasla In rats exposed to 0.05 ppm (0.06 mg/m*) hydrazlne 6 hours/day, 5
days/week for 1 year (Rec. #15, Appendix C.2.I.). The HEC at which these
effects appeared (0.02 mg/m*) Is a LOAEL and Is an order of magnitude
lower than the HEC (0.26 mg/m*) associated with significant mortality In
mice (Haun and Klnkead, 1973) In a subchronlc Inhalation study. Therefore,
U Is not appropriate to derive a chronic Inhalation RfD from this LOAEL.
Hamsters exposed to 0.25 ppm (0.32 mg/m*) hydrazlne, 6 hours/day, 5
days/week (HEC > 0.057 mg/m*) for 1 year had widespread toxic effects
(amyloldosls 1n the livers, spleens, kidneys, thyroids and adrenals, liver
0329d
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01/22/90
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hemoslderosls, kidney mineralization, senile atrophy and hypospermato-
genesls) at the 2-year sacrifice (MacEwen et al. 1981) (Rec. #14, Appendix
C.2.I.). The NEC for these effects 1n hamsters Is higher than the HEC for
respiratory hyperplasla In rats. No other chronic Inhalation studies were
located that would be suitable for derivation of an RfD.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME (SUBCHRONIC) - Data regarding subchronlc
oral exposure to hydrazlne are Inadequate for derivation of a subchronlc
oral RfD. Blandflorl (1970a) reported only serious liver effects (cirrho-
sis, atrophy and necrosis) after oral exposure to hydrazlne 1n hamsters that
received 2.8 mg hydrazlne 5 days/week for 20 weeks, or 3.0 mg hydrazlne 4
days/week for IS weeks (Recs. #2 and 3, Appendix C.2.2.). No other doses
were tested; therefore, these data are not suitable for use as LOAEL values
for RfD determinations. Sever 1 and Blandflorl (1968) treated mice orally
with 37.7 mg hydrazlne/kg/day but reported only Increased tumor Incidences
and decreased llfespan. Weatherby and Yard (1955) administered hydrazlne
orally at various doses; however, 3/10 rats died at 100 mg/i (Rec. #1,
Appendix C.2.2.), the lowest concentration tested.
8.2.2.2. CHRONIC Pertinent data regarding nonneoplastU effects of
chronic oral exposure of humans or animals to hydrazlne were not located 1n
the available literature cited In Appendix A. Therefore, no data are
available for derivation of a chronic oral RfD.
0329d
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01/22/90
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxlclty of hydrazlne was discussed In Chapter 6. A chronic non-
cancer toxlclty RQ has been derived for hydrazlne {U.S. EPA, 1985), based on
mortality In mice exposed Intermittently to 1.3 mg/m* for 6 months (Haun
and Klnkead, 1973), and 1s summarized 1n Table 9-1. More recent data were
not located; hence, there has been no reconsideration of this derivation.
The RQ of 10 derived by U.S. EPA (1985) Is adopted for the purposes of this
document.
9.2. BASED ON CARCINOGENICITY
Data regarding the cardnogenldty of hydrazlne are discussed 1n Chapter
6 and presented 1n Tables 6-1 through 6-8. Several studies have reported an
Increase 1n tumor Incidence after Inhalation and oral exposure to hydrazlne.
NacEwen et al. (1981) observed significantly Increased Incidences of lung
adenomas In mice, nasal cavity adenomas and adenocarclnomas In rats, and
nasal cavity polyps 1n hamsters, after Inhalation exposure to hydrazlne.
B1anc1f1or1 (1970a) observed a dose-related Increase In hepatic carcinomas
after oral exposure to hydrazlne. Other studies also documented Increased
lung and liver tumor Incidences after oral exposure 1n mice (Blandf 1or1,
1970c; Toth. 1969, 1972; Roe et al., 1967; Seven and BlandfloM, 1968).
An increase in liver tumor incidence was also reported 1n hamsters after
oral exposure to hydrazlne (Bosan et al., 1987).
The genotoxldty of hydrazlne has been demonstrated 1n prokaryotes,
lower eukaryotes, Insects and 1n human and animal cells jn vitro (Table 6-9).
0330d 9-1 08/01/90
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TABLE 9-1
Hydrazlne
(302-01-2)
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Species/sex:
Oose*:
Duration:
Effect:
RVd:
RVe:
CS:
RQ:
Reference:
Inhalation
mouse/female
1.6 rag/day
6 months
mortality
5.2
10
52
10
Haun and Klnkead, 1973
'Equivalent human dose
0330d
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On the basis of the available data, hydrazlne has been assigned to EPA
we1ght-of-evidence group 82 as a probable human carcinogen (U.S. EPA, 1988,
1989).
A human potency factor has been derived (U.S. EPA, 1988) based on the
incidence of nasal tumors In rats (MacEwen et a!., 1981) and Is presented 1n
Table 9-2. On the basis of this potency factor, hydrazlne 1s assigned to
the "high" potency group, which, for EPA we1ght-of-evidence Group 82
chemicals, results In a cancer-based RQ of 1.
0330d 9-3 01/22/90
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TABLE 9-2
Derivation of Potency Factor (F) for Hydrazlne
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight3:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental doses/exposures:
Transformed dosesb:
(mg/kg/day)
Tumor Incidence:
Animal Potency (mg/kg/day)"1:
Human Potency0:
{ mg/kg/day T1
MacEwen et al. ,
Inhalation
rat
F344
M
air
0.35 kg
365 days
910 days
910 days
nasal cavity
1981
M
air
365 days
910 days
910 days
N
air
NA
910 days
910 days
adenoma/adenocarclnoma
5.0 ppm
0.30
72/99
19.33
1.0 ppm
0.06
11/98
0.0 ppm
0.0
0/149
Estimated
bTo derive the transformed doses from the experimental dose data, convert
experimental dose 1n (ppm) to (mg/m>): 0.041 x mol wt hydrazlne x concen-
tration (ppm); calculate preliminary transformed dose (mg/kg/day) based on
breathing rate and animal weight: concentration (mg/m*) x breathing rate
for rats (0.22 m»/day)/an1mal weight (0.35 kg); determine final trans-
formed dose by adjusting for duration of study, and discontinuous exposure:
transformed dose (mg/kg/day) x duration of treatment (days)/durat1on of
study (days) x 5 (treatment days/week)/? (days/week) x 6 (treatment hours/
day)/24 (hours/day). :
cHuman potency « animal potency x (70 kg/0.35 kg)1/3
NA - Not available
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The disappearance of fuel hydrazlne vapors 1n fluorocarbon-fllin environ-
mental chambers. Experimental observations and kinetic modeling. Environ.
Sc1. Techno!. 23: 328-333.
Toth, B. 1969. Lung tumor Induction and Inhibition of breast adenocarcl-
nomas by hydrazlne sulfate 1n mice. J. Natl. Cancer Inst. 42: 469-475.
Toth, B. 1971. Investigations on the relationship between chemical struc-
ture and carcinogenic activity of substituted hydrazlnes. Proc. Am. Assoc.
Cancer Res. 12: 55.
0331d 10-17 08/09/90
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Toth, 8. 1972a. Hydrazlne. methylhydrazlne and methylhydrazlne sulfate
cardnogenesls In Swiss mice. Failure of ammonium hydroxide to Interfere In
the development of tumors. Int. J. Cancer. 9: 109-118.
Toth, B. 1972b. Tumour 1genes 1s studies with 1,2-dlmethylhydrazlne
dlchloMde, hydrazlne sulfate and 1son1cot1n1c acid 1n golden hamsters.
Cancer Res. 32: 804-807.
Tsuchlmoto, T. and B.E. Matter. 1981. Activity of coded compounds In the
mlcronucleus test. Prog. Hut. Res. 1: 705-711.
Tuazon, E.C.. W.P.L. Carter, A.M. Miner and J.N. Pitts, Jr. 1981. Reaction
of hydrazlnes with ozone under simulated atmospheric conditions. Environ.
Scl. Techno1. 15: 823-828.
U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
U.S. EPA. 1984a. Methodology and Guidelines for Ranking Chemicals Based on
Chronic Tox1c1ty Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati. OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1984b. Health and Environmental Effects Profile for Hydrazlne
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Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Solid Haste, Washington. DC.
0331 d
10-18
08/09/90
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U.S. EPA. 1985. Reportable Quantity Document for Hydrazlne and Hydrazlne
Sulfate. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1986a. Methodology for Evaluating Reportable Quantity Adjust-
ments Pursuant to CERCLA Section 102. Prepared by the Carcinogen Assessment
Group, Office of Health and Environmental Assessment for the Office of
Emergency and Remedial Response, Washington. DC.
U.S. EPA. 1986b. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
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DC.
U.S. EPA. 1986c. Guidelines for Carcinogen Risk Assessment. Federal
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U.S. EPA. 1988. Evaluation of the Potential CareInogenlcity of Hydrazlne
In Support of Reportable Quantity Adjustments Pursuant to CERCLA Section
102. Prepared by the Carcinogen Assessment Group, Office of Health and
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0331 d 10-19 08/09/90
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0331 d
10-20
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Hakabayashl, T., K. Yamashlta, K. Adachl, et al. 1987. Changes In physico-
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691, 872.
Hrangsjo, K. and A. Martensson. 1986. Hydrazlne contact dermatitis from
gold plating. Contact Derm. 15(4): 244-245. (Taken from NIOSH/00166309)
Wryobek, A., L. Gordon and G. Watchmaker. 1981. Effect of 17 chemical
agents Including 6 carclnogen/noncardnogen pairs on sperm shape abnormali-
ties In mice. Prog. Mutat. Res. 1(Eva1. Short-Term Tests Carclnog.: Rep.
Int. Collab. Program): 712-717.
0331d 10-21 08/09/90
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Yamamoto, R.S. and J.H. Uelsburger. 1970. failure of arglnlne glutamate to
Inhibit lung tumour formation by 1son1az1d and hydrazlne 1n mice. Life Scl.
9: 285-289.
Yaws, C.L., J.R. Hooper and M.G. Rojas. 1974. Ammonia and hydrazlne.
Chem. Eng. 81: 91-100.
Yoon, J.S., J.H. Mason, R. Valencia, R.C. Woodruff and S. Z1mmer1ng. 1985.
Chemical mutagenesls testing 1n DrosophHa. IV. Results of 45 coded com-
pounds tested for the National Toxicology Program. Environ. Nol. Mutagen.
7: 349-367.
0331 d
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
CHEHLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
SCISEARCH
Federal Research In Progress
These searches were conducted 1n July, 1989, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances In the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton. 6.0. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 28. John Wiley and
Sons, NY. p. 2879-3816.
0332d A-l 01/22/90
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Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev, ed., Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
Grayson, N. and D. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, MenTo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington. DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz. M.t Ed. 1983. The Merck Index,'10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
0332d
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01/22/90
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In addition, approximately 30 compendia of aquatic toxicity data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxicity
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxicity Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
HcKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, 8.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0332d A-3 01/22/90
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