Registration Dossier

Administrative data

Description of key information

Short-term repeated dose toxicity: oral

A 28-day repeated-dose oral toxicity study of test item was performed to characterize the toxicity of the test substance in accordance with OECD 407. The No-Observed-Adverse-Effect Level (NOAEL) of test item under the conditions tested was estimated to be 150 mg/kg/day since anemia and decreased body weights were mainly observed in males and females of the 750 mg/kg group.

Short-term repeated dose toxicity: Dermal and inhalation

Waived as s a reliable oral toxicity study is available

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2013-05-01 to 2013-07-24
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
October 3, 2008
Deviations:
no
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
- Purity: 100.0%
- Lot No.: KNC110310
Species:
rat
Strain:
other: Crl:CD(SD)
Details on species / strain selection:
This strain is established as a laboratory animal and widely used in general toxicity studies, and the test facility has historical data of this strain.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan Hino Breeding Center
- Age at study initiation: 5 weeks
- Weight at study initiation: 131.7-153.8 g for males and 108.2-133.6 g for females
- Fasting period before study:
- Housing: housed in hanging stainless steel cages with wire-mesh floor in size of 260 Wx380 Dx180 H mm for quarantine and acclimation, and 165 Wx300 Dx150 H mm after grouping. Undertrays were changed at the end of quarantine period and at grouping, twice a week after grouping, and before carrying animals from the animal room to the autopsy room. Feeders, cages and racks were changed once at the grouping and at the termination of the dosing period for the recovery groups.
- Diet: free access to a pelleted diet (MF, lot no. 130205 and 130403, Oriental Yeast) in the stainless steel feeder.
- Water: Chlorinated water maintained at 3-5 ppm of chloric level by adding sodium hypochlorite (Purelox) to Hita City supply was given by an automatic watering system with sipper tubes. When the animals were placed in a metabolic cage, water was supplied with water bottle.
- Acclimation period: 7 days

DETAILS OF FOOD AND WATER QUALITY:
The data of contaminants in the diets was obtained from supplier and confirmed to meet the requirements in our laboratory of the "Toxic Substances Control Act of US-EPA" (1979). Contaminants in the drinking water were analyzed twice a year according to the water regulations of the "Ordinance on drinking water quality standards" [Ordinance No. 101 of MHLW]. The analytical data of contaminants in the water were confirmed to be within the stated ranges of Lab.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.3-23.6
- Humidity (%): 47.4-65.1
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-12 hours (light on: 7:00 and light off: 19:00).
Route of administration:
oral: gavage
Details on route of administration:
administered to the animals daily by gavage using a syringe (Terumo) connected to a Nelaton catheter (Terumo) for 28 days
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The test substance was weighed accurately and dissolved in purified water to prepare 7.50 w/v% formulation. A part of this formulation was taken and diluted with purified water to prepare 0.300 and 1.50 w/v% formulations.
The formulations and vehicle were subdivided into plastic containers and stored in the cold place (actual temperature: 2-10℃). On each dosing day these formulations were taken out from the storage place and dosed to the animals within 10 days after preparation.

VEHICLE
- Justification for use and choice of vehicle: The test substance was dissolved in purified water at 10.0 w/v%.
- Concentration in vehicle: 7.50, 0.300 and 1.50 w/v%
- Amount of vehicle (if gavage): 10 mL/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations of 0.300, 1.50 and 7.50 w/v% formulations were analyzed with HPLC immediately after the first preparation.
The concentrations of all formulations (0.300 w/v% formulation: 0.300 w/v%, 1.50 w/v% formulation: 1.52 w/v% and 7.50 w/v% formulation: 7.39 w/v%) were confirmed to be within an acceptable range of each nominal concentration.
Duration of treatment / exposure:
28d
Frequency of treatment:
daily
Dose / conc.:
750 mg/kg bw/day (actual dose received)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Dose / conc.:
30 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
As a range finding study, a 7-day repeated-dose oral toxicity study of test item in rats was performed. In this study, three male and three female of Crl:CD(SD) rats in each group were treated orally with the test substance dissolved in purified water at dose levels of 0, 25, 250, 500 and 1000 mg/kg/day for 7 days.
Body weights gain were strongly suppressed in the 1000 mg/kg group in the7 days study. Sever toxicities such as death were expected when this dose was set at 28-day study. Thus, the high dose was selected at 750 mg/kg/day to show toxicities by the test substance without death. Lower dose levels were chosen at 150 and 30 mg/kg/day with common ratio of five.
- Rationale for animal assignment: allocated using body weight-stratified randomization
- Fasting period before blood sampling for clinical biochemistry: approx. 16 hours from the afternoon at the last day of the dosing period for the main groups and at the last day of the recovery period for the recovery groups to each next morning.
- Recovery groups: high dose and vehicle control groups without treatrnent for 14 days after the dosing period.
Positive control:
Not performed
Observations and examinations performed and frequency:
- General Clinical Observations:
During the dosing period animals were observed twice a day; before dosing, between just after dosing and approx. 30 minutes after dosing from day 1 to day 9, and three times a day; before dosing, between just after dosing and approx. 2 hours after dosing, and in the afternoon (until 6 hours and 30 minutes after dosing) from day 10. The animals were observed once a day during the recovery period.
- Detailed Clinical Observations:
Detailed clinical observations were performed in all animals once before dosing. Thereafter, the animals were examined once a week during the dosing and recovery periods on a blind test basis. The blind test was performed using the random numbers and observation labels without identifying the dosing groups.
- Sensorimotor Function Examinations:
All animals were examined in week 4 of the dosing period. Reflex tests and measurements of grip strength were performed on a blind test basis. In the recovery period the examinations were not performed since no abnormalities related to the test substance were observed in the high dose groups during the dosing period.
- Body Weight Measurements:
Body weights were measured using an electric balance for all animals on days 1, 3, 8, 12, 17, 21 , 26 and 28 of the dosing period, on days 1, 5, 10 and 14 of the recovery period, and on the necropsy days (before carrying animals from the animal room).
- Food Consumption Measurements:
Food weights were measured for all animals at the following days: feeding weights at the group allocation, remainder weights on days 1, 3, 8, 15, 22 and 28 of the dosing period, feeding weights on day 1 of the recovery, and remainder weights on days 4, 8 and 14 of the recovery period. Feeding weight on days 8, 15 and 22 of the dosing period and on day 8 of the recovery period were measured after food was replenished.

- Urinalyses:
Collecting urine samples: Urine samples were collected in individual metabolic cages (150 Wx200 Dx263 H mm) with drinking water and without food for approx. 16 hours from the afternoon at the last day of the dosing period for the main groups and at the last day of the recovery period for the recovery groups to each next morning.
Parameters and Methods: Urine samples were examined for parameters in the following table 1. Urinary sediments were stained and examined in males and females of all groups including the control, low, middle and recovery groups since abnormalities related to the test substance were noted in both sex of the high dose group.

- Clinical Laboratory Investigations:
Blood sampling and preparation of test samples: Blood was collected from the abdominal aorta under isoflurane anesthesia after the urine collection (fasting for 16-20 hour) on the next day of the last dosing for the main groups and the last withdrawal day for the recovery groups. Serum was stored at -20℃.
Hematological examinations: Whole blood or plasma samples were used to determine the following parameters in table 2.
Blood Chemical Examinations: Serum samples were used to determine the following parameters in table 3.
Sacrifice and pathology:
- Gross Necropsy:
All animals were subjected to a detailed gross necropsy after blood sampling. External surface of the body, all orifices, subcutis, cranial, thoracic, abdominal and pelvic cavities, and their contents were observed.
Vaginal smears were collected before the gross necropsy for females, and the stages of estrous cycle were determined with light microscope after Giemsa staining.
The organs and tissues were collected and weighted.
- Histopathological Examinations:
The organs and tissues were preserved in 10% neutralized buffered formalin. Bone marrow and bone were decalcified with 10% formnic acid/formalin and preserved in 10% neutralized buffered formalin. The testes and epididymides were fixed in modified Davidson's fixative.
Light microscopic examinations were performed for the organs and tissues after embedding in paraffin, sectioning and hematoxylin and eosin (HE) staining. Spleen was stained with Berlin blue in each male and female of the control and 750 mg/kg groups since brown pigments were observed in the spleen stained with HE and hemosiderin deposition was suggested.
Statistics:
Data regarding body weights, food consumption, grip strength and locomotor activity counts during the dosing period and parameters of hematological and blood chemical examinations, urine volume, urine osmotic pressure, organ weights and body weights on the necropsy day of the main groups were analyzed by the Bartlett's test for homogeneity of variances. When the variances were homogeneous at a significance level of 5%, the Dunett's test was used. When the variances were not homogeneous, the nonparametric Dunnett's test was used. The frequencies of defecation and urination during the dosing period were analyzed by the nonparametric Dunnett's test.
Data regarding body weights, food consumption, grip strength and locomotor activity during the recovery period, and parameters of hematological and blood chemical examinations, urine volume, urine osmotic pressure, organ weights and body weights on the necropsy day of the recovery groups were analyzed by the F-test for variance ratio. When there were no significant differences at a significance level of 5% in this analysis, the Student's t-test was used. When there was a significant difference in the F-test, the Aspin-Welch t-test was used. The frequencies of defecation and urination during the recovery period were analyzed by the Mann-Whitney U-test.
Qualitative data of the detailed clinical examination, reflex test and urinalyses, incidence data of the necropsy and histopathology were evaluated with the Fisher's exact test. Graded histopathological data were evaluated by the Mann-Whitney U test.
All evaluation was two-sided and statistical significance were judged at p< 1 or 5% compared to the control group.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
GENERAL CLINICAL OBSERV ATIONS
- During Dosing Period:
In males, salivation was observed in nine of 10 in the 750 mg/kg group from day 10. Slight decreased spontaneous locomotion was observed in nine in the 750 mg/kg group from day 17. Staining around the nose and mouth related to the salivation was observed in six in the 750 mg/kg group from day 14. One animal of the 750 mg/kg group showed decreased respiratory rate and incomplete eyelid opening on day 24. The salivation and decreased spontaneous locomotion were observed from just after dosing to a few minutes after dosing from a few minutes after dosing to afternoon, or at only afternoon without just after dosing. These changes were not observed before dosing on each next day. One animal of the 750 mg/kg group showed loss of hair. No abnormalities were noted in the 30 or 150 mg/kg groups.
In females, salivation was observed in nine of 10 in the 750 mg/kg group from day 13. Slight decreased spontaneous locomotion was observed in six in the 750 mg/kg group from day 16. Staining around the nose and mouth related to the salivation was observed in nine in the 750 mg/kg group from day 18. One animal of the 750 mg/kg group showed incomplete eyelid opening on day 27. The salivation and decreased spontaneous locomotion were observed from just after dosing to a few minutes after dosing, from a few minutes after dosing to afternoon, or at only afternoon without just after dosing. These changes were less frequent than those of males and not observed before dosing on each next day. One animal showed staining around the anus in the 750 mg/kg group on day 11, and another animal showed loss of hair in the same group. No abnormalities were noted in the 30 or 150 mg/kg groups.

- During Recovery Period:
No abnormalities were observed in either sex of the 750 mg/kg group.

DETAILED CLINICAL OBSERVATIONS
- During Dosing Period:
In males, salivation was observed in three of 10 in the 750 mg/kg group in week 4. Abnormal signs were not noted in the 30 or 150 mg/kg groups. In females, urination was increased in the 750 mg/kg group in weeks 1 and 2. Salivation was observed in two of 10 in the 750 mg/kg group in week 4. Staining hair related salivation was observed in one in the 750 mg/kg group in week 4. Continuous vocalization was observed in one in the 750 mg/kg group in week 4, when the animal was taken from her cage. There were no abnormal changes in the 30 or 150 mg/kg groups.
- During Recovery Period:
All animals showed normal signs in both sex of the 750 mg/kg group.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
- During Dosing Period:
In males, body weights were decreased in the 750 mg/kg group from day 8 to 28, and the final body weight of this group was 85% of the control group. No abnormal body weight changes were noted in the 30 or 150 mg/kg groups.
In females, body weights were decreased in the 750 mg/kg group from day 17 to 28, and final body weights were 91 % of the control group. No abnormalities were noted in the 30 or 150 mg/kg groups.
- During Recovery Period:
In males, no statistically significant changes were noted in the 750 mg/kg group.
In females, body weight was decreased in the 750 mg/kg group on day 1 of recovery period (89% of the control group) followed by normal body weight gains.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
- During Dosing Period:
In males, food consumption was significantly decreased on day 3. Trends toward decreases of food consumption were noted in other treatment days. Food consumption of throughout the treatment period was lower than those of the control group. No abnormal changes were noted in the 30 or 150 mg/kg groups.
In females, food consumption was decreased from day 3 to 15. Trends toward decreases of food consumption were noted in other treatment days. Food consumption of throughout the treatment period was lower than control values. No abnormal changes were noted in the 30 or 150 mg/kg groups.
- During Recovery Period:
No statistically significant changes were noted in either sex of the 750 mg/kg group.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
- Main Group:
In males, although WBC was increased (157% of the control group) in the 750 mg/kg group, this change was within the range of the historical control data. APTT was shortened (80% of the control group) in the 750 mg group. No statistically significant changes were noted in the 30 or 150 mg/kg groups.
In females, decreased RBC (92% of the control group), decreased Hb (89% of the control group), decreased Ht (91 % of the control group), decreased MCHC (98% of the control group) and increased reticulocytes (175% of the control group) were noted in the 750 mg/kg group. WBC was increased (268% of the control group) in the 750 mg/kg group. No significant changes were noted in the 30 or 150 mg/kg groups.
- Recovery Group:
In males, reticulocytes were increased (144% of the control group) in the 750 mg/kg group. Although WBC was increased (138% of the control group) in the 750 mg/kg group this change was within the range of the historical control data.
In females, decreased RBC (95% of the control group), decreased MCHC (99% of the control group) and increased reticulocytes (145% of the control group) were noted in the 750 mg/kg group; however, these changes were smaller compared to those at the end of dosing period.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
- Main Group:
In males, total bilirubin was increased (168% of the control group) in the 750 mg/kg group. Decreased BUN (76% of the control group), increased inorganic phosphorus (121% of the control group) and decreased calcium (92% ofthe control group) were noted in the 750 mg/kg group. The decrease of BUN was within the range of the historical data. Decreased AST in the 30 and 150 mg/kg groups and increased sodium in the 30 mg/kg group were noted without dose-relationships.
In females, total bilirubin was increased (186% of the control group) in the 750 mg/kg group. Increased triglyceride (258% of the control group), decreased creatinine (59% of the control group) and increased inorganic phosphorus (126% of the control group) were noted in the 750 mg/kg group. The increase of triglyceride was within the historical control data. Although ALP was decreased in the 150 mg/kg group this change was not dose-related. Abnormal changes were not noted in the 30 mg/kg group.
- Recovery Group:
In males, although total bilirubin was increased (121 % of the control group) in the 750 mg/kg group, this change was within the historical control data, and was smaller compared to those at the end of the dosing period.
In females, potassium was increased (109% of the control group) in the 750 mg/kg group. This change was within the range of the control data.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
- During Dosing Period:
In males, urine volume was increased (165% of the control group) in the 750 mg/kg group. Acidification and decreased crystals were observed in the 750 mg/kg group. No abnormal changes were noted in the 30 or 150 mg/kg groups.
In females, urine volume was increased (247% of the control group) in the 750 mg/kg group. Acidification and decreased crystals were observed in the 750 mg/kg group. No abnormal changes were noted in the 30 or 150 mg/kg groups.
- During Recovery Period:
No statistically significant changes or abnormal signs were noted in the 750 mg/kg group.
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
- During dose period:
In males, no abnormalities were observed in any treatment groups.
In females, locomotor activity counts were increased in the 150 mg/kg group in 30-40 minutes without a dose-relationship. No abnormalities were noted in the 30 or 150 mg/kg groups.
- During recovery period:
In either sex, the examinations were not performed since the test substance related changes were not noted in week 4 of the dosing period.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
- Main Group:
In males, a relative weight of the spleen was increased (143% of the control group) in the 750 mg/kg group. Relative weights of the heart and kidneys were increased in the 30 and 750 mg/kg groups. Decreased absolute weight of the prostate, and increased relative weights of the testes, brain and adrenals were noted in the 750 mg/kg group. No weight changes of the any organs were noted in the 150 mg/kg group.
In females, a relative weight of the spleen was increased (139% of the control group) in the 750 mg/kg group. Decreased absolute and relative weights of the adrenals, and increased relative weights of the liver, heart and kidneys were noted in the 750 mg/kg group. Absolute weight of the brain was increased in the 150 mg/kg group without a dose-relationship. No abnormal organ weights were noted in the 30 mg/kg group.
- Recovery Group:
In males, spleen weights were increased in absolute (120% of the control group) and relative (128% of the control group) weights in the 750 mg/kg group.
In females, no statistically significant changes were noted in the 750 mg/kg group.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
- Main Group:
In males, one animal showed unilateral edematous change of the testis in the control group. No abnormalities were observed in all test substance treatment groups.
In females, no abnormal signs were observed in any treatment groups.
- Recovery Group:
In males, abnormal changes were not noted in the 750 mg/kg group.
In females, blackish region of the mucosa in the glandular stomach and sparsed fur were observed in each one animal of the 750 mg/kg group.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
- Main Group:
In males, hemosiderin deposition in the spleen was observed in all animals of the 750 mg/kg group with a statistically significance. Unilateral diffuse atrophy of the seminiferous tubules of the testis, unilateral decreased spermatozoa and germ cell debris in the lumen of the epididymis, and unilateral osseous metaplasia in the cortex of the adrenal were observed in one animal of the control group. Focal myocardial degeneration and necrosis in the heart in one animal and solitary cyst in the medulla of the kidney in another animal were observed in the 750 mg/kg group. No histopathological changes were noted in the 30 or 150 mg/kg groups.
In females, hemosiderin deposition in the spleen was observed in all animals of the 750 mg/kg group and this change was a statistically significant. Congestion and increased extramedullary hematopoiesis in the spleen were observed in each one animal of the 750 mg/kg group without a statistically significant. No abnormal signs were noted in the 30 or 150 mg/kg groups.
Spleens of males and females were stained with Berlin blue in the control and 750 mg/kg groups. Deposition of the hemosiderin was confirmed in the spleen since positive substance of Berlin blue was increased in the red pulp of the spleen in the 750 mg/kg group compared to the control group.
- Recovery Group:
Hemosiderin deposition was observed in all males and females of the 750 mg/kg group with a statistically significance. No histopathological changes were noted in one female of the 750 mg/kg group, showing blackish region of the mucosa in the glandular stomach and sparsed fur macroscopically.
Other effects:
not specified
Description (incidence and severity):
Estrous Cycle Stage
- Main Group:
In the control group one female out of five was in oestrus, one was in metestrus, and three were in diestrus. In the 30 mg/kg group one female was in proestrus and four were in metestrus. In the 150 mg/kg group two females were in proestrus, one was in estrus, one was in metestrus, and one was in diestrus. In the 750 mg/kg group one female was in proestrus, two were in estrus, one was in metestrus, and one was in diestrus.
- Recovery Group:
In the control group two females were in estrus, one was in metestrus, and two were in dietrus. In the 750 mg/kg group two females were in proestrus, one was in estrus, one was in metestrus, and one was in diestrus.

The test substance did not considered to affect the female reproductive organs, since no abnormal changes were noted in the stage of the estrous cycle, ovary
or uterus.
Key result
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
haematology
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
750 mg/kg bw/day (actual dose received)
System:
haematopoietic
Organ:
spleen
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
No-Observed-Adverse-Effect Level (NOAEL) of test item under the conditions tested was estimated to be 150 mg/kg/day since anemia and decreased body weights were mainly observed in males and females of the 750 mg/kg group.
Executive summary:

A 28-day repeated-dose oral toxicity study of test item was performed to characterize the toxicity of the test substance in accordance with OECD 407. Male and female CrI:CD(SD) rats at 5 weeks old were treated orally with test item dissolved in purified water for 28 days at 0 (purified water), 30, 150 and 750 mg/kg/day.

In the clinical observations, salivation and decreased spontaneous locomotion in males and females, incomplete eyelid opening in one male and one female, and decreased respiratory rate in one male were observed in the 750 mg/kg group.

In the detailed clinical observations, salivation was observed in males and females of the 750 mg/kg group in week 4.

In the 750 mg/kg group, body weights were decreased in males from day 8 to the end of the dosing period, and in females from day 17 of the dosing period to day 3 of the recovery period.

Food consumption in the 750 mg/kg group was significantly decreased in males on day 3 and in females from day 3 to day 15 during the dosing period, and food consumption was slightly decreased in males and females of the 750 mg/kg group throughout the dosing period.

In the hematology, RBC, hemoglobin conc., hematocrit value and MCHC were decreased, and reticulocytes and WBC were increased in females of the 750 mg/kg group.

In the blood chemical examinations, total bilirubin was increased in males and females of the 750 mg/kg group.

In the organ weights, relative weight of the spleen was increased in males and females of the 750 mg/kg group.

In the histopathological examinations, hemogiderin deposition in the spleen was observed in males and females of the 750 mg/kg group. Congestion and increased hematopoiesis in the spleen were observed in one each female of the 750 mg/kg group.

No toxic effect due to test substance administration was observed in the functional observations, urinalyses or necropsy.

At the end of the recovery period, increased reticulocytes and hemogiderin deposition in the spleen in males and females, increased total bilirubin, increased absolute and relative weights of the spleen in males, and decreased RBC and MCHC in females were observed in the 750 mg/kg group. However, the severity of anemia was decreased and reversibility of the effects of the test substance was good.

From these results, the No-Observed-Adverse-Effect Level (NOAEL) of test item under the conditions tested was estimated to be 150 mg/kg/day since anemia and decreased body weights were mainly observed in males and females of the 750 mg/kg group.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
150 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
1 (reliable without restriction)
System:
haematopoietic
Organ:
spleen

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

Justification for classification or non-classification

28d repeated oral: LOAEL: 750 mg/kg/day

Significant effects:

In the hematology, RBC, hemoglobin conc., hematocrit value and MCHC were decreased, and reticulocytes and WBC were increased in females of the 750 mg/kg group.

In the blood chemical examinations, total bilirubin was increased in males and females of the 750 mg/kg group.

In the organ weights, relative weight of the spleen was increased in males and females of the 750 mg/kg group.

In the histopathological examinations, hemogiderin deposition in the spleen was observed in males and females of the 750 mg/kg group. Congestion and increased hematopoiesis in the spleen were observed in one each female of the 750 mg/kg group.

Classification:

The effects observed are considered as not to support classification for specific target organ toxicity following repeated exposure, according to Regulation (EC) No 1272/2008, section 3.9.2.7 and 3.9.2.8. Therefore, this substance should not be classified for this endpoint.