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Description of key information

Key study: For the test item, tested for the repeated dose toxicity, the NOAEL was evaluated to 18.1 mg/kg/day in males and 21.1 mg/kg/day in females, which is equivalent to < 250 ppm in both sexes.

Key study: In the chronic toxicity study combined with carcinogenic study, test substance in the chronic study showed toxic effects on bones cartilage and aorta in rats. Adverse effects (Disarrangement of the chondrocytes accompanied by increased connective tissues and degeneration of the articular cartilage) of SEM-HCl were observed in males at 50 ppm and above and in females at 250 ppm.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
no
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:4 weeks, room temperature or 8 weeks at 4ºC.
- Stability under test conditions:Yes, 89% stability under both condition.
Species:
rat
Strain:
Wistar
Remarks:
Hannover GALAS
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:CLEA Japan, Inc. (Tokyo, Japan)
- Age at study initiation: 5 weeks old
- Weight at study initiation: Females:126.3+-4.3 g, Males: 166.5+-4.5g (mean value+- standard deviations)
- Fasting period before study: One night fasting, prior to scheduled sacrifice.
- Housing: 2-4 per plastic cage with sterilized softwood chips as bedding in a barrier-maintened animal room.
- Diet (e.g. ad libitum):ad libitum,basal diet CE-2, CLEA Japan Inc.
- Water (e.g. ad libitum): ad libitum, free access
- Acclimation period:1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C):24+-1
- Humidity (%):55+-5
- Photoperiod (hrs dark / hrs light):12-h light/dark
Route of administration:
oral: feed
Details on route of administration:
SEM-HCl was well mixed at concentrations 0 (control), 250,500 or 1000 ppm into powdered basal diet (CE-2).
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): every 2 weeks, stored at 4ºC before use.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability of SEM-HCL was prepared by Japan Food Research Laboratories (Osaka, Japan). Concentrations after storage at room temperature for 4 weeks or at 4ºC for 8 weeks, were analyzed and more than 89 % stability of the test compound was confirmed under both conditions. SEM was no detected in basal diet (detection limit, 0.01 ppm).
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily
Dose / conc.:
0 ppm
Remarks:
Control
Dose / conc.:
250 ppm
Dose / conc.:
500 ppm
Dose / conc.:
1 000 ppm
Remarks:
The highest dose
No. of animals per sex per dose:
4 groups, each containing of 10 males and 10 females.
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Preliminary examination a 2-week dose finding study (Weisburger, E.K., Ulland, B.M., Nam, J., Gart, J.J., Weisburger, J.H., 1981. Carcinogenicity tests of certain environmental and industrial chemicals. J.Natl. Cancer Inst. 67, 75–88) with 1000 ppm selected as the highest dose for subsequent study.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes, mortality

DETAILED CLINICAL OBSERVATIONS: Yes, daily

BODY WEIGHT: Yes: Every week.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Every week
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data:Not specified

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes (RBC,Hb,Ht,MCV, MCH, MCHC,Plt, WBC,band form neutrophils,segment neutrophils, eosinophils, basophils, lymphocytes, monocytes, reticulocytes.
- Anaesthetic used for blood collection: Yes (identity) - Ether

CLINICAL CHEMISTRY: Yes (TP,Alb,A/G,Total bil,glucose,TG, TC,BUN, CRB, Na, Cl,K,IP,AST,ALT,ALP,GAMA-GTP)

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes,posting and gait abnormalities and deformation of four limbs, thorax and tail.

IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all organs (the brain, thymus, heart, lungs, liver, spleen, adrenals, kidneys and testes were removed and weighed).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.

HISTOPATHOLOGY: Yes, 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:
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.).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.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Suppression was observed at 1000 ppm group 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.
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:
no effects observed
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):
Both sexes:Differential leukocyte showed significant decrease and increase in the propotions of segmented neutrophils and lymphocytes, respectively, in the 1000 ppm group. The WBC counts
were decreased in males and increased in females, although not statistically significant in the 1000 ppm group.
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):
Changes in CRN, ALT, A/G, total Bil and K were found in males at 500 and/or 1000 ppm.I n 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
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
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.
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.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute weights of the lungs in both sexes.
The thymus, heart and liver in males were statistically lowered at 1000 ppm.
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.
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):
Bowing of the tibia was apparent in males and females at 500 and 1000 ppm.
An 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 specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
effects observed, treatment-related
Description (incidence and severity):
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.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.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Histipathological findings for bones and joints:
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 ppm.In the metaphysis, spongy bones were decreased and irregularly-branched.
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.
Wrist joint :the epiphyseal plates of the radius and ulna exhibited similar histological lesions with the tibia.
Knee joints and intervertebral joints:Deformation and fissures of articular cartilage with disarrangement of chondrocytes were observed at all doses tested. 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.
Thinning of bone in the vertebral body was obvious in the 1000 ppm group, suggesting loss of bone mass.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.
Thoracic aorta: 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.
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 18.1 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Bones, cartilage and the aorta
Remarks on result:
other: < 250 ppm in both sexes.
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 21.1 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Bones, aorta and cartilage
Remarks on result:
other: < 250 ppm in both sexes.
Key result
Critical effects observed:
not specified
Conclusions:
For the test item, tested for the repeated dose toxicity, the NOEAL was evaluated as less than 250 ppm in both sexes (equivalent to 18.1 mg/kg/day in males and 21.1 mg/kg/day in females).
Executive summary:

According the study, the subchronic toxicity was examinated with the test substance in Wistar Hannover GALAS rats, obtained from CLEA Japan. Rats (males and females) were 5 weeks old and fed with diet containing the test compound at concentration 0, 250,500 and 1000 ppm.Study was carried out during 90 days at the temperature 24 -+1ºC. The diets were prepared every 2 weeks and stored at 4ºC before use. Animals were divided into 4 groups containing 10 males and ten females. During the study, body weights and food consumption were observed every weeks, observation of mortality,clinical signs, including posture, gait abnormalities, deformation of four limbs thorax and tail were conducted daily.Hematology, histopathological and gross examination were provided also. Suppression in body weight gain and food consumption was observed in both sexes at 1000 ppm. 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. 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 into acount effects of subchronic exposure to SEM-HCl, the NOAEL was set as less than 250 ppm in both sexes (equivalent to 18.1 mg/kg/day in males and 21.1 mg/kg/day in females).

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
No GLP.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
no
GLP compliance:
no
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: 4 weeks, at room temperature and 8 weeks at 4ºC.
- Stability under test conditions:Yes
Species:
rat
Strain:
Wistar
Remarks:
Hannover GALAS
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:CLEA Japan, Inc. (Tokyo, Japan)
- Age at study initiation: 5 weeks old
- Housing: 2-3 per plastic cage with sterilized softwood chips as bedding in a barrier-maintened animal room.
- Diet (e.g. ad libitum): a basal diet (CE-2, CLEA Japan, Inc.)
- Water (e.g. ad libitum): ad libitum
- Acclimation period:1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C):24+-1
- Humidity (%):55+-5
- Photoperiod (hrs dark / hrs light):12-h light/dark
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): every 4 weeks, stored at 4ºC
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability of SEM-HCL was prepared by Japan Food Research Laboratories (Osaka, Japan). For each dose, test compound retained 69-100% purity (average= 87%) after sotrage at room temperature for 4 weeks or 82-100% (average=94%) after storage at 4ºC for up to 8 weeks. SEM was not detected in the basal diet (detection limit =0.01 ppm)
Duration of treatment / exposure:
52 weeks
Frequency of treatment:
Daily
Dose / conc.:
0 ppm
Remarks:
Control
Dose / conc.:
10 ppm
Dose / conc.:
50 ppm
Dose / conc.:
250 ppm
No. of animals per sex per dose:
Four groups, each containing 10 males and 10 females
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Based on the previous study (90-day toxcicity study of semicarbazide hydrochloride in wistar Hannover GALATS rats), the highest dose was selected as 250 ppm because of no effects to body growth.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes, mortality

DETAILED CLINICAL OBSERVATIONS: Yes (thorax, Enlargement and deformation of the knee joint)

BODY WEIGHT: Yes (every week)

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, recorded every week until week 13 and every 4 weeks thereafter.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

OPHTHALMOSCOPIC EXAMINATION:No

HAEMATOLOGY: Yes (leukocyte, white blood cells)
- Anaesthetic used for blood collection: Yes (identity) -for hematology and serum biochemistry.

CLINICAL CHEMISTRY: Yes (Cl and glucose, AST, ALT, K)

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes (palpation of the joints of limbs)

IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, pituitary, eyes, Harderian glands, spinal cord (cervical, thoracic, and lumbar portions together with corresponding vertebral bones), salivary glands, stomach, small intestine (duodenum, jejunum, and ileum), large intestine (cecum, colon, and rectum), pancreas, urinary bladder, skin, mammary gland, mesenteric lymph nodes, thoracic aorta, trachea, esophagus, thyroid glands, tongue, thigh muscle, sciatic nerve, epididymides, seminal vesicles, prostate, uterus, vagina, and macroscopic lesions were removed. All organs were fixed in 10% buffered formalin, except for testes, which were fixed in Bouin’s solution overnight
Organ weights: Yes, Absolutive and relative organ weights - the brain, heart, lungs, liver, spleen, adrenals, kidneys, testes, and ovaries.


HISTOPATHOLOGY: Yes, For examination of osteochondral lesions, the nasal cavity, sternum, right femur, right tibia, left knee joint, and spine (transverse sections of the cervical, thoracic, and lumbar vertebrae and a vertical section of the thoracic vertebrae) were fixed in 10% buffered formalin and then decalcified in EDTA solution at room temperature for a month. All tissues were routinely processed for paraffin embedding, sectioned, and stained with hematoxylin and eosin (HE).
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 comparison test was employed for comparison between the control and treatment groups. Survival rates and the incidences of histopathological findings, including tumors, were compared using the Fisher’s exact test. The severity of the histopathological lesions observed in the chronic toxicity study was analyzed with the Mann–Whitney U-test.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Enlargement of the knee joints in males and females at 250 ppm from week 24, and in the males was higher than in the females.
Mortality:
no mortality observed
Description (incidence):
No deaths occurred.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No difference in body weights of both sexes.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
No interference during the feeding period in males. In females, differences among the groups were not found except one case on the beginning of the experiment, at the 10 and 250 ppm groups - increase food consumption. Compared with 0 ppm group, the mean values for food consumption/ animal were lower in males in the 10 ppm groups and higher in females in the 10,50 and 250 ppm groups.
The mean value of food consumption / kg body weight were increased in females in the 50 and 250 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):
Leukocyte counts were decreased in the 500 and 250 ppms groups of males. White blood cell (WBC)- no differences between the groups. No significant changes were found in any of the hematological parameters in females.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
A significant increase in Cl and glucose were observed in males and females in the 250 ppm groups, respectively. Decreases in K in males in the 10 and 50 ppm groups and in asparate amino trasnferase (AST), alanineaminotransferaze (ALT) in females in the 50 ppm group were detected - NO DOSE DEPENDENCY
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Enlargement of the knee joints in males and females at 250 ppm from week 24, and in the males was higher than in the females.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Not differences among groups in both sexes.
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The incidence of retinal atrophy in females was significantly lower in the 250 ppm group compared with control group. Additionally, various spontaneous lesions were observed, but the differences were not statistically significant.
Histopathological findings: neoplastic:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
HISTOPATHOLOGICAL FINDINGS IN BONES, JOINTS AND AORTA:
Rats - 1 year old, dissarangement of epiphyseal chondrocytes associated with aging and protrusion of chondrocytes to the marrow cavity occasionally appeared in the 0 ppm and SEMI-HCL treated groups.
In the tibia, the degree of protrusion of chondrocytes increased at 50 ppm and above in males, and at 250 ppm in females. In the front part of leg,dissarangement of epiphyseal chondrocytes accompanied by increased connective tisues was obvious.Disarrangement of the chondrocytes accompanied by increased connective tissues was also significantly increased in the vertebral epiphyseal plate of the thoracic vertebra in rats of both sexes in the 250 ppm group. These SEM-HCl-specific changes were not apparent in the femur. With regard to the articular cartilage, degeneration and fissures were found in the intervertebral joint from 50 ppm in males and at 250 ppm in females. The incidence of degeneration of the articular cartilage was also elevated in the knee joint in rats of both sexes in the 250 ppm group.In the thoracic aorta, roughened edges of the elastic laminae were observed at 250 ppm, but all changes were mild.
Key result
Dose descriptor:
NOAEL
Effect level:
< 50 ppm
Based on:
test mat.
Sex:
male
Remarks on result:
other: Disarrangement of the chondrocytes accompanied by increased connective tissues and degeneration of the articular cartilage
Key result
Dose descriptor:
NOAEL
Effect level:
< 250 ppm
Based on:
test mat.
Sex:
female
Remarks on result:
other: Disarrangement of the chondrocytes accompanied by increased connective tissues and degeneration of the articular cartilage
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
50 ppm
System:
other: Not specified
Organ:
cartilage
other: Disarrangement of the chondrocytes
Treatment related:
yes
Conclusions:
Test substance in the chronic study showed toxic effects on bones cartilage and aorta in rats. Adverse effects (Disarrangement of the chondrocytes accompanied by increased connective tissues and degeneration of the articular cartilage) of SEM-HCl were observed in males at 50ppm and above and in females at 250 ppm.
Executive summary:

According the available data from the present study, carcinogenicity effects of Semicarbazide hydrochloride were examinated in the male/females rats from Japan. Chronic toxicity study combined with carcinogenic study was performed. In the chronic study, 10 males and 10 females rats were used per group (total 4 groups) during 52 weeks. The rats were fed a powdered diet containing SEMI HCl in 0 (control), 10,50 and 250 ppm. Animals were checked daily for clinical signs of toxicity and mortality, for body weights and food consumption,hematology analysis and gross examination. No deaths occured in the chronic study. Mild changes in the elastic laminae were observed at 250 ppm for both sexes. SEM-HCl exerted no toxic effects on hematology, serum biochemistry, or organ weights. Disarrangement of the chondrocytes accompanied by increased connective tissues and degeneration of the articular cartilage were observed as adverse effects of SEM-HCl in males at 50ppm and above and in females at 250 ppm. The toxicological targets of chronic exposure to SEM-HCl were the bones,cartilage,and aorta in rats.


 

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Quality of whole database:
K2, study well documented, meets generally accepted scientific principles, acceptable for assessment.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Key study:

According the study,test substance was examinated for toxicity in Wistar Hannover GALAS rats, obtained from CLEA Japan. Males and females rats were 5 weeks old and during the study thew were fed with diet containing the test compound at concentration 0, 250,500 and 1000 ppm. Study was carried out during 90 days at the temperature 24 -+1ºC. The diets were prepared every 2 weeks and stored at 4ºC before use. Animals were divided into 4 groups containing 10 males and ten females. The body weights and food consumption were observed every weeks, observation of mortality,clinical signs, including posture, gait abnormalities, deformation of four limbs thorax and tail were conducted daily. Hematology, histopathological and gross examination were provided also. Based on the fact, that the toxicological effects of subchronic exposure to SEM-HCl were mainly observed in the bones, cartilages and aorta from 250 ppm, the NOAEL was set as less than 250 ppm in both sexes (equivalent to 18.1 mg/kg/day in males and 21.1 mg/kg/day in females).

Key study:

According the available data from the present study,chronic toxicity study combined with carcinogenic study was performed. In the chronic study, 10 males and 10 females rats were used per group (total 4 groups) during 52 weeks. The rats were fed a powdered diet containing SEMI HCl in 0 (control), 10,50 and 250 ppm. Animals were checked daily for clinical signs of toxicity and mortality, for body weights and food consumption,hematology analysis and gross examination. No deaths occured in the chronic study. Mild changes in the elastic laminae were observed at 250 ppm for both sexes. SEM-HCl exerted no toxic effects on hematology, serum biochemistry, or organ weights. Disarrangement of the chondrocytes accompanied by increased connective tissues and degeneration of the articular cartilage were observed as adverse effects of SEM-HCl in males at 50ppm and above and in females at 250 ppm. The toxicological targets of chronic exposure to SEM-HCl were the bones,cartilage,and aorta in rats.


 

Justification for classification or non-classification

Based on the available data from the repeated dose toxicity study and chronic toxicity study combined with carcinogenicity study, Semicarbazide hydrochloride has toxic effects mainly in bones, cartilages and aorta, but these data are not sufficient for classification, therefore Semicarbazide hydrochloride cannot be classified according to CLP Regulation (EC) no. 1272/2008.