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Diss Factsheets

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental 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 is from authoritative database.

Data source

Reference
Reference Type:
other: authoritative database
Title:
Repeated Dose Toxicity Study of the given test chemical.
Author:
J Check
Year:
2010
Bibliographic source:
J-Check

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:
Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test was conducted by using the given test chemical.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data

Test material

Constituent 1
Chemical structure
Reference substance name:
9,10-Anthracenedione, 1,8-dihydroxy-4-nitro-5-(phenylamino)-
Cas Number:
20241-76-3
Molecular formula:
C20-H12-N2-O6
IUPAC Name:
9,10-Anthracenedione, 1,8-dihydroxy-4-nitro-5-(phenylamino)-
Test material form:
solid: pressed powder
Details on test material:
Details on test material
- Name of test material (as cited in study report): 1,8-Dihydroxy-4-nitro-5-(phenylamino)anthracene-9,10-dione
- Molecular formula (if other than submission substance): C20H12N2O6
- Molecular weight (if other than submission substance): 376.32 g/mol
- Substance type: Organic
- Physical state: Solid: Powder
- Impurities (identity and concentrations): Unknown

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
No Data Available

Administration / exposure

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5% w/v Methylcellulose aqueous solution (suspended)
Details on exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): 0.5 % Methylcellulose solution was used because the test chemical was insoluble in water.
- Concentration in vehicle: 5 mL/kg
Details on mating procedure:
.- M/F ratio per cage: 12 pairs/dose
- Length of cohabitation: Male and female were allowed to live in a male cage one to one.
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The prepared solution was confirmed by UV-visible absorbance method
Duration of treatment / exposure:
Males: 42 Days
Females: 41-45 days(from 14 days before mating to day 4 of lactation)
Frequency of treatment:
Daily
Details on study schedule:
No Data Available
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Remarks:
Control Group
Dose / conc.:
0 mg/kg bw/day
Remarks:
Control Group (Recovery)
Dose / conc.:
40 mg/kg bw/day
Remarks:
Low Dose Group
Dose / conc.:
200 mg/kg bw/day
Remarks:
Mid-Dose Group
Dose / conc.:
1 000 mg/kg bw/day
Remarks:
High Dose Group
Dose / conc.:
1 000 mg/kg bw/day
Remarks:
High Dose (Recovery) Group
No. of animals per sex per dose:
Males: 12 animals/group/sex (5 animals for recovery group)
Females: 12 animals/group/sex (5 animals for recovery group)
Control animals:
yes, concurrent vehicle
Details on study design:
No Data Available
Positive control:
No Data Available

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No Data Available

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: No Data Available

BODY WEIGHT: Yes
- Time schedule for examinations: No Data Available

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes

OTHER: No Data Available
Oestrous cyclicity (parental animals):
Yes, Oestrus cycle was examined.
Sperm parameters (parental animals):
Parameters examined in [P] male parental generations: testis weight, epididymis weight
Litter observations:
Yes, The effect of the test chemical was observed on the litter parameters.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals.
- Maternal animals: All surviving animals

GROSS NECROPSY
- Yes, gross necropsy was performed on all the organs in abdomen, viscera and reproductive organs.

HISTOPATHOLOGY / ORGAN WEIGHTS: Yes, Organs weights and Histopathology was performed.
Postmortem examinations (offspring):
No Data Available
Statistics:
No Data Available
Reproductive indices:
Gestational Index, estrous cycle examination, Copulation Index, Copulation interval, fertility index, gestation period, no of corpora lutea, number of implantations, implantation index, delivery index, nursing behaviour.
Offspring viability indices:
Pup Viability Index

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Test item coloured fecal matter in both male and female animals was observed in both the dose groups.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
No Mortality was observed in all animals in either of the dose groups.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No abnormal effects were observed in body weight changes in males or females due to the test chemical administration.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No abnormal effects were observed in feed consumption patterns in males or females due to the test chemical administration.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
No abnormal effects were observed in hematological parameters in males or females due to the test chemical administration.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Significant decrease in Albumin content, Total Protein, and significant increase in α2-Globulin (%) in males of 1000 mg/kg bw was observed. No effects in females were observed. However, these effects were considered to be toxicolgically insignificant since, therse effects were observed to be reversed in the recovery group.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Abnormal coloration in the urine was observed in males and females at 200 mg/kg bw and 1000 mg/kg bw dose groups. This coloration was attributed to the test chemical or a metabolite of the test chemical.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No effect of the test chemical was observed on the grip strength, locomotor activity and other functional observation battery parameters in either sex at all the dose groups.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No histopathological abnormalities were observed in any animals of either sex and at all the dose levels, including the high dose recovery groups.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No effects on the estrous cyclicity due to the test chemical was observed at any dose groups.
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
Description (incidence and severity):
No effects on the reproductive performance due to the test chemical was observed at any dose groups.

Details on results (P0)

Based on all the data of observations and results, the test chemical was not considered as toxic to reproductive parameters.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
reproductive function (oestrous cycle)
reproductive performance
Remarks on result:
other: No effects observed

Target system / organ toxicity (P0)

Critical effects observed:
not specified
System:
other: Not Specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
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:
no effects observed
Anogenital distance (AGD):
not specified
Nipple retention in male pups:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
No effects were observed on number of pups delivered, number of live pups, live birth index, viability index and sex ratio on day 0 and day 4 at any dose groups.

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Details on results (F1)

Based on the observation and results of the test chemical, no effects were observed on the developmental parameters of the pups at any dose levels.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
sexual maturation
clinical signs
mortality
body weight and weight gain
gross pathology
histopathology: non-neoplastic
other: number of pups delivered, number of live pups, live birth index, viability index and sex ratio on day 0 and day 4
Remarks on result:
other: No effects observed

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: Not Specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified

Applicant's summary and conclusion

Conclusions:
Based on all the observations and results it was concluded that the NOAEL for the test chemical was considered to be 1000 mg/kg bw.
Executive summary:

In a combined repeated and reproductive toxicity studies according to OECD 422 guideline, the test chemical was administered to Crl:CD (SD) male and female rats, aged 10 weeks old at the initiation of dosing. The rats were dosed at concentrations of 0, 40, 200, 1000 mg/kg/day with two revesal groups of 0 and 1000 mg/kg bw/day as control and high dose group recovery group, respectively. The vehicle used in the study was 0.5% w/v Methylcellulose aqueous suspended solution. Male animals were dosed for 42 Days, while females were dosed for 41-45 days.

After the administration of the test chemical, test item coloured fecal matter in both male and female animals was observed in both the dose groups. However, no mortality was observed in all animals in either of the dose groups. No abnormal effects were observed in body weight changes and feed consumption in males or females due to the test chemical administration. In hematological parameters, no abnormal effects were observed in hematological parameters in males or females due to the test chemical administration. In blood chemistry parameters, significant decrease in Albumin content, Total Protein, and significant increase in α2-Globulin (%) in males of 1000 mg/kg bw was observed. No effects in females were observed. However, these effects were considered to be toxicolgically insignificant since, therse effects were observed to be reversed in the recovery group. Also, abnormal coloration in the urine was observed in males and females at 200 mg/kg bw and 1000 mg/kg bw dose groups. This coloration was attributed to the test chemical or a metabolite of the test chemical. No effect of the test chemical was observed on the grip strength, locomotor activity and other functional observation battery parameters in either sex at all the dose groups. No adverse effects were observed on any abdominal, visceral or reproductive organs / 100 grams of body weight due to the test chemical in either of the sex at any dose groups. In gross necropsy, colored aqueous content in the alimentary tract was observed in males, and in males and females both 40 mg/kg bw dose group and 200 mg/kg bw dose group, respectively. Also, mucosal discoloration of alimentary tract in males of 200 mg/kg bw was also observed. Colored aqueous content in the alimentary tract and  mucosal discoloration of alimentary tract in both males and females were observed in 1000 mg/kg bw dose group. However, these effects were reversed in the recovery group doses and thus were not considered to be of toxicological significance. No histopathological abnormalities were observed in any animals of either sex and at all the dose levels, including the high dose recovery groups. No effects on the estrous cyclicity due to the test chemical was observed at any dose groups. No effects on the reproductive performance due to the test chemical was observed at any dose groups. No effects were observed on number of pups delivered, number of live pups, live birth index, viability index and sex ratio on day 0 and day 4 at any dose groups. Also, no test chemical changes were noted in the number of pups delivered, number of live pups, live birth index,viability index or sex ratio on day 0 and 4, clinical signs, body weights, external examinations, body weights or necropsy. Thus, based on all the observations and results it was concluded that the NOAEL for the test chemical was considered to be 1000 mg/kg bw.