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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
reproductive toxicity, other
Remarks:
organ toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data from secondary source

Data source

Reference
Reference Type:
secondary source
Title:
Twenty-eight-day Repeat Dose Oral Toxicity Test of test material in Rats
Author:
J-check
Year:
2010
Bibliographic source:
Japanese Ministry of Health; Labour and Welfare,2010

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Twenty-eight-day Repeat Dose Oral Toxicity study of test material was performed in Rats
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- IUPAC Name: Disperse Red 206
- Smiles: CCN(CCO)c1ccc(N=NC2=N{+}(C)(.O{-}C(C)=O)c3ccc(OC)cc3S2)cc1
- Molecular formula : C21H26N4O4S
- Substance type: Organic
- Physical state: reddish brown odorless powder
- Purity: 97.65%

Test animals

Species:
rat
Strain:
other: Crj: CD (SD)IGS
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals and environmental conditions:
Details on test animals and env. conditions
TEST ANIMALS
- Source: Charles River Co., Ltd. Atsugi Breeding Center Co., Ltd.
- Age at study initiation: 5 weeks of age
- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g
- Fasting period before study:
- Housing: The animals were placed in a bracket-type metallic wire mesh floor cage
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet (e.g. ad libitum): gamma-irradiated solid feed CRF-1 (Oriental Yeast Co., Ltd.) ad libitum
- Water (e.g. ad libitum): drinking water was freely ingested by Sapporo city tap water
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 to 24 ° C
- Humidity (%):45 to 68%
- Air changes (per hr): 10 to 15 times / hour
- Photoperiod (hrs dark / hrs light): an illumination time of 8 to 20 hours

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% methyl cellulose aqueous solution
Details on exposure:
Details on exposure
PREPARATION OF DOSING SOLUTIONS:
The test substance was suspended using a 0.5% methyl cellulose aqueous solution.
DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food)
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil
- Concentration in vehicle: 0, 250, 500, and 1000 mg / kg
- Amount of vehicle (if gavage): 5 mL / kg

- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Details on study schedule:
No data available
Doses / concentrations
Remarks:
0, 250, 500, and 1000 mg / kg
No. of animals per sex per dose:
Total: 42 male and 42 female
0 mg / kg:7 male and 7 female
250 mg / kg:7 male and 7 female
500 mg / kg:7 male and 7 female
1000 mg / kg:7 male and 7 female
Recovery group
0 mg / kg:7 male and 7 female
1000 mg / kg:7 male and 7 female

Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available

Examinations

Parental animals: Observations and examinations:
Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule: daily


BODY WEIGHT: Yes
Time schedule for examinations: Body weight of individual animals were measured on days 1, 7, and 14 before administration on days 1, 2, 7, 14, 21 and 28, and on the autopsy day of each day after the end of each period
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):Yes food intake of individual animals were measured on days 1, 7, and 14 before administration on days 1, 2, 7, 14, 21 and 28, and on the autopsy day of each day after the end of each period,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 / No / No data: No data available


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
Time schedule for examinations:

OTHER:
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
Parameters examined in [all/P/F1/F2] male parental generations:
testis weight and epididymis weight were observed
Litter observations:
No data available
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals
- Maternal animals: All surviving animals

GROSS NECROPSY:yes
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGHTS: yes
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.
Postmortem examinations (offspring):
No data available
Statistics:
Quantitative items of urinalysis (excluding urine specific gravity), hematological test (excluding percentage of leukocytes), blood chemistry test, results of absolute and relative weight of organs, body weight, weight gain and rate of increase, We analyzed equi dispersibility by Bartlett's test method, and analyzed by one-way analysis of variance in the case of equal variance and by Kruskal-Wallis's test in case of unequal variance. If a significant difference is found as a result of one-way ANOVA, Dunnett's test method is used, and if there is a significant difference as a result of analysis by the Kruskal-Wallis method, Mann-Whitney's U- , And compared with the control group, respectively.
For the qualitative items of urinalysis, the results of urine specific gravity and white blood cell percentage, the tendency of each group is analyzed by the Kruskal-Wallis test method, and when a significant difference is
observed, the Mann-Whitney U-test method is used And compared with controls. For each percentage of
leukocytes, average values and standard deviations were also calculated. Regarding the comparative test with the control group, statistically significant less than the risk ratio of 5% was taken.
Reproductive indices:
No data available
Offspring viability indices:
No data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
No abnormality was observed in both sexes in each administration group in either administration period or recovery period.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Only the males in the 250 mg / kg administration group showed significant increase in body weight gain and body weight gain during 28 days of administration, but not a dose-dependent change.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Only the males in the 250 mg / kg administration group showed a significant increase compared with the control group on the 28th administration but not the dose-dependent change.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
A significant lower value was found in males of the group receiving 250 mg / kg or more in the γ-globulin fraction ratio as compared with the control group, and at the end of the recovery period, females with a dose of 1000 mg / kg showed significant High level was recognized.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There was no significant change in each treatment group of males and females as compared with the control group in either the administration period or the recovery period.
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Only mild changes such as kidney, liver, pituitary gland and the like were observed in one males and two females in the 1000 mg / kg administration group. Even at the end of the recovery period, only mild changes were observed in the lungs, liver, kidneys, etc. of 3 males in the 1000 mg / kg administration group
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified

Details on results (P0)

No effects on reproductive organ weight was observed

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
Remarks on result:
other: No effects on reproductive organ weight was observed

Target system / organ toxicity (P0)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
other: not specified
Generation:
other: not specified
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
not measured/tested

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
No Observed Adverse Effect Level (NOAEL) was considered to be 500mg/kg/day, Whenmale and female Crj:CD(SD)IGS rats were treated with test material orally.
Executive summary:

 The reproductive organ toxicity study of test material was performed using twenty-eight-day Repeat Dose Oral Toxicity study of test material in Crj: CD (SD)IGS male and female rats. The test material was suspended using a 0.5% methyl cellulose aqueous solutionand administeried in dose concentration 0, 250, 500, and 1000 mg / kg orally for 28 days. Each dose group and recovery group contain 7 male and 7 female. Doses were selected on preliminary study in which male and female SD rats were administered 0, 250, 500 and 1000 mg / kg for 14 days, Body weight and food intake of individual animals were measured on days 1, 7, and 14 before administration on days 1, 2, 7, 14, 21 and 28, and on the autopsy day of each day after the end of each period, All the cases were autopsied on day 28 of administration or the next day after recovery 14 days.

No abnormality was observed in both sexes in each administration group in either administration period or recovery period. Only the males in the 250 mg / kg administration group showed significant increase in body weight gain and body weight gain during 28 days of administration, but not a dose-dependent change. Only the males in the 250 mg / kg administration group showed a significant increase in food intake compared with the control group on the 28th administration but not the dose-dependent change. There was no significant change in Urinalysis each treatment group of males and females as compared with the control group in either the administration period or the recovery period. Male of 250 mg / kg or higher administration group and female of 500 mg / kg or more administration group were reddish purple jejunum ileum contents, dark greening of contents of cecum in males and females of 250 mg/ kg or more administered group , Pale reddening of jejunum ileum and intraabdominal fat tissue were observed. These changes showed an increase in the number of cases as the dose increased and it was judged that the change in color tone itself had no toxicological significance.

Significant higher values of absolute and relative weights of liver in male of 250 mg / kg or more in comparison with control group, significant lower value of absolute and relative weight of thymus in males and females of 500 mg / kg administered group Significantly high values of relative weight of liver, high value trend of absolute weight, significant low value of ovarian relative weight, low value trend of absolute weight were observed in females at low trend, 1000 mg / kg administration group, recovery At the end of the period, a significant high value of the absolute weight of the liver, a high value tendency of the relative weight, a low tendency of the absolute weight of the spleen, and a significant low value of the relative weight were observed in the male of 1000 mg / kg administration group. Besides, a significant high value of the absolute weight of the adrenal glands was seen in the males of the 250 mg / kg administration group, but it was not a dose-dependent change, and at the end of the recovery period female of 1000 mg / kg administration group received pituitary Significant lower values of absolute and relative weights were observed, but not changed at the end of the administration. Only mild changes such as kidney, liver, pituitary gland and the like were observed in one males and two females in the 1000 mg / kg administration group. Even at the end of the recovery period, only mild changes were observed in the lungs, liver, kidneys, etc. of 3 males in the 1000 mg / kg administration group. As no effects on reproductive organ weight was observed at 500mg/kg dose group hence,No Observed Adverse Effect Level (NOAEL) was considered to be 500mg/kg/day, Whenmale and femaleCrj:CD(SD)IGS rats were treated with test material orally.