CHEMICAL HAZARD INFORMATION PROFILE
DRAFT REPORT
Semicarbazide
CAS NO. 57-56-7
April 27, 1982
DISCLAIMER
This document is a preliminary draft. It has not been released
formally by the Office of Toxic Substances, Office of Pesticides
and Toxic Substances, U.S. Environmental Protection Agency, and
should not at this stage be construed to represent Agency
policy. It is being circulated for comments on its technical
merit and policy implications.
This report represents a preliminary assessment of the subject
chemical's potential for injury to human health and the
environment and therefore may not reflect all available infor-
mation on the subject chemical. Any recommendations based on
this report are tentative and should not be construed as final
Agency policy with respect to the subject chemical.
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I. Summary of Available Data
Many sources use semicarbazide and semicarbazide hydrochloride (CAS No.
563-41-7) interchangeably without clear indication as to which is being dis-
cussed. Where it is clear, the compound is named within the text; however,
from available information, it seems that the biological action of both are
the same. Therefore production figures and exposure data are provided for
both compounds.
A. Chemical Identity
1. CAS Registry Number: 57-56-7 C5N30
2. Chemical Name: Hydrazinecarboxamide (9 CI); isosemicarbazide (8 CI)
3. Synonyms:- Carbamic acid, hydrazide; carbazamide; carbazimidic acid;
aminocarbonylhydrazine; semicarbazide; aminourea; carbamylhydrazine;
carbamoylhydrazine
0
4. Structural Formula: 5
H2N-NH-C-NH2
B. Physical and Chemical Properties
5. Molecular Weight: 75.07
6. Physical State: Solid (Weast and Astle 1981-1982)
7. Melting Point (°C) : 96 (Weast and Astle 1981-1982)
8. Boiling Point (°C) : Not available
9. Solubilities:
a) Water: Very soluble (Radding et al. 1977, Weast 1970-1971)
b) Nonaqueous Solvents: Slightly soluble in alcohol; insoluble in
ether, benzene, or chloroform (Radding et al. 1977, Weast 1970-1971)
10. Dissociation Constant: 2.7 x 10 n (pKa: 10.57) (Lange and Forker 1946)
11. Partition Coefficient (log P): -2.53 for octanol/water (Radding et al.
1977)
12. Density: Not available
13. Volatility: Not available
14. Reactivity: Though no specific information is given for semicarbazide,
hydrazines in general are oxidized in water by molecular oxygen to
diimides and then to nitrogen. This reaction could possibly be catalyzed
by metal ions:
RNHNH2 >• [RN = NH] >• RH 4- N2 + H20
(Wagnerona et al. 1973, as reviewed in Radding et al. 1977).
Semicarbazide, in reaction with aldehydes and ketones, yields semi-
carbozones (Fishbein 1979).
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C. Exposure
1. Worker Exposure Considerations
a. Production
The U.S. International Trade Commission did not report semicarbazide pro-
duction for the years of 1975-1980 implying an annual production of less than
5,000 Ibs (or less than $5,000.00 in sales) in 1976-1980 and less than 1,000
Ibs (or less than $1,000.00 in sales) in 1975 (USITC 1977-1981, as reviewed in
USEPA 1982). Semicarbazide hydrochloride production was also not reported in
the years 1975-1980.
The nonconfidential file of the TSCA Chemical Substance Inventory (USEPA
1978) indicates that in 1977 the Fairmont Chemical Company, Newark, NJ, manu-
factured between 100,000 and 1,000,000 Ibs of the free base semicarbazide and
100,000 to 1,000,000 Ibs of the HC1 salt, for a total of 200,000 to 2,000,000
Ibs. Chem-Sources-U.S.A. (1982) does not list a current producer for semi-
carbazide but it does list the Fairmont Chemical Company as a current manufac-
turer of the hydrochloride.
b. Imports
Separate data on the importing of semicarbazide were not given by the U.S.
Bureau of the Census in the years 1975-1980 (USEPA 1982). However, according to
the TSCA Chemical Substances Inventory, semicarbazide hydrochloride was imported
in 1977 by Aceto Chemical Company, Inc., Flushing, NY (10,000-100,000 Ibs) and
Sobin Chemicals, Inc., Boston, MA (0-1,000 Ibs) (USEPA 1978).
c. Exports
No information was available.
d. Process Type
The following methods can be used for the production of semicarbazide:
(1) reaction of hydrazine and urea (Durham 1965, as reviewed in Schiessl 1980);
(2) action of potassium cyanate on hydrazine sulfate (Thiele and Strange 1894,
as reviewed in Udupa et al. 1966); (3) action of hydrazine hydrate on urea
(Rossel and Frank 1894, as reviewed in Udupa et al. 1966); (4) heating hydrazine
ammonium carbonate (Fichter and Beeker 1912, as reviewed in Udupa et al. 1966);
(5) reduction of nitrourea with zinc dust and hydrochloric acid (Thiele and
Heusser 1896, as reviewed in Udupa et al. 1966); (6) electrolytic reduction of
niCrourea (Udupa et al. 1966); (7) reaction of carbon monoxide with A^V-dialkyl-
hydrazine in the presence of selenium yielding 3,3-dialkylselenocarbazic acid
and hydrazine - aminolysis followed by oxidation with oxygen gives semicarbazide
(Kondo et al. 1974); (8) heating either tf-chloroguanidine or tf-hydroxyguanidine-
0-sulfonic acid with aqueous sodium hydroxide (Ohme and Preuschhof 1969).
Schiessl (1980) states that semicarbazide is best made from hydrazine and urea.
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e. Workplace Monitoring, and Determination Methodology
Colorimetric determination of hydrazines, and by analogy, semicarbazide,
can be accomplished by the formation of colored azines with salicylaldehyde or
p-dimethylaminobenzaldehyde (Feigl 1966, as reviewed in Schiessl 1980). The
p-dimethylaminobenzaldehyde method is suitable for quantitative determination
in the ppm range and is also used for determination in waste waters and in air
by absorption from a known volume of air in a acidified solution of p-dimethyl-
aminobenzaldehyde .
f. Worker Exposure
No data were found.
g. Industrial Uses
Semicarbazide has been used as an intermediate in the production of
sulfonyl-semicarbazides such as 4-methyl-benzenesulfonyl 2-(aminocarbonyl)-
hydrazide and 4,4'-oxybisbenzenesulfonyl bis [2-(aminocarbonyl)hydrazine] which
are useful in the foaming of rubber (Schiessl 1980, as reviewed in USEPA 1982).
Miscellaneous uses of semicarbazide include the following: (1) deter-
mination of acetaldehyde in biological specimens (Stowell et al. 1980, as
reviewed in NLM printout 1982, Stowell 1979, Anderson et al. 1978, as reviewed
in Chem. Abstr. 89:101066u); (2) in removing labile glycohemoglobin (Nathan et
al. 1981, as reviewed in NLM printout 1982); (.3) in laboratory experiments in-
volving enzymes (Lee 1979, Denk et al. 1978, Roth and Gillis 1975, Sladek 1973);
(4) in investigations of morphine analgesia (Yoneda et al. 1976); (5) in investi-
gations of mescaline metabolism (Roth et al. 1976); and (6) in studies of nerve
transmission (Capek and Esplin 1977).
Semicarbazide has also been suggested ,£pr use in preventing discoloration
of wood (Minemura 1977, as reviewed in CAB Abstr. 1982); as a cross-linking
agent for oxidized ethylene polymers and acrylic fibers (Kehr 1970, Zharkova
et al. 1969 as reviewed in Fishbein 1979); as a stabilizer for ethylenevinyl-
acetate polymers (Meincke 1970, as reviewed in Fishbein 1979); in the synthesis
of plant growth regulators (Roechling et al. 1975, as reviewed in Fishbein 1979);
in the preparation of anion-exchangers from polyethylene-polyamines (Samborskii
et al. 1974, as reviewed in Fishbein 1979); and in phosphors (Isojima et al.
1974, as reviewed in Fishbein 1979).
Thiosemicarbazides and thiosemicarbazide derivatives have been studied
as meat tenderizers (Sekoguchi et al. 1978, as reviewed in Biol. Abstr. 65:70253)
and as antimicrobial agents (Bu 1975, as reviewed in Biol. Abstr, 63:31098;
Ohmori et al. 1978, as reviewed in Chem. Abstr. 63:46850). Semicarbazide hydro-
chloride is useful in the preparation of drugs, e.g., nitrofurazone (Hoover 1975,
as reviewed in USEPA 1982).
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The classification of the uses of semicarbazide and semicarbazide hydro-
chloride in accordance with the Chemical Use Standard Encoding System (ChemUSES)
(Goen et al. 1980, as reviewed in USEPA 1982) is as follows:
290 (Organic intermediate)/28.14.14-6 (Plastics and rubber chemicals)
290 (Organic intermediates)/28.06-4 (Drugs)
238 (Analytical and product testing agents)/
28.02.02.06-8 (Aldehydes);
28.02.02.05-7 (Ketones)
374 (Reagents)/28.02-0 (Organic chemicals)
h. Processors
Uniroyal, Inc. , Middlebury, CT may use semicarbazide in the production of
the blowing agents 4-methyl-benzenesulfonyl 2-(aminocarbonyl) hydrazide and
4,4'-oxybisbenzenesulfonyl bis[2(aminocarbonyl)hydrazide] (USEPA 1982). Also
Morton-Norwich Products, Inc., The Norwich-Eaton Company Division, Norwich, NY,
may use semicarbazide hydrochloride in the production of nitrofurazone (USEPA
1982).
i. Disposal
No data were available.
2. Consumer Exposure Considerations
No data were found which document consumer exposure to semicarbazide.
Consumers could be exposed to semicarbazide as an agent to prevent the discolora-
tion of wood (a use suggested by Minemura 1977, as reviewed in CAB Abstr. 1982).
Consumer exposure to derivatives of semicarbazide is possible through their use
as pesticides and meat tenderizers [thiosemicarbizides and their derivatives
(Ohmori et al. 1978, as reviewed in Biol. Abstr. 63:46850, Sekoguchi et al. 1978,
as reviewed in Biol. Abstr. 65:70253)] and in drugs [semicarbazide hydrochloride
(Hoover 1975, as reviewed in USEPA 1982)]. Davis et al. (1978) reported that
the photolytic decomposition of the drug indapamide yields semicarbazide sug-
gesting possible exposure to individuals using the drug.
3. Environmental Exposure
a. Environmental Release
No information was found on the release of semicarbazide into the environ-
ment.
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b. Environmental Fate
i. Persistence
No data were found on the fate of semicarbazide in the environment;
however, in water, simple hydrazine derivatives can be oxidized by molecular
oxygen to give diimides and subsequently nitrogen (Radding et al. 1977; also see
section II.B.14), The octanol/water partition coefficient (log P) of -2.53 sug-
gests that bioaccumulation will not be significant Radding et al. 1977).
ii. Transport
No data were available, documenting the environmental transport of semi-
carbazide; however, Radding et al. (1977) indicate that simple hydrazine deri-
vatives are polar, nonvolatile, and soluble in water and therefore, will not
readily transfer to the atmosphere from water nor are they likely to adsorb to
sediments in significant amounts. It should be noted, however, that some amines
do bind well to soil via ion-exchange or other mechanisms.
c. Environmental Occurrence
No data were available.
D. Human Health Effects
1. Metabolism
No information was found on the metabolism of semicarbazide. It should be
noted that if semicarbazide hydrochloride enters the body, dissociation to semi-
carbazide will occur.
2. Lethality
Semicarbazide is very toxic when administered acutely to mice and rats via
oral, intraperitoneal, subcutaneous and intravenous routes. Some LDsg values
are listed in Table 1.
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TABLE 1. Lethality
Route
Species
(m§/kg)
Reference
Oral
Intraperitoneal
Intraperitoneal
Subcutaneous
Subcutaneous
Intravenous
Mouse
Mouse
Rat
Rat
Mouse
Mouse
176
123
140
173
105
126
Lewis
Lewis
Lewis
Lewis
Lewis
Lewis
1979
1979
1979
1979
1979
1979
3. Carcinogenicity
Mori et al. (1960) designed an experiment to determine the minimum dose
of various compounds, including semicarbazide, required to induce pulmonary
adenomas in strain dd mice. Female mice, 1h to 2 months old, were fed a diet
containing 0.1% semicarbazide hydrochloride for seven months and were killed
for tumor evaluation. Lung nodules were counted macroscopically. Six of
eight surviving mice developed tumors (75% incidence) averaging one nodule per
mouse. Control dd mice had a tumor incidence of 5% and averaged 0.05 nodules
per mouse. Structural comparisons of semicarbazide hydrochloride with other
chemicals which gave positive results demonstrated the presence of the carbamyl
group in. each compound.
Weisburger et al. (1981) investigated the carcinogenic potential of semi-
carbazide hydrochloride in Charles River CD rats. The compound was administered
continuously in the diet at either 1000 ppm (the maximum tolerated dose as
determined by range finding studies) or 500 ppm for 18 months, after which time
the animals were observed for 6 months. Each dose was given to 26 male and 26
female rats, a total of 104 animals. In the high dose group treatment was dis-
continued at week 32 because of the large number of deaths. Comprehensive
pathological examinations revealed no evidence of tumorigenicity at either dose
level.
Toth et al. (1975) administered 0.0625% semicarbazide hydrochloride in
the drinking water to 50 female and 50 male Swiss albino mice for life, beginning
at six weeks of age. The average daily intake was 3.3 mg for a female and 4.8 mg
for a male. An untreated control group of 100 female and 100 male mice were also
maintained. All organs were examined macroscopically and histological examination
was conducted on the liver, spleen, kidney, bladder, thyroid, heart, pancreas,
testis, brain, nasal turbinates and at least four lobes of the lungs of each
mouse as well as on those organs showing gross pathological changes.
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The results are shown in Table 2. The development of tumors of the lungs
and blood vessels was significantly enhanced by continuous lifetime feeding of
the compound. In comparison with the controls, the incidence of lung neoplasms
in the test group rose from 22% (in the controls) to 40% while the incidence of
blood vessel tumors increased from 5 to 12%. The other types of tumors listed
in Table 2 occurred in low incidences and their appearance could not be attri-
buted to the treatment.
Parodi et al. (1981) tested sixteen hydrazine derivatives, including
semicarbazide, for in vivo DNA-damaging activity using the alkaline elution
assay. The assay, which measures single-strand breaks in DNA is thought to be
somewhat predictive of carcinogenic potency. Eleven non-inbred male Swiss
albino mice 2 to 3 months old were injected intraperitoneally with a total of
3.28 mmol/kg semicarbazide either as a single administration of the L.DSQ twice,
or by daily administration of one-third the LDsg for 5 successive days. DNA
damage was evaluated by the alkaline elution method using lung and kidney pre-
parations. The results indicated that semicarbazide did not cause DNA damage.
4. Mutagenicity
Sixteen hydrazine derivatives, including semicarbazide, were tested for
mutagenic activity in the Ames test (Parodi et al. 1981) . Salmonella typhimia'-ium
strains TA 1535, TA 100, TA 1537, TA 1538, and TA 98 were used in a plate incor-
poration test and a spot test. In the spot test 10 y& of a 10% solution (1 mg/
plate) of semicarbazide was assayed whereas 100 yJl (8.3 - 133 ymol/plate) was
tested in the plate incorporation test; in both tests mutagenic activity was
assessed with and without metabolic activation. Semicarbazide did not demon-
strate any mutagenic activity in the spot test and was only weakly mutagenic
in the plate incorporation test and in only strain TA 1535. The mutagenic
activity was optimal at 67 ymol/plate and was only present without metabolic
activation; addition of S-9 mix abolished activity.
Injections of 0.005 mJl of 0.1M semicarbazide hydrochloride into adult male
grasshoppers (Spachosternum pras-inifemm*) caused chromatid and chromosome breaks ,
translocations, fragments, and bridges in spermatocyte chromosomes (Bhattacharya
1976). It was suggested that semicarbazide acts similarly to hydroxylamine in
liberating all the four base pairs from DNA, resulting in the breakage of the
sugar-phosphate backbone.
Hayatsu et al. (1966) demonstrated that, in vitro, semicarbazide replaces
the C-4 amino group of cytidine and deoxycytidine with a semicarbaride residue.
The addition of bisulfite as a catalyst increased the rate of reaction, which
was absolutely specific for cytosine nucleotides and nucleosides that are located
in the single-stranded region of a nucleic acid (Hayatsu 1976) .
Hayatsu (1977) also demonstrated inactivation of, and mutation in, bacte-
riophage lambda as a result of the co-operative action of semicarbazide and
bisulfite upon DNA. In his experiment, bacteriophage strain lambda papa and its
host bacteria, EschevLchia coli,, were treated with IM-sodium bisulfite in the
presence of IM-semicarbazide at 37°C and pH5. Inactivation of the phage took
place rapidly, accompanied by induction of the "clear" mutation. Inactivation
was faster to the extent of 0.002 in the survivors in 30 min with the combination
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TABLE 2. Tumor distribution in seraicarbazide hydrocliloride (CH)-treated and control Swiss mice
Animals with:
Lung tumors
Blood vessel tutnora
Number of
Treatment Animals Sex No. % Latent periods* No. % Latent periods*
Other Tumors
50 F 25 50 89 (50-111)
0.0625Z CM
in drinking
water daily
for life ,n „ ., ,- 7_ ,,_ -, . , \
9 18 92 (74-107) 5 Malignant lymphomaa (54,73,75,91,107)
5 Malignant histiocytoma (104)
1 Sarcoma of glandular stomach (52)
1 Papilloma of forestomach (105)
1 £ P1 11,1, Oil 1 Uannf-nnne 7 711
1 Hlbernoma (111)
1 Malignant lytnphoma (79)
Untreated
Control
99
99
21 21 95 (60-122)
5 5 113 (97-130) 24 Malignant lymphomas (31,36,68,69,71,79, 1 Malignant histiocytoma (58)
80,80,90,94,96,97,101,102,103,105,106, 1 Papillary adenoma of ovary (103)
109,115,118,122,123,130)
2 Adenocarcinomas of breast (73,93)
2 Adenocnrcinomas of ovaries (104,106)
1 Adenoma of thyroid (116)
1 Papilloma of skin (109)
1 Fibrosarcoma, subcutaneous (44)
1 Papilloma of esophagus (103)
1 Leiomyosarcoma of uterus (81)
1 Adenoma of glandular stomach (115)
M 23 23 92 (53-125)
6 88 (65-105) 12 Molignaot lyphotnss (40,57,76,88,93,94,
95,97,102,107,116,126)
1 Fibrosarcoma, subcutaneous (82)
1 Adenocarclnoma of duodenum (113)
1 Malignant histiocytoma (101)
1 Carcinoma of skin (122)
1 Adrenocortlcal adenoma (130)
1 Papilloma of esophagus (63)
1 Vapllloma of forestomach (63)
* Age In weeks (average and ranp.e)
•I- Latent period given in parenthesis .
Source: Adapted from Toth et al. 1975, p. 19.
I
co
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of bisulfite and semicarbazide than with either of the two alone; a similar
enhancement was seen in the mutation frequency (100 mutants/10^' survivors after
30 min).
The phage was then reactivated by IM-sodium phosphate at pH7; reactivation
did not significantly alter the freqency of mutation. It was concluded that the
cooperativity between bisulfite and semicarbazide in inactivation and mutagenesis
of bacteriophage lambda is similar to that of their chemical reaction with
cytosine, suggesting that the effects produced on the phage were caused by the
modification of cytosine.
In a similar study, Levinson and Helling (1976) found that the infectivity
of intact lambda phage and transfection by lambda DNA were inactivated by exposure
to a copper complex of semicarbazide. 'Their results indicated that the inactiva-
tion was due to action on DNA.
5. Teratogenicity/Reproductive Effects
a. Type Test: Teratogenicity
Species: Golden Syrian hamster (5-6 pregnant hamsters/group)
Dose/Route: 100, 150 or 200 mg/kg, by gavage, on day 7 of gestation.
Results: Doses of 150 and 200 mg/kg resulted in the death of all
females, generally within 48 hours of administration. The
animals of the 100 mg/kg group were killed on day 14 or
gestation. This dose resulted in the following fetal effects:
1% mortality, 16.5% growth retardation, 5% malpositioned limbs,
but no visceral or skeletal abnormalities. No gross external,
skeletal or visceral abnormalities were found among litters of
untreated or vehicle-treated controls. The authors concluded
that semicarbazide appeared to be mildly teratogenic early
(day 7) in gestation, but had significant maternal toxic
effects at the dose levels tested (Wiley and Joneja 1978) .
b. Type Test; Teratogenicity
Species; Sprague-Dawley rat
Dose/Route: See Table 3.
Results: See Table 3. The authors concluded that semicarbazide pro-
duced high incidences of cleft palate at 50 mg/day when given
on gestation days 10-16; there was also an increased incidence
of resorptions. 100 mg/day on days 12-15 of gestation produced
a significant number of resorrtions and cleft palate in 22/22
fetuses; three of nine treated animals died (Steffak et al. 1972)
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10
TABLE 3. Cleft palate in Sprague-Dawley rats produced by multiple
oral doses of semicarbazide HC1
No. of
females
treated
Dose
Days of
gestation
administered
Resorption
Cleft palate
mg/day
No.
Semicarbazide
1 Death occurred in 3 additional pregnant rats.
Source: Steffek et al. 1972, p. 33.
No.
61
8
3
11
4
100
50
25
10
5
12-15
10-16
10-16
12-15
12-15
28/50
26/68
1/29
0/107
1/33
56
38
3
0
3
22/22
40/42
12/28
1/107
1/32
100
95
43
0
0
Type Test: Teratogenicity
Species: Rat
Dose/Route:
Dose not specified; intraperitoneal injection on day
10 or day 13.
Results: The authors determined the LD50 to be 140 mg/kg and stated
that even at sub lethal doses there was no effect on the
embryonic development of the rat (Von Kreyburg 1967). No
further details were given.
Type Test; Teratogenicity/Lathyrogenicity
Species; Porton mice
Dose/Route:
150-180 mg, total, in the diet of pregnant mice during
the last week of pregnancy.
Results: The minimal doses to produce aortic rupture or spinal kyphosis
in the offspring of treated mothers were 180 and 150 mg,
respectively. No maternal deaths were observed (McCallum 1965)
Type Test: Teratogenicity
Species; Rat
Dose/Route:
50 mg/kg x 2 on day 7 of gestation or 75 mg x 2/day on
days 8-15; subcutaneous injection.
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11
Results: No fetal effects were observed when semicarbazide was the
sole treatment. However, when the pregnant animals were
fed a pyridoxine-deficient diet in combination with the
semicarbazide injections, the fetuses were dead and mummified.
These effects were attributed to an inhibition of histamine
formation induced by the treatments (Kahlson and Rosengren
1959).
f. Type Test; Teratogenicity
Species: White Leghorn chicken (eggs incubated for 0-16 days) .
Dose/Route: 1.0 to 5.0 mg/egg; egg yolk injection
Results; Injections at 4-6 days produced malformations which were
dose-related and which included shortened and malformed
lower beaks, and bent tarsometatarsal and tibiotarsal bones
(Neuman et al. 1956).
g. Type Test: Teratogenicity/Lathyrogenicity
Species: Turkey
Dose/Rotate: 2 mg; yolk sac injection on day 6 of incubation.
Results: The major effects were in the beak (L-shaped deformity of
the lower beak, asymmetrical twisting of the upper beak) and
spine (slight lateral scoliosis of the cervical spine)
(Cameron 1962).
6. Other Effects
Levene (1968) tested chick embryo monolayer cells in culture for changes
in morphology and growth after receiving semicarbazide at doses of 0.25 and 1.5
to 4 mM. No effect on cell morphology or on growth as determined by cell counts
was observed.
Weisburger et al. (1981) discovered osteolathyrism and osteoporosis in
rats administered semicarbazide hydrochloride (see Section II.D.3 for doses, etc.)
Signs of the disorder were rough coats, sternum protrusion and bowing of the legs,
and stiffness of the joints with bony growths.
In a study designed to study the effect of lathyrogenic agents on soft
tissues, weanling male Sprague-Dawley rats were given finely granulated semicar-
bazide hydrochloride (0.5 or 0.75 g/kg) in a commercial diet and fed ad libitum
for 49 days (Lalich 1966). The 0.5 g/kg dose given to 14 rats, reduced the
average weight gains from 4.8 g/day to 3.5 g/day. Autopsies revealed minimal
deformities of the sternum, femur, and vertebral column. One of the 14 rats
died of aortic rupture. When the level of semicarbazide hydrochloride was in-
creased to 0.75 g/kg in the diet of a separate group of 10 rats, weight gains
were reduced to 2.7 g/day, and skeletal deformities were considered to be of
moderate severity. Aneurysmal dilation and aortic perforations were not seen
at the 0.75 g/kg level; however, prolapse of the penis was seen in 4 of 10 rats
after the fifth week. Also one of 10 rats died with acute purulent orchitis and
gastrointestinal distention.
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12
Stanley et al. (1975) showed that 0.1% by weight of semicarbazide admini-
stered to male weanling Sprague-Dawley rats in their diet caused rupturing of
the lungs at much lower recoil pressures than those required for controls.
Dilatation of terminal air spaces, rupturing of alveolar walls, and mean linear
intercept increases were noted. Biochemical analyses revealed reduced cross-
linking in lung collagen. It was concluded that semicarbazide selectively
impaired the maturation of lung collagen and that the immaturity was associated
with a reduction in the tensile strength of lung tissue.
Many studies of the effects of semicarbazide on the central nervous system
have been reported. Jenney and Pfeiffer (1958) give the approximate parenteral
convulsant dose (CDso) °f semicarbazide in mg/kg as follows: man, 40 i.m. (intra-
muscularly); monkey, 60 i.p. (intraperitoneally); cat, 40 i.p.; dog, 10 i.m.;
guinea pig, 75 i.p.; rabbit, 175 i.p.; rat, 150 i.p.; and mouse, 116.4 ± 3.2 i.p.
It was found that fasted mice are more sensitive to the convulsant and to its
lethal action; the LD^g for intraperitoneal injection being as low as
112 ±5.4 mg/kg after 16 hours of fasting. Killam and Bain (1957) found that
semicarbazide induced seizures in Holtzman adult white rats at a dose of 200 mg/
kg administered intraperitoneally. This was associated with a decreased level
of gamma-aminobutyric acid (GABA) in the brain. GABA is an end product of the
£-glutamic acid decarboxylase enzyme system which was found to be inhibited by
semicarbazide. Of the hydrazides tested by Killam and Bain (1957), (thiosemi-
carbazide, furoyl hydrazide, isonicotinic acid hydrazide and semicarbazide)
semicarbazide was the least active as a convulsant. Carlton et al. (1965) pro-
duced tremors, ataxia, and paresis in white Peking ducks fed 0.1% semicarbazide
hydrochloride for 2 weeks. Microscopic lesions included degenerative changes
in the nuclei of cerebellar Purkinje cells, motor neurons of the ventral horn of
the spinal cord, and neurons of the medulla oblongata.
Other effects of semicarbazide are as follows: (1) inhibition of amine
oxidase activity in the rat aorta (Wibo et al. 1980); (2) weakening of rat tail
skin tissue by a possible rupture of bonds involving aldehyde functions (Brown
et al. 1969); (3) inhibition of mitochondria! Pi-ATP exchange activity and DNP-
stimulated ATPase activity in rat liver (Dallam and Chen 1969); (4) inhibition
of copper-linked amino oxidases (Sourkes 1980); and (5) inhibition of renal
glutamate decarboxylase in the rat (Goodyer et al. 1980).
E. Environmental Effects
1. Metabolism
No data were available.
2. Lethality
No data were available.
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13
3. Reproduction
No data were available.
4. Behavior
No data were available.
5. Growth and Development
Buning-Pfaue and Rehm (1972) showed that bacterial (Pseudcmonas aernglnosa)
metabolism during decanol oxidation in "batch" fermentation is inhibited by semi-
carbazide; concentrations too low to influence bacterial respiration inhibited
growth.
Propionibacter-ium shermanni bacteria grown in a cobalt-containing medium,
and treated with 10 micromoles/m£ of semicarbazide, was slightly inhibited in
its ability to produce vitamin B12 (161 yg/g for the treated cells, compared to
207 yg/g for control cells) and markedly inhibited in the production of porphyrins
(142.5 yg/g for the treated cells, compared to 238.3 yg/g for control cells)
(Bykhovskii et al. 1966).
6. Population and Community Effects
No data were available.
7 Abiotic Effects
No data were available.
8. Other Effects
No data were available.
F. Existing Standards, Recommended Standards, Regulations
No data were available for semicarbazide; however, hydrazine has a TLV
of 1 ppm and it is proposed that this be lowered to 0.1 ppm to conform to the
European standard (Schiessl 1980).
G. Other Relevant Information
Adamson (1965), knowing that hydroxyurea had shown antitumor activity,
studied the antitumor activity of semicarbazide and other analogs of hydroxyurea
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14
against advanced mouse leukemia L1210 in the hope of determining the active group
or groups on the molecule. Mouse leukemia L1210 was implanted into CDBA mice and
after 5-7 days, treatment with semicarbazide was initiated at doses of 12.5-150
mg/kg (100 mg/kg/day optimal) per group of 10 animals. The results of the
studies showed no increase in the median survival time of the mice when 'created
with semicarbazide.
Grossberg et al. (1966) demonstrated in KB human malignant cells and other
primate cells that semicarbazide (0.3 to 20 mM) increases the development of
poliovirus. Specifically, the length of the latent period was diminished, the
rate of production of virions was increased; and the final yield of virus was
increased.
II. Prelimary Risk Assessment
A. Exposure Assessment
Production figures for semicarbazide were not reported by the U.S. Inter-
national Trade Commission for the years 1975-1980 implying an annual production
of less than 1000 Ibs in 1975 (or less than $1,000 in total sales) and less than
5000 Ibs in 1976-1980 (or less than $5,000 in total sales) (USITC 1977-1981, as
reviewed in USEPA 1982). The nonconfidential file of the TSCA Chemical Substances
Inventory (USEPA 1978) indicates that in 1977 between 100,000 and 1,000,000 Ibs
of the free base semicarbazide and 100,000 to 1,000,000 Ibs of the HC1 salt were
manufactured, a total of 200,000 to 2,000,000 Ibs.
No studies documenting either worker, consumer, or environmental exposure
were available. Semicarbazide has been used as a chemical intermediate, an
analytical reagent and a product testing agent (Goen et al. 1980, as reviewed
in USEPA 1982). The latter two uses, in particular, suggest the potential for
human exposure. Semicarbazide hydrochloride has been used in the preparation
of drugs (Hoover 1975, as reviewed in USEPA 1982) and derivatives of semicarbazide
(thiosemicarbazides) have been evaluated for use as meat tenderizers (Sekoguchi
197?, as reviewed in Biol. Abstr. 65:70253).
Available information indicates the potential for significant human expo-
sure to semicarbazide but the exposure assessment would be more complete with
the following information: quantification of the amount that is used as a
chemical intermediate, documentation of the number of workers and levels to
which they are exposed, and quantification of the amount of the hydrochloride
used in the manufacture of drugs and residues of the compound remaining in the
drugs.
B. Human Health Risk Assessment
When given as acute doses, semicarbazide is apparently very toxic as
demonstrated in animals [e.g., intraperitoneal LDso in rats is 140 mg/kg
(Lewis 1979) and the intraperi meal convulsant dose CCD50) in rats is 150 mg/kg
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15
(Jenney and Pfeiffer 1958)] and in humans [e.g., intravenous dose of 40 mg/kg
caused unspecified central nervous system effects (Lewis 1979) and the intra-
muscular convulsant dose (CD50) is 40 rag/kg (Jenney and Pfeiffer 1958)].
Osteolathyrism has been observed in rats (Weisburger et al. 1981), and
rabbits (Kasanina and Torbenko 1974) as a result of exposure to semicarbazide
but according to Barrow et al. (1974) osteolathyrism (not only that induced by
semicarbazide) has not been observed in man.
The published data documenting the tumorigenicity of semicarbazide is
conflicting. Weisburger et al. (1981) did not observe any evidence of tumori-
genicity in rats fed-either 1000 or 500 ppm semicarbazide hydrochloride in the
diet for 18 months. On the other hand, Mori et al. (1960) and Toth et al.
(1975) reported enhanced pulmonary adenoma development in dd and Swiss albino
mice, respectively, fed semicarbazide. Toth et al. (1975) also noted an in-
creased incidence of blood vessel tumors (18% compared to 5% in controls) in
female mice. The IARC (1976) cites the latter two studies as evidence that
semicarbazide hydrochloride is carcinogenic in mice after oral administration.
However, it should be noted that most of the tumors observed in these studies
seem to represent an increase in the incidences of spontaneously occurring
tumors rather than an inductive process.
Semicarbazide has demonstrated mutagenic potential in grasshoppers [chromo-
some damage (Bhattacharya 1976)] and in Salmonella typh-imur-iian strain TA 1535
(Parodi et al. 1981). It should be noted that in the experiments of Parodi the
compound gave negative results in strains TA 100, 1537, 1538, and 98 and was only
weakly mutagenic in the TA 1535 strain. Also, when the S-9 mix was added no
mutagenic activity was observed suggesting that semicarbazide and not a metabolite
is responsible for the mutagenic ac-tivity.
Teratogenicity has been demonstrated in hamsters, rats, mice, chickens,
and turkeys; however, in mammals abnormalities were observed only at high doses.
For example, Wiley and Joneja (1978) observed minor teratogenic effects when
Golden Syrian hamsters were administered a single oral dose of 100 mg/kg on day
seven of gestation and Steffek et al. (1972) observed no incidence of cleft
palate in Sprague-Dawley rats orally administered 10 mg/day (40 mg/kg for a
250g rat) on days 12-15 of gestation. Steffek et al. did observe high incidences
of cleft palate at a dose of 50 mg/kg (200 mg/kg for a 250g rat) administered
on days 10-16 of gestation.
Information available in the literature indicates that semicarbazide may
pose a risk to human health. However, a complete human health risk assessment
is not possible until the number of workers exposed and the levels at which
exposure occurs are known. In addition, further studies on the carcinogenicity
of semicarbazide are warranted, preferably using administration routes simula-
ting human exposure.
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16
C. Environmental Risk Assessment
Very little information is available with which to make an environmental
risk assessment. No studies were found on the metabolism of semicarbazide by
environmental species, or on the lethal, reproductive, or behavioral effects
of the compound. Studies in laboratory animals (Lewis 1979) do suggest that
semicarbazide, if released into the environment, could be toxic to feral animals.
Laboratory studies with bacteria indicate that concentrations of semicarbazide
too low to influence respiration inhibit the growth of Pseudomonas aeruginosa
(Biining-Pfaue and Rehm 1972) and that the ability of Propionibaoterium shermanni
to produce vitamin B12 and porphyrins is inhibited (Bykovskii et al. 1966).
No data documenting the fate, effects on aquatic organisms or releases of
semicarbazide to the environment are available. However, an octanol/water coef-
ficient (log P) of -2.53 suggests that bioaccumulation is not likely and in water
simple hydrazine derivatives are polar, nonvolatile, and soluble, indicating that
these compounds will not transfer to the atmosphere at significant rates, or
adsorb to sediments in significant amounts (Radding et al. 1977). Radding et al.
also states that in water, hydrazines as a class are oxidized by molecular oxygen
to diimides and then to nitrogen. Ross et al. (1971, as reviewed in Radding et
al. 1977) indicates that this may be the most important process in determining
the fate of hydrazines. Also, the solubility in water of semicarbazide suggests
that in soil leaching may occur.
Environmental monitoring data and effects on various environmental species
would add significantly to the: assessment of environmental risk associated with
semicarbazide.
III. Summary
According to the nonconfidential file of the TSCA inventory the combined
1977 production of semicarbazide.- and semicarbazide hydrochloride was in the
range of 200,000-2,000,000 Ibs. No human or environmental exposure from the
chemical was documented; however, some of the uses (e.g., laboratory reagent)
suggest that human exposure is possible. If semicarbazide enters the environ-
ment, its octanol/water partition coefficient (log P) of -2.53 suggests that
bioaccumulation will not occur and by analogy with hydrazines, in water semi-
carbazide would be oxidized by molecular oxygen to diimides and then to nitrogen.
Semicarbazide is very toxic to animals upon acute oral exposures. In
laboratory animals, tumorigenicity was demonstrated in mice but not in rats.
It has shown mutagenic activity in the grasshopper and in the Ames test but only
in Salmonella strain TA 1535 where it was classified as a weak mutagen. Muta-
genicity was not detected in TA 1535 when S-9 mix was ad^ed. In laboratory
animals teratogenicity was demonstrated. Semicarbazide is known to produce
osteolathyrism in animals but this effect has not been reported to occur in
humans. No data were available concerning the effect of semicarbazide on
aquatic organisms. Although the information available in the literature
suggests that semicarbazide is teratogenic and lathyrogenic, additional data
are required for a complete health risk assessment and include: number of
workers exposed; levels of the compound in the workplace and the environment;
and additional information relating to carcinogenicity of the compound.
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17
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for phytotoxicity. Oak Ridge, TN: Oak Ridge National Laboratory. ORNL/EIS-155.
Sax NI. 1979. Dangerous properties of industrial materials, 5th ed. New
York: Van Nostrand Reinhold Company.
Sax NI. 1981. Cancer causing chemicals. New York: Van Nostrand Reinhold
Company.
Searle CE, ed. 1976. Chemical carcinogens. ACS monograph 173. Washington,
DC: American Chemical Society.
Shepard TH. 1980. Catalog of teratogenic agents. Baltimore, MD: Johns
Hopkins University Press.
Sittig M. 1975. Environmental sources and emissions handbook. Park Ridge,
NJ: Noyes Data Corporation.
Sittig M. 1979. Hazardous and toxic effects of industrial chemicals. Park
Ridge, NJ: Noyes Data Corporation.
Toxic and hazardous industrial chemicals safety manual. 1975. Tokyo: The
International Technical Information Institute.
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26
Union Carbide Corporation. Undated. Toxicology studies. New York.
Vershueren K. 1977. Handbook of environmental data on organic chemicals.
New York: Van Nostrand Reinhold Company.
Windholz M, ed. 1976. The Merck index. An encyclopedia of chemicals and
drugs. Rahway, NJ: Merck and Company, Inc.
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27
2. Data Bases
File
Number of References
MEDLARS
TOXLINE
TOX 65
TOX 74
CANCERLINE
CANCERPROJ
MEDLINE
TDB
RTECS
EPILEPSY
CHEMLINE
BACK 77
BACK 75
BACK 72
BACK 69
BACK 66
LOCKHEED/DIALOG
AGRICOLA 79-PRESENT
AGRICOLA 70-78
APTIC
ASFA
BA 74-PRESENT
BA 69-73
CA SEARCH 67-71
CA SEARCH 72-76
CA SEARCH 77-79
CA SEARCH 80-PRESENT
CAB
CHEMICAL INDUSTRY NOTES
COMPREHENSIVE DISSERTATION ABSTRACTS
CONFERENCE PAPERS INDEX
ENVIROLINE
EXCERPTA MEDICA IN-PROCESS
EXCERPTA MEDICA 74-79
EXCERPTA MECICA 80-PRESENT
NT IS
PHARMACEUTICAL NEWS INDEX
POLLUTION ABSTRACTS
SCISEARCH 74-77
SCISEARCH 78-80
SCISEARCH 81-PRESENT
SSIE
SDC/ORBIT
CRECORD
FEDREG
106
54
170
29
0
24
0
1
19
1
21
20
9
9
9
2
4
0
0
229
190
88
126
102
84
9
0
1
5
0
11
131
29
6
0
2
28
8
1
0
0
0
Date of Search
January 12, 1982
it
it
11
11
M
II
II
II
II
II
It
It
It
II
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28
C. Search Strategy
Semicarbazide
Search terms included collective index names, synonyms, CAS Registry
Number, and CHZMLINE nomenclature. All hits from each data base were
"dumped" and the computer printouts were scanned for pertinent references.
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