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EC number: 209-247-0 | CAS number: 563-41-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- chronic toxicity: oral
- Type of information:
- other: Publication
- Adequacy of study:
- supporting study
- Study period:
- This publication was accepted on 08 July 2009
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 009
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Semicarbazide hydrochloride
- EC Number:
- 209-247-0
- EC Name:
- Semicarbazide hydrochloride
- Cas Number:
- 563-41-7
- Molecular formula:
- CH5N3O.ClH
- IUPAC Name:
- semicarbazide hydrochloride
- Test material form:
- solid: particulate/powder
Constituent 1
- Specific details on test material used for the study:
- Semicarbazide hydrochloride (SEM-HCl, CAS No. 563–41-7) was purchased from Hayashi Pure Chemical Ind., Ltd. (Osaka, Japan), as a white powder with a purity of 99.3%.
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Wistar Hannover GALAS
- Details on species / strain selection:
- Wistar Hannover GALAS rats at 5 weeks of age were obtained from CLEA Japan, Inc. (Tokyo, Japan). Wistar Hannover GALAS rat has been accepted as a suitable strain of toxicology studies (http://www.galas.org/index.html).
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Animals
Male and female Wistar Hannover GALAS rats at 5 weeks of age were obtained from CLEA Japan, Inc. (Tokyo, Japan). Wistar Hannover GALAS rat has been accepted as a suitable strain of toxicology studies (http://www.galas.org/index.html). They received powdered basal diet (CE-2, CLEA Japan, Inc.) and tap water ad libitum, housed 2–4 per plastic cage with sterilized softwood chips as bedding in a barrier-maintained animal room conditioned at 24 ± 1 C and 55 ± 5% humidity with a 12-h light/dark cycle. After a 1-week acclimatization period, animals showing no abnormalities were used at 6 weeks of age. The animal protocol was reviewed and approved by the Animal Care and Use Committee of the National Institute of Health Sciences, Japan
Administration / exposure
- Route of administration:
- oral: feed
- Details on route of administration:
- Semicarbazide hydrochloride (SEM-HCl, CAS No. 563–41-7) was purchased from Hayashi Pure Chemical Ind., Ltd. (Osaka, Japan), as a white powder with a purity of 99.3%. SEM-HCl was well mixed at concentrations of 0, 250, 500 and 1000 ppm into powdered basal diet (CE-2). Concentrations after storage at room temperature for 4 weeks or at 4 C for 8 weeks were analyzed at Japan Food Research Laboratories (Osaka, Japan), and more than 89% stability of the test compound was confirmed under both conditions. SEM was not detected in the basal diet (detection limit, 0.01 ppm). Test diets were prepared every 2 weeks, and stored at 4 C before use.
- Vehicle:
- unchanged (no vehicle)
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Concentrations after storage at room temperature for 4 weeks or at 4 C for 8 weeks were analyzed at Japan Food Research Laboratories (Osaka, Japan), and more than 89% stability of the test compound was confirmed under both conditions. SEM was not detected in the basal diet (detection limit, 0.01 ppm).
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- Daily; ad libitum
Doses / concentrationsopen allclose all
- Dose / conc.:
- 250 ppm
- Remarks:
- in powdered basal diet (CE-2)
- Dose / conc.:
- 500 ppm
- Remarks:
- in powdered basal diet (CE-2)
- Dose / conc.:
- 1 000 ppm
- Remarks:
- in powdered basal diet (CE-2)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, plain diet
- Details on study design:
- Experimental design
As a preliminary examination, a 2-week dose finding study was conducted based on a previous report (Weisburger et al., 1981), with 1000 ppm selected as the highest dose for subsequent study. Animals, weighing 166.5 ± 4.5 g for males and 126.3 ± 4.3 g for females (mean ± SD), were randomly allocated to 4 groups, each consisting of 10 males and 10 females, and given diet containing 0 (control), 250, 500 or 1000 ppm SEM-HCl for 90 days. The test diets were available ad libitum, except for one-night fasting prior to the scheduled sacrifice, and rats had free access to tap water throughout the study. Observations for mortality and clinical signs, including posture and gait abnormalities and deformation of four limbs, thorax and tail, were conducted daily. Body weight and food consumption were recorded every week. At necropsy, all animals were anesthetized with ether, weighed, and blood samples were collected from the abdominal aorta for hematology and serum biochemistry. Relative organ weights were calculated as the values relative to body weights.
Examinations
- Observations and examinations performed and frequency:
- Hematology and serum biochemistry
Hematology analysis was performed using an automated hematology analyzer, K-4500 (Sysmex Corp., Hyogo, Japan). Differential leukocyte counts and reticulocyte counts were performed with a MICROX HEG-50S (Sysmex Corp.). Parameters for Hematology and serum biochemistry, shown in Tables 1 and 2, were analyzed at SRL, Inc. (Tokyo, Japan) using sera frozen after centrifugation of whole blood. - Sacrifice and pathology:
- Histopathological examination
After macroscopic examination, the brain, thymus, heart, lungs, liver, spleen, adrenals, kidneys and testes were removed and weighed. In addition, the pituitary, eyes, Harderian glands, salivary glands, tongue, trachea, esophagus, thyroid glands, thoracic aorta, stomach, small intestine (duodenum, jejunum, and ileum), large intestine (cecum, colon, and rectum), pancreas, mesenteric lymph nodes, thigh muscle, sciatic nerve, skin, mammary gland, urinary bladder, epididymides, seminal vesicles, prostate, ovaries, uterus and vagina were similarly resected. All organs were fixed in 10% buffered formalin, except for testes, which were fixed in Bouin’s solution overnight. For examination of osteochondral lesions, the nasal cavity, sternum, right femur, right tibia, left knee joint, right and left ankles, spine (cervical, thoracic, lumbar and caudal vertebrae with corresponding spinal cord) and macroscopic lesions (in wrist joints etc.) were fixed in 10% buffered formalin and then decalcified in EDTA solution at room temperature for a month. Histopathological assessment was performed on the bones, joints and thoracic aorta of all groups. Additionally, all organs of the control and 1000 ppm groups and the heart, lungs, liver, kidneys, thyroid, trachea, testes and prostate of the intermediate dose groups were also examined. The tissues were routinely processed for paraffin embedding, sectioned and stained with hematoxylin and eosin (HE). Victoria blue and HE staining was applied to three transverse sections of the descending thoracic aorta cut at 5 mm intervals to demonstrate elastic fibers. - Statistics:
- Variance in data for body weights, food consumption, hematology, serum biochemistry and organ weights was checked for homogeneity by Bartlett’s procedure. If the variance was homogeneous, the data were assessed by one-way analysis of variance. If not, the Kruskal–Wallis test was applied. When statistically significant differences were detected, the Dunnett’s multiple test was employed for comparison between the control and treatment groups. For histopathological findings, the incidences were compared using the Fisher’s exact probability test.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- The findings of clinical observation at week 13 are summarized in Table 3.
Enlargement and deformation of the knee joints were apparent in males and females at 500 and 1000 ppm from week 3, and prominence of the thorax was also found from week 5. In the 1000 ppm group, enlargement and deformation of the wrist joints were observed from week 12 in both sexes, and some showed posture and gait abnormalities. Tails of male rats in the treated groups exhibited stiff flexion from week 4. - Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Significant suppression of body weight gain was observed at 1000 ppm from week 1 in males and from week 4 in females
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- In both sexes, food consumption was decreased at 1000 ppm throughout the study, and the mean values for food consumption/animal were significantly lowered compared to the control group. However, there were no intergroup differences in the mean values for food consumption/kg body weight in males, due to suppressed body weight gain. The mean values for food consumption/animal were significantly increased in males at 500 ppm and decreased in females at 250 and 500 ppm. Significant decrease of the mean values for food consumption/kg body weight was found in females of the 250 and 1000 ppm groups.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Hematology data are summarized in Table 1. In both sexes, differential leukocyte counts showed significant decrease and increase in the proportions of segmented neutrophils and lymphocytes, respectively, in the 1000 ppm group. At the same dose, WBC counts were decreased in males and increased in females, although not statistically significant. In males, MCH was significantly decreased at 250 and 500 ppm, but without dose-dependence
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In the serum biochemical analysis, significant alterations of CRN, ALT, A/G, total Bil and K were found in males at 500 and/or 1000 ppm (Table 2). In females, significant increases of BUN were observed in all treated groups, and K and IP were statistically increased at 500 and 1000 ppm. Significant alterations of TP, ALT and ALP were also detected at 1000 ppm.
- Urinalysis findings:
- not examined
- Description (incidence and severity):
- Final body weights were significantly decreased in both sexes of the 1000 ppm group (Table 4). Absolute weights of the lungs in both sexes and the thymus, heart and liver in males were statistically lowered at 1000 ppm. In males, significant increase in relative kidney weights was observed at 500 and 1000 ppm, and relative weights of the brain, spleen, adrenals and testes were also increased at 1000 ppm. In females, relative weights of the brain, heart and kidneys were significantly elevated in the 1000 ppm group. Decreases in relative liver weight in males and relative spleen weight in females were found at 250 ppm, but such changes were not observed in the 500 and 1000 ppm groups.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In the macroscopic examination, bowing of the tibia was apparent in males and females at 500 and 1000 ppm. Also, increases in diameter of the femur and tibia were evident due to enlargement of the marrow cavities, along with prominence of the sternum, thoracic kyphosis and deformation of the wrist joints at 1000 ppm.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Histopathological findings for bones and joints
In the femur and tibia, disarrangement of epiphyseal chondrocytes was observed in both sexes at all doses tested. The epiphyseal plate at the proximal end of the tibia was thickened at 500 and 1000 ppm, and degeneration of hypertrophic chondrocytes was found in the thickened cartilage plate. There were fissures in the cartilage matrix, and these were widened and accompanied by increase of connective tissues at 500 and 1000 pp). In the metaphysis, spongy bones were decreased and irregularly-branched. The compact bones in the metaphysis became thin with a rugged surface, and deformed to expand outward, resulting in enlargement of the marrow cavities. Also in the sternum, disarrangement of epiphyseal chondrocytes and fissures in the cartilage matrix were found at all doses tested, and severe fissures with increased connective tissues and bone deformation were more evident at 500 and 1000 ppm in a dosedependent manner. In the animals with deformation of the wrist joint macroscopically, the epiphyseal plates of the radius and ulna exhibited similar histological lesions with the tibia. Deformation and fissures of articular cartilage with disarrangement of chondrocytes were observed in the knee joints and the intervertebral joints (from cervical to caudal) at all doses tested, and synovial inflammation and fibrosis were also found in the 500 and 1000 ppm groups. In the thoracic vertebrae, fissures occurred in the epiphyseal plate adjacent to the intervertebral disk, and displacement of the vertebra originating in the fissures, as well as compression of the spinal cord by displaced vertebra, were seen in males at 1000 ppm. Additionally, thinning of bone in the vertebral body was obvious in the 1000 ppm group, suggesting loss of bone mass. Overall, the severities of the osteochondral lesions described above were higher in males than females. There were no treatment-related changes in the nasal cavity, ankles and Achilles tendons.
Histopathological findings for the thoracic aorta
In both sexes, although the number of elastic laminae was unchanged, their edges became roughened in a dose-dependent manner). The interlaminar spaces in the treated groups had a rod or globular appearance, in contrast to the fibrillar appearance in the 0 ppm group.
In other organs, the incidences of mineralization in the pulmonary arteries were significantly lowered in males of the 250 and 500 ppm group compared to the controls, but without dose-dependence (Table 8). In males, significant increase of chronic inflammation of the ventral prostate was found at 1000 ppm. The incidence of cysts in the anterior lobe of the pituitary was also significantly elevated in females of the 1000 ppm group.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- < 250 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 250 ppm
- System:
- musculoskeletal system
- Organ:
- aorta
- bone
- cartilage
- Treatment related:
- yes
- Dose response relationship:
- not specified
- Relevant for humans:
- not specified
Any other information on results incl. tables
Table 3 Findings of clinical observation at week 13 in GALAS rats fed diet containing SEM-HCl for 90 days
Sites and findings | Sex | Males | Females | ||||||
Dose (ppm) | 0 | 250 | 500 | 1000 | 0 | 250 | 500 | 1000 | |
No. of animals examined | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 | |
Hindlimb | Enlargement and deformation of the knee joint | 0 | 1 | 10 | 10 | 0 | 0 | 10 | 10 |
Forelimb | Enlargement and deformation of the wrist joint | 0 | 0 | 0 | 6 | 0 | 0 | 0 | 8 |
Thorax | Prominence | 0 | 0 | 3 | 10 | 0 | 0 | 1 | 9 |
Tail | Stiff flexion | 0 | 1 | 4 | 9 | 0 | 0 | 0 | 0 |
Table 4 Final body and organ weights of GALAS rats fed diet containing SEM-HCl for 90 days
|
SEM-HCl (ppm) |
|
|
|
0 |
250 |
500 |
1000 |
|
No. of animals examined |
10 |
10 |
10 |
10 |
Males Body weight (g) |
409.3 ± 18.6a |
407.8 ± 26.6 |
396.9 ± 27.3 |
323.8 ± 36.0** |
Brain (g) |
2.06 ± 0.08 |
2.04 ± 0.08 |
2.00 ± 0.08 |
2.00 ± 0.08 |
(g%) |
0.50 ± 0.02 |
0.50 ± 0.03 |
0.51 ± 0.03 |
0.63 ± 0.06** |
Thymus (g) |
0.30 ± 0.06 |
0.32 ± 0.08 |
0.31 ± 0.06 |
0.21 ± 0.04** |
(g%) |
0.07 ± 0.02 |
0.08 ± 0.02 |
0.08 ± 0.01 |
0.06 ± 0.01 |
Lungs (g) |
1.25 ± 0.13 |
1.25 ± 0.10 |
1.15 ± 0.12 |
0.96 ± 0.12** |
(g%) |
0.31 ± 0.02 |
0.31 ± 0.02 |
0.29 ± 0.04 |
0.30 ± 0.03 |
Heart (g) |
1.05 ± 0.12 |
1.01 ± 0.10 |
1.06 ± 0.06 |
0.89 ± 0.11** |
(g%) |
0.26 ± 0.02 |
0.25 ± 0.02 |
0.27 ± 0.02 |
0.27 ± 0.02 |
Spleen (g) |
0.66 ± 0.08 |
0.66 ± 0.05 |
0.62 ± 0.07 |
0.61 ± 0.10 |
(g%) |
0.16 ± 0.02 |
0.16 ± 0.01 |
0.16 ± 0.02 |
0.19 ± 0.02** |
Liver (g) |
10.62 ± 0.99 |
9.70 ± 0.81 |
10.28 ± 1.04 |
8.51 ± 1.43** |
(g%) |
2.59 ± 0.19 |
2.38 ± 0.07* |
2.58 ± 0.10 |
2.61 ± 0.20 |
Adrenals (mg) |
52.40 ± 7.17 |
51.30 ± 5.66 |
55.50 ± 5.40 |
56.10 ± 10.88 |
(mg%) |
12.83 ± 1.92 |
12.62 ± 1.45 |
13.99 ± 1.05 |
17.34 ± 2.78** |
Kidneys(g) |
2.28 ± 0.12 |
2.38 ± 0.20 |
2.35 ± 0.20 |
2.08 ± 0.28 |
(g%) |
0.56 ± 0.03 |
0.58 ± 0.03 |
0.59 ± 0.04* |
0.64 ± 0.03** |
Testes (g) |
3.38 ± 0.34 |
3.33 ± 0.27 |
3.37 ± 0.30 |
3.56 ± 0.43 |
(g%) |
0.83 ± 0.07 |
0.82 ± 0.05 |
0.85 ± 0.08 |
1.10 ± 0.08** |
Females Body weight (g) |
220.9 ± 13.6 |
229.2 ± 22.4 |
225.2 ± 11.6 |
189.4 ± 7.8** |
Brain (g) |
1.83 ± 0.09 |
1.82 ± 0.08 |
1.87 ± 0.09 |
1.82 ± 0.08 |
(g%) |
0.83 ± 0.05 |
0.80 ± 0.09 |
0.83 ± 0.04 |
0.97 ± 0.06** |
Thymus (g) |
0.26 ± 0.05 |
0.31 ± 0.11 |
0.25 ± 0.05 |
0.20 ± 0.04 |
(g%) |
0.12 ± 0.03 |
0.13 ± 0.04 |
0.11 ± 0.02 |
0.11 ± 0.02 |
Lungs (g) |
0.86 ± 0.06 |
0.85 ± 0.07 |
0.88 ± 0.11 |
0.75 ± 0.06* |
(g%) |
0.39 ± 0.02 |
0.37 ± 0.03 |
0.39 ± 0.04 |
0.40 ± 0.03 |
Heart (g) |
0.63 ± 0.06 |
0.67 ± 0.08 |
0.66 ± 0.06 |
0.61 ± 0.05 |
(g%) |
0.29 ± 0.02 |
0.29 ± 0.03 |
0.30 ± 0.02 |
0.32 ± 0.03** |
Spleen (g) |
0.47 ± 0.04 |
0.44 ± 0.06 |
0.45 ± 0.04 |
0.48 ± 0.05 |
(g%) |
0.21 ± 0.02 |
0.19 ± 0.01* |
0.20 ± 0.02 |
0.25 ± 0.03 |
Liver (g) |
5.40 ± 0.37 |
5.84 ± 0.87 |
5.57 ± 0.55 |
4.77 ± 0.50 |
(g%) |
2.45 ± 0.11 |
2.55 ± 0.29 |
2.47 ± 0.17 |
2.52 ± 0.23 |
Adrenals (mg) |
69.10 ± 10.34 |
65.30 ± 12.48 |
68.90 ± 10.21 |
60.00 ± 7.09 |
(mg%) |
31.27 ± 4.22 |
28.52 ± 4.94 |
30.54 ± 3.65 |
31.73 ± 3.94 |
Kidneys (g) |
1.42 ± 0.17 |
1.38 ± 0.16 |
1.47 ± 0.15 |
1.33 ± 0.11 |
(g%) |
0.64 ± 0.04 |
0.60 ± 0.05 |
0.65 ± 0.04 |
0.70 ± 0.05* |
Applicant's summary and conclusion
- Conclusions:
- Taken together, toxicological effects of subchronic exposure to SEM-HCI were mainly observed in the bones, cartilages and aorta. From the histopathological examination, since disarrangement, fissures and deformation of the cartilages were found in both sexes from 250 ppm, the no-observed-adverse-effect-levels (NOAELs) estimated from present study were less than 250 ppm in both sexes, equivalent to 18.1 and 21.1 mg/kg/day in males and females
- Executive summary:
A ninety-day toxicity study of semicarbazide hydrochloride (SEM-HCl) was conducted in male and female Wistar Hannover GALAS rats fed diet containing the compound at concentration of 0, 250, 500 and 1000 ppm. Suppression of body weight gain and food consumption was found in both sexes at 1000 ppm throughout the study. Enlargement and deformation of knee joints were obvious at 500 and 1000 ppm from week 3, together with deformation of the thorax and tail. Histopathologically, disarrangement of chondrocytes and fissures in the cartilage matrix were apparent at all doses tested in epiphyseal and articular cartilage. The severity of these lesions increased dose-dependently, accompanied by increased connective tissues and bone deformation at high doses. Additionally, compact bones at 1000 ppm became thin, suggesting loss of bone mass. In the thoracic aorta, the edges of elastic laminae became rough and the interlaminar spaces were altered from a fibrillar to a rod or globular appearance. No abnormalities were detected in any other organs. Taken together, toxicological effects of subchronic exposure to SEM-HCI were mainly observed in bone, cartilage and the aorta, with the no-observedadverse-effect-level estimated from the present histopathological examination of less than 250 ppm in both sexes
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