820K88127
August, 1987
DRAFT
MALE1C HYDRA21DE
Health Advisory
Office of Drinking Water
U.S. Environmental Protection Agency
I. INTRODUCTION
The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical method-
ology and treatment technology that would be useful in dealing with the
contamination of drinking water. Health Advisories describe nonregulatory
concentrations of drinking water contaminants at which adverse health effects
would not be anticipated to occur over specific exposure durations. Health
Advisories contain a margin of safety to protect sensitive members of the
population.
Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur. They are not to be
construed as legally enforceable Federal standards. The HAs are subject to
change as new information becomes available.
Health Advisories are developed for one-day, ten-day, longer-term
(approximately 7 years, or 10% of an individual's lifetime) and lifetime
exposures based on data describing noncarcinogenic end points of toxicity.
Health Advisories do not quantitatively incorporate any potential carcinogenic
risk from such exposure. For those substances that are known or probable
human carcinogens, according to the Agency classification scheme (Group A or
B), Lifetime HAs are not recommended. The chemical concentration values for
Group A or B carcinogens are correlated with carcinogenic risk estimates by
employing a cancer potency (unit risk) value together with assumptions for
lifetime exposure and the consumption of drinking water. The cancer unit
risk is usually derived from the linear multistage model with 95% upper
confidence limits. This provides a low-dose estimate of cancer risk to
humans that is considered unlikely to pose a carcinogenic risk in excess
of the stated values. Excess cancer risk estimates may also be calculated
using the One-hit, Weibull, Logit or Probit models. There is no current
understanding of the biological mechanisms involved in cancer to suggest that
any ->ne of these models is able to predict risk more accurately than ai other.
Because each model is based on differing assumptions, the estimates that are
derived can differ by several orders of magnitude.
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Maleic Hydrazide
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August, 1987
II. GENERAL INFORMATION AND PROPERTIES
CAS No. 123-33-1
Structural Formula
1,2-Dihydro-3,6-pyridazinedione
Synonyms
e Antergon; Chemfonn; De-Sprout; Retard; Slo-Gro; Sucker-Stuff;
(Meister, 1983).
Uses
9 Plant growth retardant (Meister, 1983).
Properties {Meister, 1983; CHEMLAB, 1985; TDB, 1985)
Chemical Formula
Molecular Weight
Physical State (25°C)
Boiling Point
Melting Point
Density
Vapor Pressure (50°C)
Specific Gravity
Water Solubility (25°C)
Log Octanol/Water Partition
Coefficient
Taste Threshold
Odor Threshold
Conversion Factor
C4H402N2
112.09
Crystalline solid
292°C
1 .60
0 mm Hg
6,000 mg/L
-3.67 (calculated)
Occurrence
No information was found in the available literature on the occurrence
of maleic hydrazide.
Environmental Fate
Maleic hydrazide is very soluble in water (6,000 ppm) and in most
organic solvents (>1,000 ppm). The vapor pressure is essentially
zero (Registrant CBI data; WSSA, 1983).
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Maleic Hydrazide August, 1987
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0 Salts of maleic hydrazide will dissociate in solutions above pH 4.5
and exist only as maleic hydrazide. Maleic hydrazide is stable to
hydrolysis at pHs of 3, 6 and 9. Photolysis potential has not been
addressed (Registrant CBI data; WSSA, 1983).
0 In field dissipation studies using various soils from the eastern,
southern and midwestern U.S., the half-lives were reported to be
between 14 and 100 days. There is no pattern, but the half-life may
be related to organic matter content. Degradation by soil micro-
organisms appears to be rapid (Registrant CBI data; WSSA, 1983).
0 There is some indication that maleic hydrazide is highly mobile
in unaged soils. Aerobic aging of maleic hydrazide results in a
lowering of leaching potential (Registrant CBI data; WSSA, 19,83).
III. PHARMACOKINETICS
Absorption
0 Mays et al. (1968) administered single oral doses of 14C-labeled
maleic hydrazide to rats. After 6 days, only 12% had been excreted
in the feces, indicating that 88% had been absorbed.
Distribution
0 Kennedy and Keplinger (1971) administered 14C-labeled maleic hydrazide
to pregnant rats in daily doses of either 0.5 or 5.0 mg/kg. Fetuses
from dams sacrificed on day 20 were found to contain label equivalent
to 20 to 35 ppb of the parent compound at the 0.5-mg/kg dose level,
and 156 to 308 ppb at the 5.0-mg/kg dose level. Pups from females
that were allowed to litter were sacrificed at 8 and at 24 hours, and
stomach coagulum was analyzed to determine transfer through the milk.
At the 0.5 mg/kg dose, the coagulum contained 4 to 7 ppb at 8 hours
and 2 ppb at 24 hours; at the 5.0 mg/kg dose, the figures for 8 and
24 hours were 79 to 89 ppb and 7 to 8 ppb, respectively. These
results showed that maleic hydrazide crossed the placenta and was
also transmitted to the pups via the milk.
Metabolism
0 Barnes et al. (1957) reported that rabbits administered a single oral
dose of 100 mg/kg of maleic hydrazide excreted 43 to 62% of the dose,
unchanged, within 48 hours. The route of excretion (urinary or
fecal) was not stated. The results were similar following a dose of
2,000 mg/kg, and no glucuronide or ethereal sulfate conjugates were
found.
0 Oral administration of maleic hydrazide labeled with 14C to rats
resulted in excretion of 0.2% labeled carbon dioxide in the expired
air over a 6-day observation period (Mays et al., 1968). Urinary
products (77% of the total dose) were largely unchanged maleic
hydrazide (92 to 94% of the urinary total) and conjugates of maleic
hydrazide (6 to 8%).
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Maleic Hydrazide August, 1987
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Excretion
Mays et al. (1968) administered single oral doses of 14C-maleic hydra-
zide to rats. Over a 6-day observation period, the animals excreted
0.. 2% of the label as carbon dioxide in the expired air, 12% in the
feces and 77% in the urine. Only trace amounts were detected in
tissues and blood after 3 days.
IVc HEALTH EFFECTS
Humans
No information on human exposure to maleic hydrazide was found in the
available literature.
Animals
Short-term Exposure
0 The acute oral toxicity of maleic hydrazide (purity not specified) in
rats was determined with administration of four dose levels to groups
of five animals, with a 15-day observation period (Reagan and Becci,
1982). At dose levels of 5,000, 6,300, 7,940 or 10,000 mg/kg, deaths
occurring in the male animals were 0/5, 0/5, 1/5 and 5/5, respectively,
while those for female animals'were 1/5, V5, 4/5 and 5/5, respectively,
The LDsQ values were calculated to be 6,300 mg/kg for males, 6,680
mg/kg for females and 7,500 mg/kg for both sexes combined. Adverse
effects noted included ataxia, diarrhea, salivation, decreased motor
activity and blood in the intestines and stomach.
0 Sprague-Dawley rats (five males and five females) were fasted for
16 hours and then given a single oral dose of technical maleic hydra-
zide (purity not specified) at a level of 5,000 mg/kg and observed
for 14 days (Shapiro, 1977a). No deaths occurred during this period.
Necropsies were not performed, and no details were given with respect
to adverse effects that may have been observed.
0 The acute oral toxicity of the diethanolamine salt of maleic hydrazide
(MH-DEA) (purity not specified) was determined in rats and rabbits
(Uniroyal Chmical, 1^71). In both species, MH-DEA was lethal at a
•level of 1,000 mg/kg, 'while doses between 300 and 500 mg/kg showed no
toxicity in either species. The LDSQ value for both species was cal-
culated to be 700 mg/kg.
0 Rats were used for a comparison of the acute oral toxicity of the
sodium and diethanolamine salts (purities not specified) of maleic
hydrazide (Tate, 1951). The diethanolamine salt showed an LDso
value of 2,350 mg/kg, while the LDso for the sodium salt (MH-Na)
was 6,950 mg/kg. No details of the study were given.
0 The acute oral LDso value of technical-grade maleic hydrazide (purity
not specified) for rabbits was greater than 4,000 mg/kg (Lehman,
1951). No details of the study were available.
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Maleic Hydrazide August, 1987
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0 The acute oral toxicity of maleic hydrazide (purity not specified) in
four species (mouse, rat, rabbit and dog) was studied by Mukhorina
(1962). For all species, the LD50 was reported as 700 mg/kg, with an
LD10O of 1fOOO mg/kg and a toxicity range from 300 to 500 mg/kg. For
rats and rabbits, adverse effects noted were cyanosis, tachypnea,
convulsions and paralysis; no other details were given.
Dermal/Ocular Effects
0 Technical-grade maleic hydrazide was tested on male and female New
Zealand rabbits for both skin and eye irritation (Shapiro, 1977b,c).
Applied at 0.5 mL, the maleic hydrazide was scored as a mild primary
skin irritant. In the eye test, 100 mg of the material was used, and
maleic hydrazide was judged not to be an eye irritant.
0 The acute dermal toxicity of maleic hydrazide (purity and form not
specified) was determined in five male and five female New Zealand
rabbits (Shapiro, 1977d). The skin of two males and three females
was abraded. A single dose of 20,000 mg/kg was applied, and the
animals were observed for 14 days. On the first day, two males
(one with abraded skin) and one female died. The animals that died
exhibited ataxia, shallow respiration and were comatose.
V
0 In an evaluation of the acute dermal toxicity of Royal MH-30 (30%
MH-DEA) and maleic hydrazide-technical, both formulations were stated
to be mild primary skin irritants and slight eye irritants (Uniroyal
Chemical, 1977). Individual details of the study were not given.
Long-term Exposure
0 Rats were fed MH-Na or MH-DEA (purity not specified) in the diet for
11 weeks (Tate, 1951). The MH-Na was given at dose levels of 0.5%
or 5.0% (5,000 or 50,000 ppm). Assuming that 1 ppm in the diet of
rats is equivalent to 0.05 mg/kg/day (Lehman, 1959), these doses
correspond to 250 or 2,500 mg/kg/day. No significant mortality or
other adverse effects were noted (no details given). The No-Observed-
Adverse-Effect-Level (NOAEL) for MH-Na in this study is 2,500 mg/kg
(the highest dose tested). The MH-DEA was fed at a level of 0.1%
(1,000 ppm) for 11 weeks.' This is equivalent to a dose of 50 mg/kg/day
(Lehman, 1959). At the end of 11 weeks, 21/24 animals had died. The
author stated that after further investigation (details not given),
it was concluded that the observed mortality was due to the DEA
component of the formulation.
0 The toxicity of maleic hydrazide in the diet for 1 year (320 to
360 days) was investigated in rats and dogs (Mukhorina, 1962). Rats
received oral doses of maleic hydrazide at 0.7, 1.5 or 3 mg/kg/day,
and a fourth group received 7 mg/kg MH-DEA. Dogs were administered
an oral dose of 0.7 mg/kg/day maleic hydrazide. Other details in
this translation on study design and conduct were not clear. Rats
exposed at the high dose had hyperemia and hemorrhage of the lungs,
myocardium, liver and brain, abnormal glucose-tolerance curves,
lowered liver glycogen, dystrophic changes in the liver, nephritis,
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interstitial pneumonia, loss of hair and significant reduction in
weight gain compared with the controls (at 4 months, controls had
gained 30%; those fed MH-DEA at 3 mg/kg/day had gained only 21%).
Dogs fed 0.7 mg/kg/day maleic hydrazide showed no significant adverse
changes, and it appears that for both the rat and the dog the level
of 0.7 mg/kg/day MH-DEA was a NOAEL.
0 Mukhorina (1962) also reported on a study done in mongrel mice given
0.7 mg/kg/day maleic hydrazide (purity not specified) in the diet for
320 to 360 days. No pathological changes were found. Based on these
data, the NOAEL for MH-DEA in the mouse is 0.7 mg/kg/day.
0 In a study by Food Research Labs (1954), MH-Na was fed in the diet
to rats (number not specified) from weaning for two years. Levels
of MH-Na (expressed as the free acid) were 0.0, 0.5, 1.0, 2.0 or 5.0%
(0, 5,000, 10,000, 20,000 or 50,000 ppm). Assuming that 1 ppm in the
diet of rats corresponds to 0.05 mg/kg/day (Lehman, 1959), this is
equivalent to doses of 0, 250, 500, 1,000 or 2,500 mg/kg/day. There
were no changes in blood or urine and no dose- or time-dependent
effects on longevity. Other study details were not presented.
Based on these observations, the NOAEL identified from this study
is 2,500 mg/kg/day (highest dose tested) for the rat.
0 In a similar study in dogs (Food Research Labs, 1954) animals were
fed doses of 0.0, 0.6, 1.2 or 2.4% maleic hydrazide (as MH-Na) in
the diet for 1 year. Assuming 1% (10,000 ppm) in the diet of dogs
corresponds to 250 mg/kg/day (Lehman, 1959), this is equivalent to
a dose of 500 mg/kg/day. No effects attributable to exposure were
detected.
0 Van Der Heijden et al. (1981) fed technical maleic hydrazide, 99%
active ingredient (a.i.) and containing less than 1.5 mg hydrazine/kg
as an impurity to rats at dietary levels of 1.0 or 2.0% (10,000 or
20,000 ppm) for 28 months. Assuming that 1 ppm in the diet of rats
is equivalent to 0.05 mg/kg/day (Lehman, 1959), this corresponds to
doses of 500 or 1,000 mg/kg/day. These two levels of maleic hydrazide
in the diet caused proteinuria and increased the protein/creatinine
ratio in the urine of both sexes, although there were no detectable
histopathological changes in the kidney or the urinary tract. Based
on the effects on kidney function, the no-effect level was considered
by the authors to be lower than 1.0% maleic hjIrazide in the diet of
rats. On this basis, a Lowest-Obcerved-Adverse-Effeet-Level (LOAEL)
of 500 mg/kg is identified.
Reproductive Effects
0 In a two-generation reproduction study by Kehoe and MacKenzie (1983),
Charles River CD(SD)BR rats (15 males and-30 females/dose) were
administered the potassium salt of maleic hydrazide (K-MH) (purity
not specified) at dietary concentrations of 0, 1,000, 10,000 or
30,000 ppm. Assuming that 1 ppm in the diet of rats is equivalent to
0.05 mg/kg/day (Lehman, 1959), these doses correspond to 0, 50, 500
and 1,500 mg/kg/day. No adverse effects on reproductive indices were
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observed at any dietary level. However, increased mortality was
observed in FI parents that received 30,000 ppm. Also at this dose
level, body weights were reduced in FQ parents during growth and
reproduction and in FI and ?2 pups during lactation. Based on the
postnatal decrease in the body weight of pups, a reproductive NOAEL
of 10,000 ppm (500 mg/kg/day) is identified.
0 In a four-generation reproduction study in rats (Food Research Labs,
1954), animals were fed MH-Na (purity not specified) in the diet at
dose levels of 0.5, 1.0, 2.0 or 5.0% (5,000, 10,000, 20,000 or 50,000
ppm) (expressed in terms of free acid). Assuming 1 ppm in the diet
of rats corresponds to 0.05 mg/kg/day (Lehman, 1959), this is equivalent
to 250, 500, 1,000 or 2,500 mg/kg/day. The authors reported that
there were no effects on fertility, lactation or other reproductive
parameters, but no data from the study were presented for an adequate
assessment of these findings.
Developmental Effects
0 Khera et al. (1979) administered maleic hydrazide (97% purity) to
pregnant rats by gavage on days 6 to 15 of gestation at doses of 0,
400, 800, 1,200 or 1,600 mg/kg/day. Animals were sacrificed on day
22. No sign of toxicity or adverse effect on maternal weight gain
was observed at any dose level tested. Values for corpora lutea,
total implants, resorptions, dead fetuses, male/female ratio and
fetal weight were within the control range. The number of live fetuses
was decreased at the 1,200-mg/kg dose, but this was not statistically
significant and did not occur at the highest dose tested. Fetuses
examined for external, soft-tissue and skeletal abnormalities showed
no increase in frequency of abnormalities at any dose level tested.
Based on the results of this study, a NOAEL of 1,600 mg/kg/day (the
highest dose tested) is identified for maternal effects, fetotoxicity
and teratogenic effects.
0 Hansen et al. (1984) studied the teratogenic effects of MH-Na and
the monoethanolamine salt (MH-MEA) on fetuses from female rats exposed
by gavage to doses of 500, 1,500 or 3,000 mg/kg/day in the diet at
various stages of gestation. Replicate tests were run. No increased
frequency of gross, skeletal or visceral abnormalities was observed in
animals dosed by gavage on days 6 to 15 of gestation with 500 mg/kg/day
of either MH-Na or MH-MEA. l& increased frequency of minor skeletal
variants (asymmetrical and bipartite sternebrae, wavy ribs, fused
ribs, rudiment of cervical rib, single bipartite or other variations
in thoracic vertebrae) was observed in animals receiving 1,500
(p <0.01) or 3,000 (p <0.1) mg/kg/day of MH-MEA on days 6 to 15, but
this was observed neither in animals exposed to 3,000 mg/kg/day for
days 1 to 21 of gestation nor in a replicate experiment. Similarly,
MH-Na produced marginal increases in minor skeletal variants in one
experiment at doses of 1,500 mg/kg/day for days 6 to 15 (p <0.1) or
3,000 mg/kg/day for days 1 to 21 (p <0.1), but this was -not observed
in a replicate experiment. Rats dosed with 3,000 mg/kg/day MH-MEA in
the diet exhibited a significant decrease in maternal body weight and
in weight gain compared to the controls. This effect was not observed
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when 3,000 mg/kg was given on days 1 to 21 by gavage, and there was
no significant effect on food intake. Exposure to 3,000 mg/kg in the
diet caused a significant increase in resorptions (p <0.001 ) and a
decrease in mean fetal weight (p <0.001). Similar but less pronounced
effects were observed when this dose was given by gavage. In addition,
postimplantation loss was increased significantly (p <0.01) in both
experiments. The authors theorized that the more severe effects
observed when the MH-MEA was fed in the diet (versus gavage) could be
due to an alteration in the palatability of the diet, resulting in
decreased food consumption. In contrast to the results with MH-MEA,
MH-Na had no adverse effects on the dams except for a reduction in
food consumption for days 1 to 6 in the group exposed from days 1 to
21 at 3,000 mg/kg. There were significant differences in body weight
of the pups (up to age 35 days) of dams administered MH-MEA by gavage
at 3,000 mg/kg/day from day 6 of gestation through day 21 of lactation;
a significant delay in the pups' startle response to an auditory
stimulus, significantly higher brain weight in both male and female
pups, and a delay in unfolding of the pinna were noted also. The
authors attributed the increase in relative brain weight to the lower
body weight. The delay in the startle response in MH-MEA dosed
offspring was considered the most significant effect, since it was
observed in both sexes, but the authors noted that it cannot be
explained. Based on these data, maternal, fetotoxic and teratogenic
NOAELs of 1,500, 1,500 and 500 mg/kg/day, respectively, were identified
for both MH-MEA and MH-Na.
0 Aldridge {1983, cited in U.S. EPA, 1985a) administered K-MH by gavage
at doses of 0, 100, 300 or 1,000 mg/kg/day to Dutch Belted rabbits
(16/dose) on days 7 through 27 of gestation. No signs of maternal
toxicity were reported, and the NOAEL for this effect is identified
as 1,000 mg/kg/day (the highest dose tested). Malformed scapulae
were observed in fetuses from the 300- and 1,000-mg/kg/day dose
groups. An evaluation of this study by the Office of Pesticide
Programs (U.S. EPA, 1985a) concluded that scapular malformations are
rare and considered to be a major skeletal defect. Historical data
for Dutch Belted rabbits from the testing laboratory (IRDC) indicated
that scapular anomalies were observed in only 1 of 1,586 fetuses
examined from 264 litters. Based on this information, a NOAEL of
100 mg/kg/day is identified for developmental effects.
Mutagenicity
0 The mutagenic activity of maleic hydrazide and its formulations has
been investigated in a number of laboratories. These studies are
complicated by the fact that hydrazine (a powerful mutagen) is a common
contaminant of these preparations, and N-nitrosoethanolamine (also a
mutagen) may be present in MH-DEA. Present data are inadequate to
determine with certainty whether any mutagenic activity of maleic
hydrazide is due to impurities and not the maleic hydrazide itself.
0 Tosk et al. (1979) reported that maleic hydrazide (purity not
specified), at levels of 5, 10 and 20 mg, was not mutagenic in
Salmonella typhimurium (TA 1530). However, two formulations (MH-30
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Maleic Hydrazide August, 1987
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and Royal MH), at 50, 100 and 200 uL (undiluted), were highly mutagenic
in this system.
0 Moriya et al. (1983) reported that maleix hydrazide was not mutagenic
in five strains of j>. typhimurium.
0 Ercegovich and Rashid (1977) observed a weak mutagenic response with
maleic hydrazide (purity not specified) in five strains of _S. typhimurium.
0 Shiau et al. (1980) reported that maleic hydrazide was mutagenic,
with and without activation, in several Bacillus subtilis strains.
0 Epstein et al. (1972) reported that maleic hydrazide (500 mg/kg) was
not mutagenic in a dominant-lethal assay in the mouse.
0 Nasrat (1965) reported a slight increase in the frequency of sex-
linked recessive lethals in the progeny of Drosophila melanogaster
males reared on food containing 0.4% maleic hydrazide.
0 Manna (1971 ) indicated that exposure to a 5% aqueous solution of
maleic hydrazide produced chromosomal aberrations in the bone marrow
of mice in a manner similar to that produced by x-rays and other
known mutagens.
0 Chaubey et al. (1978) reported that intraperitoneal injection of 100
or 200 mg/kg maleic hyerazide (purity not specified) did not affect
the incidence of bone marrow erythrocyte micronuclei or the ratio of
poly- to normochromatic erythrocytes in male Swiss mice.
0 Sabharwal and Lockhard (1980) reported that at concentrations above
100 ppm, maleic hydrazide induced dose-related increases in sister
chromated exchange (SCE) in human lymphocytes and V79 Chinese hamster
cells. Commercial formulations of maleic hydrazide (Royal MH and
MH-30) at the 250- and 500-mg/kg doses did not cause an increase in
micronucleated polychromatic erythrocytes in a mouse micronucleus test.
0 Stetka and Wolff (1976) reported that maleic hydrazide (11 and 112 mg/L;
purity not specified) caused no significant effect in an SCE assay.
0 Nishi et al. (1979) reported that maleic hydrazide (1,000 ug/L; purity
not specified), MH-DEA (20,000 ug/mL) and MH-K (20,000 ug/mL) produced
cytogenetic effects in Chinese hamster V79 cells in vitro.
0 Paschin (1981) reported that in the concentration range of 1,800 to
2,500 mg/L maleic hydrazide (purity not specified) was mutagenic for
the thymidine kinase locus of mouse lymphoma cells.
Carcinogenicity
0 The carcinogenicity of maleic hydrazide (purity not specified)
was evaluated in two hybrid strains of mice (C57BL/6 x AKR and
C57BL/6 x C3H/Anf) (Kotin et al., 1968; Innes et al., 1969). Beginning
at 7 days of age, mice were given maleic hydrazide at 1,000 mg/kg/day
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Maleic Hydrazide August, 1987
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(suspended in 0.5% gelatin) by stomach tube. After 28 days of age,
they were given maleic hydrazide in the diet at 3,000 ppm for 18
months. Assuming that 1 ppm in the diet of mice corresponds to
0.15 mg/kg/day (Lehman, 1959), tftis is equivalent to a dose of
450 mg/kg/day.- These were the maximum tolerated doses. No evidence
of increased tumor frequency was detected in gross or histologic
examination.
Barnes et al. (1957) fed maleic hydrazide at a level of 1% (10,000 ppm)
in the diet of rats and mice (10 to 15/sex/dose) for a total of 100
weeks. Assuming that 1 ppm in the diet corresponds to 0.05 mg/kg/day
in rats and 0.15 mg/kg/day in mice (Lehman, 1959), this is equivalent
to a dose of 500 mg/kg/day in rats and 1,500 mg/kg/day in mice.
A concurrent study was conducted in which the maleic hydrazide
(500 mg/kg/week, corresponding to 71 mg/kg/day) was injected subcu-
taneously (sc) for the same length of time. No increase in the
incidence of tumors was observed in animals exposed by either route
when compared with controls (data were pooled).
Cabral and Ponomarkov (1982) administered maleic hydrazide by gavage
in weekly doses of 510 mg/kg in 0.2 mL olive oil to male and female
C57BL/B6 mice for 120 weeks. Controls received 0.2 mL olive oil
alone, and a third group served as untreated controls. A simultaneous
study was conducted using sc injection as the route of administration.
There was no evidence of carcinogenicity in the study.
Van Der Heijden et al. (1981) fed maleic hydrazide (99% pure)
containing less than 1.5 mg hydrazine/kg as impurity to rats at
dietary levels of 1.0 or 2.0% (10,000 or 20,000 ppm) for 28 months.
Assuming that 1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day
(Lehman, 1959), this corresponds to doses of 500 or 1,000 mg/kg/day.
Histological examination revealed no increase in the tumor incidence
in exposed animals compared with the control group.
In a study by Uniroyal Chemical (1971), mice were administered maleic
hydrazide (0.5% in water) by gavage twice weekly beginning at 2 months
of age (weight 15 to 18 g) for a total of 2 years. A parallel study
was conducted using sc administration. No carcinogenic effect was
reported, but specific details of the study were not presented.
Uniroyal Chemical (1971) reported a 2-year study in Wistar-derived
rats in which MH-Na was included in the diet at levels of 0, 0.5, 1,0,
2.0 or 5.0% (0, 5,000, 10,000, 20,000 or 50,000 ppm). Assuming that
1 ppm in the diet of rats corresponds to 0.05 mg/kg/day (Lehman, 1959),
this is equivalent to doses of 0, 250, 500, 1,000 or 2,500 mg/kg/day.
Although no experimental details were presented, it was concluded
that the MH-Na resulted in no blood dyscrasias or tissue pathology,
and no indication of carcinogenic potential was detected.
Epstein and Mantel (1968) used random-bred infant Swiss mice (ICR/Ha)
to assess the carcinogenic effects of maleic hydrazide when admini-
stered during the neonatal period. The free acid form of maleic
hydrazide (containing 0.4% hydrazine impurity) was prepared as an
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Maleic' Hydrazide August, 1987
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aqueous solution of 5 mg/mL, or as a suspension in redistilled
tricaprylin at a concentration of 50 mg/mL. The mice were given
injections in the nape of the neck on days 1, 7, 14 and 21 following
birth. Six litters received the maleic hydrazide aqueous solution
(total dose: 3 ing), and 16 litters received the maleic hydrazide
suspension (total dose: 55 mg). One litter received one injection
of the suspension at a higher dose (100 mg/mL, total dose: 10 mg),
but this was lethal to all mice. A total of 16 litters served as
controls (treated with solvents alone). The experiment was terminated
between 49 and 51 weeks. The mice that received a total dose of
55 mg in the 3-week period had a high incidence of hepatomas: 65% of
26 male mice alive at 49 weeks, in contrast to solvent controls in
which hepatomas occurred in 8% of 48 male mice. The males that
received 3 mg total had an 18% incidence of hepatomas. In addition
to these lesions, hepatic "atypia" was observed in five males
(at 55 mg) and eight females, which the authors judged might be
preneoplastic. At the 3-mg level, one atypia was seen in each sex.
It was concluded that maleic hydrazide was highly carcinogenic in the
male mice. The authors also noted that since there was a complete
absence of multiple pulmonary adenomas and pulmonary carcinomas, it
was unlikely that the carcinogenicity of maleic hydrazide was due
to hydrazine (either present as trace contamination or formed by
metabolism), since hydrazine is a potent lung carcinogen in several
species of rats and mice (including CBA mice).
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS .
Health Advisories (HAs) are generally determined for one-day, ten-day,
longer-term (approximately 7 years) and lifetime exposures if adequate data
are available that identify a sensitive noncarcinogenic end point of toxicity.
The HAs for noncarcinogenic toxicants are derived using the following formula:
HA = (NOAEL or LOAEL) X (BW) = mg/L ( /L,
(UF) x ( L/day)
where:
NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
in mg/kg bw/day.
BW = assumed body weight of a child (10 kg) or
an adult (70 kg).
UF = uncertainty factor (10, 100 or 1,000), in
accordance with NAS/ODW guidelines.
L/day = assumed daily water consumption of a child
(1 L/day) or an adult (2 L/day).
Several studies (Tate, 1951; Mukhorina, 1962; Hansen et al., 1984)
indicate that the DEA ion is toxic and may contribute to the toxicity of the
MH-DEA salt. For this reason, studies involving MH-DEA have not been consid-
ered as candidates in calculating HA values for maleic hydrazide.
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Maleic Hydrazide <• August, 1987
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One-day Health Advisory
No information was found in the available literature that was suitable
for deriving a One-day HA value for maleic hydrazide. It is, therefore,
recommended that the Ten-day HA value for a 10-kg child (10 mg/L, calculated
below) be used at this time as a conservative estimate of the One-day HA
value.
Ten-day Health Advisory
The developmental toxicity study by Aldridge (1983, cited in U.S. EPA,
1985a) has been selected to serve as the basis for the Ten-day HA. In this
study, the potassium salt of maleic hydrazide (K-MH) was administered by
gavage at doses of 0, 100, 300 or 1,000 mg/kg/day to Dutch Belted rabbits
(16/dose) on days 7 through 27 of gestation. Malformed scapulae were observed
in fetuses from the 300- and 1,000-mg/kg/day dose groups. Although the
incidence of these malformations was not statistically significant and did
not occur in a dose-related fashion, malformed scapulae are a rare, major
skeletal defect. Additionally, historical data for this breed of rabbits
indicate that scapular anomalies were observed in only 1 of 1,586 fetuses
examined from 264 litters. For these reasons U.S. EPA (1985a) concluded that
the possibility of teratogenic activity at these dose levels cannot be ruled
out. The NOAEL for teratogenic effects is identified as 100 mg/kg/day.
Although a teratogenic response is clearly a reasonable basis upon which
to base an HA for an adult, there is some question about whether the Ten-day HA
for a 10-kg child can be based upon such a study. However, a teratogenic
study is of appropriate duration and does supply some information concerning
fetotoxicity. Since the fetus may be more sensitive to the chemical than
a 10-kg child and since a teratogenic study is of appropriate duration,
it is judged that, though possibly overly conservative, it is reasonable in
this case to base the Ten-day HA for a 10-kg child on a developmental toxicity
study.
Using a NOAEL of 100 mg/kg/day, the Ten-day HA for a 10-kg child is
calculated as follows:
Ten-day HA = OOP mg/kg/day) (10 kg) = 10 mg/L (-|0,000 ug/L)
(100) (1 L/day)
where:
100 mg/kg/day = NOAEL, based on the absence of teratogenic effects
in rabbits exposed to K-MH by gavage on days 7 to 27
of gestation.
10 kg = assumed body weight of a child.
100 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a NOAEL from an animal study.
1 L/day = assumed daily water consumption of a child.
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Maleic Hydrazide August, 1987
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Longer-term Health Advisory
No studies were found that were adequate for calculation of Longer-
term HA values for maleic hydrazide. An 11-week feeding study in rats by
Tate (1951) identified a NOAEL of 2,500 mg/kg/day, and 2-year feeding
studies in rats and dogs by Food Research Laboratories (1954) identified
NOAEL values of 2,500 and 500 mg/kg/day, respectively. These studies have
not been selected because they provided too little experimental detail to be
suitable for calculation of an HA value. It is, therefore, recommended that
the Drining Water Equivalent Level (DWEL) of 17.5 mg/L, calculated below, be
used as a conservative estimate of the Longer-term HA for a 70-kg adult and
that the modified DWEL of 5 mg/L (adjusted for a 10-kg child) be used as a
conservative estimate of the Longer-term HA for a 10-kg child.
Lifetime Health Advisory
The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure. The Lifetime HA
is derived in a three-step process. Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI). The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s). From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2). A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult. The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC). The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals. If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.
The 28-month feeding study in rats by Van Der Heijden et al. (1981) has
been selected to serve as the basis for the Lifetime HA value for malt-ic
hydrazide. Based on proteinuria (in the absence of visible histological
effects in kidney), a LOAEL of 500 mg/kg/day was identified. This is a
conservative selection, since 2-year feeding studies in dogs and rats by Food
Research Laboratories (1954) identified NOAEL values of 500 and 2,500 mg/kg/day,
respectively; those studies were not selected, however, because few data or
details were provided.
Using the LOAEL identified by Van Der Heijden et al. (1981), the Lifetime
HA is calculated as follows:
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Maleic Hydrazide August, 1987
-14-
Step 1: Determination of the Reference Dose (RfD)
RfD = (500 mg/kg/day) = 0.5 mg/kg/day
(1,000) y
where:
500 mg/kg/day = LOAEL, based on decreased amino acid resorption in
kidney of rats exposed to maleic hydrazide in the
diet for 28 months.
1,000 = uncertainty factor, chosen in accordance with NAS/ODW
guidelines for use with a LOAEL from an animal study.
Step 2: Determination of the Drinking Water Equivalent Level (DWEL)
DWEL = (0.5 mg/kg/day) (70 kg) , 17<5 mg/L (17,500 ug/L)
(2 L/day)
where:
0.5 mg/kg/day = RfD.
70 kg = assumed body weight of an adult.
2 L/day = assumed daily water consumption of an adult.
Step 3: Determination of the Lifetime Health Advisory
Lifetime HA = (17.5 mg/L) (20%) * 3.5 mg/L (3,500 ug/L)
where:
17.5 mg/L = DWEL.
20% = assumed relative source contribution from water.
Evaluation of Carcinogenic Potential
0 No evidence of carcinogenic activity was detected in five studies in
which maleic hydrazide was administered orally to mice or rats for
periods from 18 to more than 2 years (Kotin et al., 1968; Innes et ale,
1969; Barnes et al., 1957; Cabral and Ponomarkov, 1982; Van Der Heijden
et al., 1981; Uniroyal Chemical, 1971). Increased incidence of
hepatomas has been reported in mice exposed by sc injection during
the first 3 weeks of life (Epstein and Mantel, 1968).
0 The International Agency for Research on Cancer has not evaluated the
carcinogenic potential of maleic hydrazide.
0 Applying the criteria described in EPA's guidelines for assessment of
carcinogenic risk (U.S. EPA, 1986), maleic hydrazide may be classified
in Group D: not classified. This group is used for substances with
inadequate human or animal evidence of carcinogenicity.
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Maleic Hydrazide August, 1987
-15-
VI. OTHER CRITERIA, GUIDANCE AND STANDARD^
0 The U.S. EPA (1985b) has established residue tolerances for maleic
hydrazide in or on raw agricultural commodities that range from 15.0
to 50.0 ppm.
VII. ANALYTICAL METHODS
* There is no standardized method for the determination of maleic
hydrazide in water samples. A procedure has been reported for the
estimation of maleic hydrazide residues on various foods (U.S. FDA,
1975). In this procedure, the sample is boiled in an alkaline solution
to drive off volatile basic interferences. Distillation with zinc and
a nitrogen sweep expel hydrazine liberated from maleic hydrazide.
Hydrazine is reacted in acid solution with p-dimethylaminobenzaldehyde
to form a yellow compound that is measured spectrophotometrically.
VIII. TREATMENT TECHNOLOGIES
0 Currently available treatment technologies have not been tested for
their effectiveness in removing maleic hydrazide from drinking water.
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Maleic Hydrazide August, 1987
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