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EC number: 203-250-0 | CAS number: 104-90-5
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- Ecotoxicological Summary
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Endpoint summary
Administrative data
Description of key information
A sub-acute toxicity study was carried out according to OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents) and EU Method B.7. The test item was administered per gavage to groups of 6 rats, male and female at dose levels of 30, 95 and 300 mg/kg bw/day. The NOAEL was determined to be 30 mg/kg bw/day. The LOAEL was determined at 95 mg/kg bw/day with slight clinical effects and minimal renal lesions in the male rats. At 300 mg/kg bw/day moderate clinical and clinicopathological effects and moderate renal lesions in male rats were found.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: 4 weeks / period
- Weight at study initiation: 90 - 100 g at start of acclimatization
- Fasting period before study: None
- Housing: Makrolon type II
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: At least 1 week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C +/- 20 °C
- Humidity (%): 55 % +/- 10 %
- Air changes (per hr): 15 - 20 times/hour
- Photoperiod (hrs dark / hrs light): 12/12 hours light-dark cycle
IN-LIFE DATES: From: 24.09.1987 To: 22.10.1987 - Route of administration:
- oral: gavage
- Vehicle:
- other: 1.2-propylene glycol (7 parts) + double distilled water (11 parts)
- Details on oral exposure:
- VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 3, 9.5 and 30 mg/mL
- Amount of vehicle (if gavage): 1 mL/100 g bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical method: UV; identity proven by UV-spectra
- Duration of treatment / exposure:
- 28 days, 7 days per week
- Frequency of treatment:
- once daily
- Remarks:
- Doses / Concentrations:
30, 95, 300 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 6 animals per dose group.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Range finding study
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: None.
- Post-exposure recovery period in satellite groups: None.
- Section schedule rationale (if not random): Random - Positive control:
- None.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily on 7 days/week.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice daily on 7 days/week.
BODY WEIGHT: Yes
- Time schedule for examinations: Body weight was recorded daily, starting at pretreatment period and reported weekly.
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
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
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: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At week 4 of treatment blood samples for hematology and blood chemistry were obtained from the right orbital vein plexus and collected into EDTA tubes (hematology) and lithium - heparin tubes (blood chemistry). Food was removed overnight prior to blood collection. Blood samples were collected between 7.00 and 9.00 a.m. (24 hours after compound administration) to prevent chronobiologic variations.
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes, overnight.
- How many animals: 6 per control and dose group
- Parameters checked in table were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: see hematology above
- Animals fasted: Yes
- How many animals: 6 per control and dose group
- Parameters checked in table were examined.
URINALYSIS: No, investigation was not indicated by clinical signs
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see below for details)
HISTOPATHOLOGY: Yes (see below for details) - Statistics:
- Routine evaluation of the data was done by:
* Student's t-test (t) +)
Normal distributed values, single treatment groups are compared against the control group.
* U-test (U) +)
In not normal distributed values the U-test of Wilcoxon, Mann and Whitney was employed to compare two autonomous random samples.
* William's test (Wi) ++)
The control group was compared with treatment groups of constant increasing or decreasing dosage, to determine the lowest dosage, where a significant difference was apparent. The method used therefore was the Williams test (Trend test).
* Bartlett's test (Ba) +)
This test checks the homogeneity of variance in normal distributed data groups.
* Global test (Kr) +)
In biological data mostly a sufficient normal distribution of values cannot be assumed. Therefore the H-test of Kruskal and Wallis is applied to compare several autonomous random samples.
+) SACHS, L: "Angewandte Statistik", Springer, Berlin, 6. Auflage, 1984
++) WILLIAMS, D.A.: 'The comparison of several dose levels with a zero dose control" Biometrics, 28, (1972): 519 - 531 - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- At weeks 2, 3 and 4 of treatment salivation was found at doses 95 and 300 mg/kg bw/day, in both sexes. None of the animals died during the study.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- At weeks 2, 3 and 4 of treatment salivation was found at doses 95 and 300 mg/kg bw/day, in both sexes. None of the animals died during the study.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At dose 300 mg/kg bw/day, group males, body weight gain was lower in comparison to control (statistically significant at days 8 and 15 of treatment and at termination).
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- At dose 300 mg/kg bw/day, group males, food consumption was significantly lower in comparison to control at week (p < 0.05) of treatment.
- 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):
- Erythrocytes and hematocrit were significantly different to controls in high dose females.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- MCV, MCH and MCHC were significantly different to controls in high dose females.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Lesions were seen either in both control and treated rats or occurred at a very low incidence and were considered not to be due to treatment with the test item.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Mottled kidneys were present in high dose males. Other leasions were considered chance occurence.
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Nephropathy was observed in males animales. Other leasions were not considered treatment related.
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
At weeks 2, 3 and 4 of treatment salivation was found at doses 95 and 300 mg/kg bw/day, in both sexes. None of the animals died during the study.
BODY WEIGHT AND WEIGHT GAIN
At dose 300 mg/kg bw/day, group males, body weight gain was lower in comparison to control (statistically significant at days 8 and 15 of treatment and at termination). No difference to control was found in females.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
At dose 300 mg/kg bw/day, group males, food consumption was significantly lower in comparison to control at week (p < 0.05) of treatment. In the other dose groups food consumption was similar to control.
FOOD EFFICIENCY
At dose 300 mg/kg bw/day, group males, mean food utilization was slightly lower in comparison to control.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Not examined.
OPHTHALMOSCOPIC EXAMINATION
Not examined.
HAEMATOLOGY
Parameters determined:
RBC
Hemoglobin
Hematocrit
MCV
MCH
MCHC
Reticulocytes
WBC (total and differential)
Platelet count
Erythrocytes and Hematocrit:
The number of erythrocytes was significantly higher at dose 30 mg/kg bw/day, group males, and lower at dose 300 mg/kg bw/day, group females, in comparison to control. The increase at dose 30 mg/kg bw/day is considered not to be related to treatment (lack of dose-dependence; historical data).
At doses 30 and 300 mg/kg bw/day, group females, hematocrit values were significantly lower and at dose 30 mg/kg bw/day, group males, hematocrit was significantly higher relative to control. The changes at dose 30 mg/kg bw/day in both sexes are considered not to be treatment related (historical data).
MCV, MCH and MCHC:
At dose 95 mg/kg bw/day, group females, MCV was significantly lower in comparison to control, but considered not to be treatment related (lack of dose-dependence, historical data).
At dose 300 mg/kg bw/day, group females, MCH was significantly higher in comparison to control. At dose 30 mg/kg bw/day, group males, MCH was significantly lower in comparison to control, but considered not to be treatment related (lack of dose dependence, historical data).
At dose 300 mg/kg bw/day, group females, MCHC was significantly higher relative to the control. At doses 30, 95 and 300 mg/kg bw/day, group males, values were significantly lower in comparison to control, but considered not to be treatment related (lack of dose-dependence, historical data).
CLINICAL CHEMISTRY
Parameters determined:
Glucose
Urea
Creatinine
Total bilirubin
Total cholesterol
ASAT
ALAT
LDH
GGT
AP
Total protein
Inorganic phosphorus
Page 7 of 221
Chloride
Sodium
Potassium
Calcium
Protein-electrophoresis
(absolute and relative)
Urea:
At dose 300 mg/kg bw/day, group males, significantly higher in comparison to control.
Creatinine:
At doses 95 and 300 mg/kg bw/day, group males, higher relative to the control, but statistically significant at dose 95 mg/kg bw/day only.
ASAT:
At dose 300 mg/kg bw/day, group males, significantly higher in comparison to control.
ALANIN-AMINOTRANSFERASE:
At dose 95 mg/kg bw/day, group males, ALA T activity was markedly increased in 1/6 animals, but no statistically significant difference to control was found in group mean values.
LDH:
At dose 95 mg/kg bw, group males, LDH activity was markedly increased in one animal. Also in one female of control LDH activity was increased.
Chloride:
At dose 300 mg/kg bw/day, group females, significantly lower in comparison to control.
Potassium:
At dose 95 mg/kg bw/day, group males, significantly higher in comparison to control, which might be treatment related, but the potassium concentration at dose 300 mg/kg bw was not significantly higher than in the control group.
ALPHA 1 - GLOBULINS (Fraction 2):
Absolute and relative values were significantly low rat dose 95 mg/kg bw/day, group females, and dose 300 mg/kg bw/day, group males, in comparison to control. At dose 30 mg/kg bw/day, group males, absolute values were significantly lower relative to control, but considered not to be treatment related (lack of dose-dependence, historical data).
ALPHA 1 - GLOBULINS (Fraction 3):
Absolute and relative values at dose 30 mg/kg bw/day, in both sexes and at dose 300 mg/kg bw/day, group females, were significantly higher in comparison to control. Additionally a significant increase relative to the control was seen in relative values at dose 95 mg/kg bw/day, group females. The changes were considered not to be treatment related (lack of dose-dependence, historical data).
BETA - GLOBULINS (Fraction 4):
Relative values at doses 95 and 300 mg/kg bw/day, group males, were significantly higher in comparison to control. No difference to control was seen in absolute values. Because of historical data and the lack of a clear dose-dependence the changes might be not treatment related.
URINALYSIS
CLINICAL SIGNS AND MORTALITY
At weeks 2, 3 and 4 of treatment salivation was found at doses 95 and 300 mg/kg bw/day, in both sexes. None of the animals died during the study.
BODY WEIGHT AND WEIGHT GAIN
At dose 300 mg/kg bw/day, group males, body weight gain was lower in comparison to control (statistically significant at days 8 and 15 of treatment and at termination). No difference to control was found in females.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
At dose 300 mg/kg bw/day, group males, food consumption was significantly lower in comparison to control at week (p < 0.05) of treatment. In the other dose groups food consumption was similar to control.
FOOD EFFICIENCY
At dose 300 mg/kg bw/day, group males, mean food utilization was slightly lower in comparison to control.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Not examined.
OPHTHALMOSCOPIC EXAMINATION
Not examined.
HAEMATOLOGY
Parameters determined:
RBC
Hemoglobin
Hematocrit
MCV
MCH
MCHC
Reticulocytes
WBC (total and differential)
Platelet count
Erythrocytes and Hematocrit:
The number of erythrocytes was significantly higher at dose 30 mg/kg bw/day, group males, and lower at dose 300 mg/kg bw/day, group females, in comparison to control. The increase at dose 30 mg/kg bw/day is considered not to be related to treatment (lack of dose-dependence; historical data).
At doses 30 and 300 mg/kg bw/day, group females, hematocrit values were significantly lower and at dose 30 mg/kg bw/day, group males, hematocrit was significantly higher relative to control. The changes at dose 30 mg/kg bw/day in both sexes are considered not to be treatment related (historical data).
MCV, MCH and MCHC:
At dose 95 mg/kg bw/day, group females, MCV was significantly lower in comparison to control, but considered not to be treatment related (lack of dose-dependence, historical data).
At dose 300 mg/kg bw/day, group females, MCH was significantly higher in comparison to control. At dose 30 mg/kg bw/day, group males, MCH was significantly lower in comparison to control, but considered not to be treatment related (lack of dose dependence, historical data).
At dose 300 mg/kg bw/day, group females, MCHC was significantly higher relative to the control. At doses 30, 95 and 300 mg/kg bw/day, group males, values were significantly lower in comparison to control, but considered not to be treatment related (lack of dose-dependence, historical data).
CLINICAL CHEMISTRY
Parameters determined:
Glucose
Urea
Creatinine
Total bilirubin
Total cholesterol
ASAT
ALAT
LDH
GGT
AP
Total protein
Inorganic phosphorus
Page 7 of 221
Chloride
Sodium
Potassium
Calcium
Protein-electrophoresis
(absolute and relative)
Urea:
At dose 300 mg/kg bw/day, group males, significantly higher in comparison to control.
Creatinine:
At doses 95 and 300 mg/kg bw/day, group males, higher relative to the control, but statistically significant at dose 95 mg/kg bw/day only.
ASAT:
At dose 300 mg/kg bw/day, group males, significantly higher in comparison to control.
ALANIN-AMINOTRANSFERASE:
At dose 95 mg/kg bw/day, group males, ALA T activity was markedly increased in 1/6 animals, but no statistically significant difference to control was found in group mean values.
LDH:
At dose 95 mg/kg bw, group males, LDH activity was markedly increased in one animal. Also in one female of control LDH activity was increased.
Chloride:
At dose 300 mg/kg bw/day, group females, significantly lower in comparison to control.
Potassium:
At dose 95 mg/kg bw/day, group males, significantly higher in comparison to control, which might be treatment related, but the potassium concentration at dose 300 mg/kg bw was not significantly higher than in the control group.
ALPHA 1 - GLOBULINS (Fraction 2):
Absolute and relative values were significantly low rat dose 95 mg/kg bw/day, group females, and dose 300 mg/kg bw/day, group males, in comparison to control. At dose 30 mg/kg bw/day, group males, absolute values were significantly lower relative to control, but considered not to be treatment related (lack of dose-dependence, historical data).
ALPHA 1 - GLOBULINS (Fraction 3):
Absolute and relative values at dose 30 mg/kg bw/day, in both sexes and at dose 300 mg/kg bw/day, group females, were significantly higher in comparison to control. Additionally a significant increase relative to the control was seen in relative values at dose 95 mg/kg bw/day, group females. The changes were considered not to be treatment related (lack of dose-dependence, historical data).
BETA - GLOBULINS (Fraction 4):
Relative values at doses 95 and 300 mg/kg bw/day, group males, were significantly higher in comparison to control. No difference to control was seen in absolute values. Because of historical data and the lack of a clear dose-dependence the changes might be not treatment related.
URINALYSIS
Investigation was not indicated by clinical signs.
NEUROBEHAVIOUR
Not examined.
ORGAN WEIGHTS
Organs weighed:
Adrenals
Brain
Heart
Kidneys
Liver
Spleen
Testes
Brain:
Relative organ weight at dose 300 mg/kg bw/day, group males, was significantly higher in comparison to control.
Heart:
Absolute organ weight at dose 30 mg/kg bw/day, group females, was significantly lower in comparison to control.
Kidneys:
Relative organ weight at dose 300 mg/kg bw/day, group males, was significantly higher relative to control.
Liver:
Relative organ weight at doses 95 mg/kg bw/day, group males, and 300 mg/kg bw/day in both sexes was significantly higher in comparison to control. Absolute organ weight was significantly higher at dose 95 mg/kg bw/day, group males.
Spleen:
Absolute organ weight at dose 300 mg/kg bw/day, group males, was significantly (p < 0.05) lower in comparison to control.
Testes:
Relative organ weight at dose 300 mg/kg bw/day, was significantly higher relative to the control.
GROSS PATHOLOGY
Mottled kidneys were present in 5/6 male rats at dose 300 mg/kg bw/day, but not in the other treated or control groups. Other gross lesions (red mucosa of stomach, enlarged or swollen liver) occurred in a non-dose related manner and were found to be due to chance occurrence.
HISTOPATHOLOGY: NON-NEOPLASTIC
The principal treatment related lesion was nephropathy which was seen in the male rats only. Nephropathy was slight to marked and characterized by swelling of the renal epithelial cells with occasional vacuolation and increased eosinophilia due to the presence of intracytoplasmic eosinophilic granules and hyaline droplets principally in the renal cortex.
Nephropathy was more severe at dose 300 mg/kg bw/day (marked nephropathy) than in the other treated groups but was more frequent at dose 95 mg/kg bw/day (5/6 rats) than at 300 mg/kg bw/day (2/6 rats). Slight nephropathy was also seen in one rat each of the control and at dose 30 mg/kg bw/day. Other renal lesions, as tubular casts, tubular basophilia and dilation, hydronephrosis and congestion were one time occurrences and were considered not to be treatment-related.
Other lesions were seen in the heart (myocarditis and myopathy), spleen (congestion), stomach (dilated crypts and degeneration), liver (microgranuloma) and adrenal (cytoplasmic vacuolation). These lesions were seen either in both control and treated rats or occurred at a very low incidence and were considered not to be due to treatment with the test item.
HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Not applicable.
HISTORICAL CONTROL DATA (if applicable)
Not applicable.
OTHER FINDINGS
None.
NEUROBEHAVIOUR
Not examined.
ORGAN WEIGHTS
Organs weighed:
Adrenals
Brain
Heart
Kidneys
Liver
Spleen
Testes
Brain:
Relative organ weight at dose 300 mg/kg bw/day, group males, was significantly higher in comparison to control.
Heart:
Absolute organ weight at dose 30 mg/kg bw/day, group females, was significantly lower in comparison to control.
Kidneys:
Relative organ weight at dose 300 mg/kg bw/day, group males, was significantly higher relative to control.
Liver:
Relative organ weight at doses 95 mg/kg bw/day, group males, and 300 mg/kg bw/day in both sexes was significantly higher in comparison to control. Absolute organ weight was significantly higher at dose 95 mg/kg bw/day, group males.
Spleen:
Absolute organ weight at dose 300 mg/kg bw/day, group males, was significantly (p < 0.05) lower in comparison to control.
Testes:
Relative organ weight at dose 300 mg/kg bw/day, was significantly higher relative to the control.
GROSS PATHOLOGY
Mottled kidneys were present in 5/6 male rats at dose 300 mg/kg bw/day, but not in the other treated or control groups. Other gross lesions (red mucosa of stomach, enlarged or swollen liver) occurred in a non-dose related manner and were found to be due to chance occurrence.
HISTOPATHOLOGY: NON-NEOPLASTIC
The principal treatment related lesion was nephropathy which was seen in the male rats only. Nephropathy was slight to marked and characterized by swelling of the renal epithelial cells with occasional vacuolation and increased eosinophilia due to the presence of intracytoplasmic eosinophilic granules and hyaline droplets principally in the renal cortex.
Nephropathy was more severe at dose 300 mg/kg bw/day (marked nephropathy) than in the other treated groups but was more frequent at dose 95 mg/kg bw/day (5/6 rats) than at 300 mg/kg bw/day (2/6 rats). Slight nephropathy was also seen in one rat each of the control and at dose 30 mg/kg bw/day. Other renal lesions, as tubular casts, tubular basophilia and dilation, hydronephrosis and congestion were one time occurrences and were considered not to be treatment-related.
Other lesions were seen in the heart (myocarditis and myopathy), spleen (congestion), stomach (dilated crypts and degeneration), liver (microgranuloma)and adrenal (cytoplasmic vacuolation). These lesions were seen either in both control and treated rats or occurred at a very low incidence and were considered not to be due to treatment with the test item.
HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Not applicable.
HISTORICAL CONTROL DATA (if applicable)
Not applicable.
OTHER FINDINGS
None. - Dose descriptor:
- NOAEL
- Effect level:
- 30 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No treatment related effects were found at dose 30 mg/kg bw/day.
- Dose descriptor:
- LOAEL
- Effect level:
- 95 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: The administration of 95 mg/kg bw/day resulted in slight clinical effects and minimal renal lesions in the male rats.
- Critical effects observed:
- not specified
- Conclusions:
- In a sub-acute toxicity study the test item was administered to groups of 6 rats (Sprague-Dawley, Cd: CDR (SD) BR), male and female by gavage] at dose levels of 30, 95 and 300 mg/kg bw/day.
Nephropathy in the male rats at doses 95 and 300 mg/kg bw/day was the principal treatment effect following administration of the test item. The lesion might be similar to the protein nephropathy induced by xenobiotics in the male rat. Alden (1986) reported that several chemicals specifically increase significantly alpha-2u globulin accumulation in the proximal convoluted tubular epithelium of the male rat as a primary acute toxicological effect, although it was demonstrated that the spontaneous hyaline droplet in the otherwise normal male rat-kidney consists exclusively of alpha-2u globulin. This lesion is present in the male rat only but not in the female, because the female rat does not synthesize alpha-2u globulin.
A higher relative weight of kidneys with increased blood urea nitrogen and creatinine might be related to kidney lesions. A higher ASAT activity at high dose of males and increased relative liver weights, more pronounced in males than in females, might suggest an influence on the hepatic system due to treatment with the test item. However, no treatment-related pathomorphologic alterations were found at histologic examination of the livers. Clinicopathologic changes such as lowered erythrocytes counts and hematocrit values, elevated MCH and MCHC and lowered chloride concentration in females were of uncertain relationship to drug-treatment and were noted in the rats treated with 300 mg/kg bw/day.
The test item produced no clinical effects, no clinicopathological effects and no histopathologic lesions, when administered at 30 mg/kg bw/day to rats. No treatment related effects were found at dose 30 mg/kg bw/day. The administration of 95 mg/kg bw/day resulted in slight clinical effects and minimal renal lesions in the male rats. At 300 mg/kg bw/day moderate clinical and clinicopathological effects and moderate renal lesions in male rats were found.
Ref: C.L. Alden (1986) 'Unique Male Rat Xenobiotic induced Protein Nephropathy" Proceedings of the thirtyseventh Annual Meeting of the American College of Veterinary Pathologists, pp. 145 – 148. - Executive summary:
A sub-acute toxicity study was carried out according to OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents) and EU Method B.7. The test item was administered per gavage to groups of 6 rats (Sprague-Dawley, Cd: CDR (SD) BR), male and female at dose levels of 30, 95 and 300 mg/kg bw/day.
Nephropathy in the male rats at doses 95 and 300 mg/kg bw/day was the principal treatment effect following administration of the test item. The lesion might be similar to the protein nephropathy induced by xenobiotics in the male rat. Alden (1986) reported that several chemicals specifically increase alpha-2u globulin accumulation in the proximal convoluted tubular epithelium of the male rat as a primary acute toxicological effect, although it was demonstrated that the spontaneous hyaline droplet in the otherwise normal male rat-kidney consists exclusively of alpha-2u globulin. This lesion is present in the male rat only, but not in the female, because the female rat does not synthesize alpha-2u globulin.
A higher relative weight of kidneys with increased blood urea nitrogen and creatinine might be related to kidney lesions. A higher ASAT activity at high dose of males and increased relative liver weights, more pronounced in males than in females, might suggest an influence on the hepatic system due to treatment with the test item. However, no treatment-related pathomorphologic alterations were found at histologic examination of the livers. Clinicopathologic changes such as lowered erythrocytes counts and hematocrit values, elevated MCH and MCHC and lowered chloride concentration in females were of uncertain relationship to drug-treatment and were noted in the rats treated with 300 mg/kg bw/day.
The test item produced no clinical effects, no clinicopathological effects and no histopathologic lesions, when administered at 30 mg/kg bw/day to rats.
The no observed adverse effect level (NOAEL) was determined to be 30 mg/kg bw/day. The lowest observed adverse effect level (LOAEL) was determined at 95 mg/kg bw/day with slight clinical effects and minimal renal lesions in the male rats. At 300 mg/kg bw/day moderate clinical and clinicopathological effects and moderate renal lesions in male rats were found.
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 30 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
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
Repeated dose toxicity - oral
A sub-acute toxicity study was carried out according to OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents) and EU Method B.7. The test item was administered per gavage to groups of 6 rats (Sprague-Dawley, Cd: CDR (SD) BR), male and female at dose levels of 30, 95 and 300 mg/kg bw/day.
Nephropathy in the male rats at doses 95 and 300 mg/kg bw/day was the principal treatment effect following administration of the test item. The lesion might be similar to the protein nephropathy induced by xenobiotics in the male rat. Alden (1986) reported that several chemicals specifically increase alpha-2u globulin accumulation in the proximal convoluted tubular epithelium of the male rat as a primary acute toxicological effect, although it was demonstrated that the spontaneous hyaline droplet in the otherwise normal male rat-kidney consists exclusively of alpha-2u globulin. This lesion is present in the male rat only, but not in the female, because the female rat does not synthesize alpha-2u globulin.
A higher relative weight of kidneys with increased blood urea nitrogen and creatinine might be related to kidney lesions. A higher ASAT activity at high dose of males and increased relative liver weights, more pronounced in males than in females, might suggest an influence on the hepatic system due to treatment with the test item. However, no treatment-related pathomorphologic alterations were found at histologic examination of the livers. Clinicopathologic changes such as lowered erythrocytes counts and hematocrit values, elevated MCH and MCHC and lowered chloride concentration in females were of uncertain relationship to drug-treatment and were noted in the rats treated with 300 mg/kg bw/day.
The test item produced no clinical effects, no clinicopathological effects and no histopathologic lesions, when administered at 30 mg/kg bw/day to rats.
The no observed adverse effect level(NOAEL) was determined to be 30 mg/kg bw/day. The lowest observed adverse effect level (LOAEL) was determined at 95 mg/kg bw/day with slight clinical effects and minimal renal lesions in the male rats. At 300 mg/kg bw/day moderate clinical and clinicopathological effects and moderate renal lesions in male rats were found.
Justification for classification or non-classification
Based on the data available the substance is not classified and labeled according to Regulation 1272/2008/EEC (CLP) and Directive 67/548/EEC (DSD).
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