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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Weight of evidence based on the studies of different test chemical.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
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 a handbook or collection of data.
Qualifier:
according to guideline
Guideline:
other: as mentioned below
Principles of method if other than guideline:
The above experiment was performed to evaluate and assess the effect of the test chemical on the developmental parameters of SPF-derived Wistar rats.
GLP compliance:
no
Specific details on test material used for the study:
Molecular Weight: 867.6873 g/mol
Substance Type: Organic
Physical state: Solid
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
No Data Available
Route of administration:
oral: unspecified
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Details on exposure:
No Data Available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data available
Details on mating procedure:
No data available
Duration of treatment / exposure:
For first and second study : from day 0-19 of pregnancy
Frequency of treatment:
Exact frequency was not menton
Duration of test:
From F1 to F3 generation
Remarks:
0, 0.1, 1.0 or 3% (0, 50, 500,1500 mg/kg bw per day)
No. of animals per sex per dose:
First study:15 animals
Second study: 30 animals
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Maternal examinations:
Body weight of the maternal animals was examined.
Ovaries and uterine content:
The number of corpora lutea in each ovary was recorded and the foetuses examined.
Fetal examinations:
Live foetuses, embryonic and foetal resorptions and dead foetuses were counted and the number and position of implantation sites were recorded.
Statistics:
No data available
Indices:
No data available
Historical control data:
No data available
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality:
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
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
No Data Available
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:no effects
Details on maternal toxic effects:
At autopsy, no signs of embryo-toxicity or teratogenicity were observed.
Dose descriptor:
NOAEL
Effect level:
1 500 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Remarks on result:
other: behaviour of the dam, embryo-toxicity
Abnormalities:
not specified
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
No abnormalities in condition or behaviour of the dams were observed in either study
Dose descriptor:
NOAEL
Effect level:
1 500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
Remarks on result:
other: Not Specified
Abnormalities:
not specified
Developmental effects observed:
not specified
Treatment related:
not specified
Conclusions:
From all the observations and results it was concluded that, the NOAEL for the test chemical was found to be 2500 mg/kg bw for SPF-derived Wistar rats.
Executive summary:

Developmental studies were performed on SPF-derived Wistar female rats. Study was conducted in two stages as the preliminary study four groups of 15 pregnant rats was administered by gavage from day 0-19 of pregnancy. In second study, 30 pregnant rats were used with same protocol. On 21 days the animals were killed and ovaries and uterus removed. The number of corpora lutea in each ovary was recorded and the foetuses examined. Live foetuses, embryonic and foetal resorptions and dead foetuses were counted and the number and position of implantation sites were recorded. In the second study, half the foetuses in the control and top dose groups were examined for skeletal malformations and half for visceral defects. No abnormalities in condition or behaviour of the dams were observed in either study. At autopsy, no signs of embryo-toxicity or teratogenicity were observed. Thus, based on all the observations and results it was concluded that, the NOAEL for the test chemical was found to be 2500 mg/kg bw for SPF-derived Wistar rats.

Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
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 a NTP report.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
The above experiment was performed to evaluate and assess the effect of the test chemical on the developmental parameters of the test animals.
GLP compliance:
not specified
Limit test:
yes
Specific details on test material used for the study:
- Molecular weight (if other than submission substance): 248.30 g/mol
- Substance type: Organic
- Physical state: Powder
- Purity: > 99%
Species:
mouse
Strain:
Swiss
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Sex: Female
- Housing: solid-bottom polycarbonate cages with stainless steel wire lids and certified hardwood cage litter
- Diet (e.g. ad libitum): NIH-07 Certified Mouse/Rat Diet, ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 67-77°F
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12:12 light:dark cycle
Route of administration:
oral: gavage
Vehicle:
other: 0.5% aqueous methylcellulose
Details on exposure:
Total daily dose volume was 20 ml/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
analytical verification done by HPLC
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: Overnight
- Proof of pregnancy: The morning on which a copulation plug was found in the vagina was designated as gd 0.
Duration of treatment / exposure:
10 days (Gestation day 6 to 15)
Frequency of treatment:
Twice daily
Duration of test:
17 days
Remarks:
Doses / Concentrations:
0, 50, 100 or 200 mg/kg/day
Basis:
nominal conc.
No. of animals per sex per dose:
20-21 mated females per group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose selection was based on previous studies in which CD-1 mice were treated by gavage with dapsone from gd 6 through 15
Maternal examinations:
Body weight (g) was recorded on the mornings of gd 0, 6-15, and 17, and immediately following sacrifice on gd 17.
Females were observed for clinical condition at least once/day on gd 0 to 5 (prior to dosing). From gd 6 through 15, females were observed for clinical condition twice daily at dosing. On gd 17, females were observed for clinical condition at weighing and at scheduled termination.
Feed consumption was monitored during the study, with measurements on the mornings of gd 0, 6, 9, 12, 15 and 17.
The body, and uterus of each timed-mated female were weighed. Thoracic and abdominal cavities were examined.
Ovaries and uterine content:
Ovarian corpora lutea were counted. Pregnancy status was confirmed by uterine examination. Uterine contents were examined to determine the number of implantation sites, resorptions, dead fetuses, and live fetuses.
Fetal examinations:
Dead fetuses were counted, weighed, and discarded. All live fetuses were counted, weighed, sexed (external), and examined for external morphological abnormalities, including cleft palate.
Statistics:
No Data Available
Indices:
Resorption Index, Fetal Viability Index, Implantation Index
Historical control data:
No Data Available
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
10% of the maternal mortality was observed after the administration of the test chemical.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Maternal body weight change were each reduced at the highest dose of the test chemical (200 mg/kg/day).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
There was a tendency for the test chemical consuming groups to consume more feed than the controls. Maternal feed consumption was usually at or above controls for subsequent measurement periods.
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
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Gravid uterine weight were each reduced at the highest dose of the test chemical (200 mg/kg/day).
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At scheduled necropsy (gd 17), gross findings included enlarged spleens in 1, 12, 13 or 17 dams in the control through high dose groups, respectively.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
not specified
Pre- and post-implantation loss:
effects observed, treatment-related
Total litter losses by resorption:
effects observed, treatment-related
Description (incidence and severity):
Indices of prenatal mortality appeared to be elevated at the highest dose of the test chemical.
Early or late resorptions:
effects observed, treatment-related
Description (incidence and severity):
Indices of prenatal mortality appeared to be elevated at the highest dose of the test chemical.
Dead fetuses:
effects observed, treatment-related
Description (incidence and severity):
Indices of prenatal mortality appeared to be elevated at the highest dose of the test chemical.
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
not specified
Other effects:
not specified
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Maternal mortality (10%) was noted at the high dose, but otherwise clinical observations were unremarkable.
At scheduled necropsy (gd 17), gross findings included enlarged spleens in 1, 12, 13 or 17 dams in the control through high dose groups, respectively. Maternal body weight, weight change, and gravid uterine weight were each reduced at the highest dose of dapsone
Dose descriptor:
LOAEL
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
early or late resorptions
food consumption and compound intake
gross pathology
mortality
organ weights and organ / body weight ratios
pre and post implantation loss
total litter losses by resorption
Abnormalities:
not specified
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Fetal body weights (male, female or both) were significantly reduced by 25% at the highest dose of the test chemical.
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
Indices of prenatal mortality appeared to be elevated at the highest dose of the test chemical (e.g., 16% resorbed implantation sites vs. 2% for controls).
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
effects observed, non-treatment-related
Skeletal malformations:
effects observed, non-treatment-related
Visceral malformations:
effects observed, non-treatment-related
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Indices of prenatal mortality appeared to be elevated at the highest dose of dapsone (e.g., 16% resorbed implantation sites vs. 2% for controls).
Fetal body weights (male, female or both) were significantly reduced by 25% at the highest dose of dapsone. Altered incidences of fetal morphological anomalies (malformations or variations) were noted, but patterns of effects varied across replicates.
Dose descriptor:
LOAEL
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
fetal/pup body weight changes
external malformations
skeletal malformations
visceral malformations
Abnormalities:
not specified
Developmental effects observed:
not specified
Treatment related:
not specified
Conclusions:
Based on all the observations and results, it was concluded that the NOAEL value for the test chemical was found to be 100 mg/kg/day for parental as well as F1 generation.
Executive summary:

The above experiment was performed to evaluate and assess the effect of the test chemical on the developmental parameters of the test animals. Timed-mated Swiss albino (CD-1®) mice were dosed by gavage with the test chemical 0, 50, 100 or 200 mg/kg/day. on gestational days (gd) 6 through 15. The vehicle was 0.5% aqueous methylcellulose. Total daily doses were administered in two divided doses (morning and afternoon), each with a volume of 10 ml/kg body weight. The oral route corresponds to one of the commonly used routes in human patients. Timed-mated mice (20-21 per group) were monitored at regular intervals for clinical signs of toxicity, feed consumption, and body weight. At necropsy (17), the following observations were made: clinical condition; maternal body, and gravid uterine weights; pregnancy status; and number of corpora lutea. In the gravid uterus, the numbers of prenatal deaths (resorptions and/or dead fetuses) and live fetuses were recorded. Live fetuses were weighed, sexed, and examined for morphological anomalies (external, visceral, and skeletal). For the test chemical, maternal mortality (10%) was noted at the high dose, but otherwise clinical observations were unremarkable. At scheduled necropsy (17), gross findings included enlarged spleens in 1, 12, 13 or 17 dams in the control through high dose groups, respectively. Maternal body weight, weight change, and gravid uterine weight were each reduced at the highest dose of the test chemical (200 mg/kg/day). Maternal feed consumption was usually at or above controls for subsequent measurement periods. Indices of prenatal mortality appeared to be elevated at the highest dose of the test chemical (e.g., 16% resorbed implantation sites vs. 2% for controls). Fetal body weights (male, female or both) were significantly reduced by 25% at the highest dose of the test chemical. Thus, based on all the observations and results, it was concluded that the NOAEL value for the test chemical was found to be 100 mg/kg/day for parental as well as F1 generation.

Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data is from a secondary literature source.
Qualifier:
no guideline available
Principles of method if other than guideline:
The above experiment was performed to evaluate and assess the effect of the test chemical on the developmental parameters of the test animals.
GLP compliance:
not specified
Specific details on test material used for the study:
- Molecular weight (if other than submission substance): 248.30 g/mol
- Substance type: Organic
- Physical state: Powder
- Impurities (identity and concentrations): Not available
Species:
rat
Strain:
other: Crl:CD(SD)IGS BR VAF/Plus
Details on test animals or test system and environmental conditions:
Sex: female
No other details available
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5 %
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: 0.5% carboxymethyl cellulose in purified deionised water was used as the vehicle.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No Data Available
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: Virgin females were paired with males
- Proof of pregnancy: Day on which mating was confirmed by presence of vaginal plug or sperm in vaginal smear was referred to as day 0 of pregnancy
Duration of treatment / exposure:
15 days prior to pairing upto day 17 of gestation
Frequency of treatment:
Daily
Duration of test:
Upto day 21 of pregnancy
Remarks:
Doses / Concentrations:
0, 12, 30 and 75 mg/kg/day
Basis:
nominal conc.
No. of animals per sex per dose:
25 females per group
Control animals:
yes, concurrent vehicle
Details on study design:
No Data Available
Maternal examinations:
Maternal survival and body weight
Ovaries and uterine content:
Number of live, dead and resorbed fetuses were determined
Fetal examinations:
Live fetuses were weighed and examined for external, visceral and skeletal abnormalities.
Statistics:
No Data Available
Indices:
Resorption Index, Fetal Viability Index.
Historical control data:
No Data Available
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Increased licking, sniffing, chewing and salivation in animals were observed at 75 mg/kg/day.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Significantly reduced body weight gain at 30 mg/kg/day and above during treatment period. Increased at 30 mg/kg/day and above on days 18-21 (after stopping of treatment).
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Slightly reduced at 30 mg/kg/day and above during treatment period. Increased at 30 mg/kg/day and above on days 18-21 (after stopping of treatment).
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
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
effects observed, treatment-related
Description (incidence and severity):
Number. of early resorptions were significantly increased at 75 mg/kg/day.
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
not specified
Other effects:
not specified
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Mortality: None
Clinical signs: Increased licking, sniffing, chewing and salivation at 75 mg/kg/day.
Body weight: significantly reduced body weight gain at 30 mg/kg/day and above during treatment period. Increased at 30 mg/kg/day and above on days 18-21 (after stopping of treatment)
Food consumption: slightly reduced at 30 mg/kg/day and above during treatment period. Increased at 30 mg/kg/day and above on days 18-21 (after stopping of treatment)
No effects on latency to mate or fertility index
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
early or late resorptions
food consumption and compound intake
mortality
pre and post implantation loss
total litter losses by resorption
other: not specified
Remarks on result:
other: not specified
Abnormalities:
not specified
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
Number of live fetuses were slightly reduced at 30 mg/kg/day; significantly reduced at 75 mg/kg/day.
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
not specified
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Mean implantations: reduced at 75 mg/kg/day
Body weight of live fetuses: no remarkable observations
No. of live fetuses at C-section: Slightly reduced at 30 mg/kg/day; significantly reduced at 75 mg/kg/day
No. of early resorptions: significantly increased at 75 mg/kg/day only
Dose descriptor:
NOAEL
Effect level:
12 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: fetotoxicity
Remarks on result:
other: not specified
Abnormalities:
not specified
Localisation:
other: not specified
Description (incidence and severity):
not specified
Developmental effects observed:
not specified
Treatment related:
not specified
Conclusions:
The NOAEL value of the test chemical for the F1 generation was 12 mg/kg/day based on the reduction in number of implantations, increase in early resorption rate and reduction in mean litter size.
Executive summary:

The above experiment was performed to evaluate and assess the effect of the test chemical on the developmental parameters of the test animals. 25 females per group were selected in this study. The animals were dosed with the test chemical in concentration of 0, 12, 30 and 75 mg/kg/day. The maternal animals were dosed from 15 days prior to pairing upto day 17 of gestation. The maternal animals were observed for Maternal survival and body weight and Number of live, dead and resorbed fetuses were also determined. Live fetuses were weighed and examined for external, visceral and skeletal abnormalities. It was observed that no mortality was present in any of the maternal animals at any dose groups. However, increased licking, sniffing, chewing and salivation in animals were observed at 75 mg/kg/day. Significantly reduced body weight gain at 30 mg/kg/day and above during treatment period. Increased at 30 mg/kg/day and above on days 18-21 (after stopping of treatment). Slightly reduced at 30 mg/kg/day and above during treatment period. Increased at 30 mg/kg/day and above on days 18-21 (after stopping of treatment). Also, no effects on latency to mate or fertility index was observed at any dose group. Number of early resorptions were significantly increased at 75 mg/kg/day. In fetal parameters, no remarkable effects were observed on fetal body weights. Although, number of live fetuses were slightly reduced at 30 mg/kg/day; significantly reduced at 75 mg/kg/day. Thus, based on all the observations and results, it was concluded that the NOAEL value of the test chemical for the F1 generation was 12 mg/kg/day based on the reduction in number of implantations, increase in early resorption rate and reduction in mean litter size.

Data source

Referenceopen allclose all

Reference Type:
secondary source
Title:
Special study on teratogenicity
Author:
WHO Food additives
Year:
1981
Bibliographic source:
WHO Food additives Series 16- 1981 ,
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report date:
2004
Reference Type:
secondary source
Title:
Pharmacology review of Dapsone
Author:
Centre for Drug Evaluation and Research
Year:
2005
Bibliographic source:
Centre for Drug Evaluation and Research, Application No.: 21-794, May 2005

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
The above experiments were performed to evaluate and assess the effects of the test chemical on the developmental parameters of the test animals.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
4'-aminoazobenzene-4-sulphonic acid
EC Number:
203-187-9
EC Name:
4'-aminoazobenzene-4-sulphonic acid
Cas Number:
104-23-4
Molecular formula:
C12H11N3O3S
IUPAC Name:
4'-aminoazobenzene-4-sulphonic acid
Test material form:
not specified
Details on test material:
Details on test material
- Name of test material (as cited in study report): 4-(4-Aminophenylazo)benzenesulfonic acid
- Molecular formula (if other than submission substance): C12-H11-N3-O3-S
- Molecular weight (if other than submission substance): 277.303 g/mol
- Substance type: Organic
- Physical state: No Data Available
- Impurities (identity and concentrations): No Data Available
Specific details on test material used for the study:
Details on test material:
- Molecular weight (if other than submission substance): 277.303 g/mol
- Substance type: Organic
- Physical state: No Data Available
- Impurities (identity and concentrations): No Data Available

Test animals

Species:
other: Study 2: Rat; Study 3: Mice Study 4: Rat
Strain:
other: Study 2: Wistar; Study 3: Swiss; Study 4: Crl:CD(SD)IGS BR VAF/Plus
Details on test animals or test system and environmental conditions:
Study 2: No Data Available

Study 3: TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Sex: Female
- Housing: solid-bottom polycarbonate cages with stainless steel wire lids and certified hardwood cage litter
- Diet (e.g. ad libitum): NIH-07 Certified Mouse/Rat Diet, ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum
- Acclimation period: 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 67-77°F
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12:12 light:dark cycle

Study 4: Sex: female
No other details available

Administration / exposure

Route of administration:
other: Study 2: oral: unspecified; Study 3 and 4 : oral:gavage
Vehicle:
other: Study 2: Unspecified; Study 3: 0.5% aqueous methylcellulose; Study 4: CMC (carboxymethyl cellulose)
Details on exposure:
Study 2: No Data Available

Study 3: Total daily dose volume was 20 ml/kg

Study 4: PREPARATION OF DOSING SOLUTIONS: 0.5% carboxymethyl cellulose in purified deionised water was used as the vehicle.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Study 2: No Data Available

Study 3: Analytical verification done by HPLC

Study 4: No Data Available
Details on mating procedure:
Study 2: No Data Available

Study 3: - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: Overnight
- Proof of pregnancy: The morning on which a copulation plug was found in the vagina was designated as gd 0.

Study 4: - Impregnation procedure: cohoused
- If cohoused: Virgin females were paired with males
- Proof of pregnancy: Day on which mating was confirmed by presence of vaginal plug or sperm in vaginal smear was referred to as day 0 of pregnancy
Duration of treatment / exposure:
Study 2: For first and second study : from day 0-19 of pregnancy

Study 3: 10 days (Gestation day 6 to 15)

Study 4: 15 days prior to pairing upto day 17 of gestation
Frequency of treatment:
Study 2: Exact frequency was not mentioned

Study 3: Twice daily

Study 4: Daily
Duration of test:
Study 2: From F1 to F3 generation

Study 3: 17 days

Study 4: Upto day 21 of pregnancy
Doses / concentrations
Remarks:
Study 2: 0, 0.1, 1.0 or 3% (0, 50, 500,1500 mg/kg bw per day)

Study 3: 0, 50, 100 or 200 mg/kg/day

Study 4: 0, 12, 30 and 75 mg/kg/day
No. of animals per sex per dose:
Study 2: First study:15 animals
Second study: 30 animals

Study 3: 20-21 mated females per group

Study 4: 25 females per group
Control animals:
yes, concurrent vehicle
Details on study design:
Study 2: No Data Available

Study 3: - Dose selection rationale: Dose selection was based on previous studies in which CD-1 mice were treated by gavage with dapsone from gd 6 through 15

Study 4: No Data Available

Examinations

Maternal examinations:
Study 2: Body weight of the maternal animals was examined.

Study 3: Body weight (g) was recorded on the mornings of gd 0, 6-15, and 17, and immediately following sacrifice on gd 17.
Females were observed for clinical condition at least once/day on gd 0 to 5 (prior to dosing). From gd 6 through 15, females were observed for clinical condition twice daily at dosing. On gd 17, females were observed for clinical condition at weighing and at scheduled termination.
Feed consumption was monitored during the study, with measurements on the mornings of gd 0, 6, 9, 12, 15 and 17.
The body, and uterus of each timed-mated female were weighed. Thoracic and abdominal cavities were examined.

Study 4: Maternal survival and body weight
Ovaries and uterine content:
Study 2: The number of corpora lutea in each ovary was recorded and the foetuses examined.

Study 3: Ovarian corpora lutea were counted. Pregnancy status was confirmed by uterine examination. Uterine contents were examined to determine the number of implantation sites, resorptions, dead fetuses, and live fetuses.

Study 4: Number of live, dead and resorbed fetuses were determined
Fetal examinations:
Study 2: Live foetuses, embryonic and foetal resorptions and dead foetuses were counted and the number and position of implantation sites were recorded.

Study 3: Dead fetuses were counted, weighed, and discarded. All live fetuses were counted, weighed, sexed (external), and examined for external morphological abnormalities, including cleft palate.

Study 4: Live fetuses were weighed and examined for external, visceral and skeletal abnormalities.
Statistics:
Study 2: No data available

Study 3: No Data Available

Study 4: No Data Available
Indices:
Study 2: No data available

Study 3: Resorption Index, Fetal Viability Index, Implantation Index

Study 4: Resorption Index, Fetal Viability Index.
Historical control data:
No Data Available

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
Study 2: No Data Available

Study 3: no effects observed

Study 4: Increased licking, sniffing, chewing and salivation in animals were observed at 75 mg/kg/day.
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
Study 2: No Data Available

Study 3: 10% of the maternal mortality was observed after the administration of the test chemical.

Study 4: no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Study 2: No data available

Study 3: Maternal body weight change were each reduced at the highest dose of the test chemical (200 mg/kg/day).

Study 4: Significantly reduced body weight gain at 30 mg/kg/day and above during treatment period. Increased at 30 mg/kg/day and above on days 18-21 (after stopping of treatment).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Study 2: No data available

Study 3: There was a tendency for the test chemical consuming groups to consume more feed than the controls. Maternal feed consumption was usually at or above controls for subsequent measurement periods.

Study 4: Slightly reduced at 30 mg/kg/day and above during treatment period. Increased at 30 mg/kg/day and above on days 18-21 (after stopping of treatment).
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Description (incidence and severity):
Study 2: No data available
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
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
Description (incidence and severity):
Study 2: No data available
Study 3: Gravid uterine weight were each reduced at the highest dose of the test chemical (200 mg/kg/day).
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Study 2: No data available
Study 3: At scheduled necropsy (gd 17), gross findings included enlarged spleens in 1, 12, 13 or 17 dams in the control through high dose groups, respectively.
Neuropathological findings:
not specified
Description (incidence and severity):
Study 2: No data available
Study 3: No data available
Study 4: No data available
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
Study 2: No effects observed
Study 3: Not Specified
Study 4: Not Specified
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Study 2: No effects observed
Study 3: Implantation losses were observed in the highest dose group.
Study 4: no effects observed
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
Study 2: No effects observed
Study 4: no effects observed
Early or late resorptions:
no effects observed
Description (incidence and severity):
Study 2: No effects observed
Study 3: Indices of prenatal mortality appeared to be elevated at the highest dose of the test chemical.
Study 4: Number. of early resorptions were significantly increased at 75 mg/kg/day.
Dead fetuses:
no effects observed
Description (incidence and severity):
Study 2: No effects observed
Study 3: Indices of prenatal mortality appeared to be elevated at the highest dose of the test chemical.
Study 4: Not Specified
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Study 2: No effects observed
Study 3: Indices of prenatal mortality appeared to be elevated at the highest dose of the test chemical.
Study 4: Not Specified
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Study 2: No effects observed
Study 4: Not Specified
Other effects:
no effects observed
Description (incidence and severity):
Study 2: No effects observed
Study 3: Not Specified
Study 4: Not Specified
Details on maternal toxic effects:
Study 2: Maternal toxic effects:no effects
Details on maternal toxic effects:
At autopsy, no signs of embryo-toxicity or teratogenicity were observed.

Study 3: Maternal toxic effects:yes
Details on maternal toxic effects:
Maternal mortality (10%) was noted at the high dose, but otherwise clinical observations were unremarkable.
At scheduled necropsy (gd 17), gross findings included enlarged spleens in 1, 12, 13 or 17 dams in the control through high dose groups,
respectively. Maternal body weight, weight change, and gravid uterine weight were each reduced at the highest dose of the test chemical.

Study 4: Maternal toxic effects:yes

Details on maternal toxic effects:
Mortality: None
Clinical signs: Increased licking, sniffing, chewing and salivation at 75 mg/kg/day.
Body weight: significantly reduced body weight gain at 30 mg/kg/day and above during treatment period. Increased at 30 mg/kg/day and above on days 18-21 (after stopping of treatment)
Food consumption: slightly reduced at 30 mg/kg/day and above during treatment period. Increased at 30 mg/kg/day and above on days 18-21 (after stopping of treatment)
No effects on latency to mate or fertility index

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
1 500 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: Developmental Toxicity
Remarks on result:
other: Not Specified

Maternal abnormalities

Abnormalities:
not specified

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Study 2: No effects observed
Study 3: Fetal body weights (male, female or both) were significantly reduced by 25% at the highest dose of the test chemical.
Study 4: no effects observed
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Study 2: No effects observed
Study 3: Indices of prenatal mortality appeared to be elevated at the highest dose of the test chemical (e.g., 16% resorbed implantation sites vs. 2% for controls).
Study 4: Number of live fetuses were slightly reduced at 30 mg/kg/day; significantly reduced at 75 mg/kg/day.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Study 2: No effects observed
Study 3: Not Specified
Study 4: Not Specified
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Study 2: No effects observed
Study 3: Not Specified
Study 4: Not Specified
Changes in postnatal survival:
no effects observed
Description (incidence and severity):
Study 2: No effects observed
Study 3: Not Specified
Study 4: Not Specified
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Study 2: Not Specified
Study 3: Unremarkable effects on the dosing of the test chemical were observed.
Study 4: Not Specified
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Study 2: Not Specified
Study 3: Unremarkable effects on the dosing of the test chemical were observed.
Study 4: Not Specified
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Study 2: Not Specified
Study 3: Unremarkable effects on the dosing of the test chemical were observed.
Study 4: Not Specified
Other effects:
not specified
Description (incidence and severity):
Study 2: Not Specified
Study 4: Not Specified
Details on embryotoxic / teratogenic effects:
Study 2: Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
No abnormalities in condition or behaviour of the dams were observed in either study

Study 3: Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Indices of prenatal mortality appeared to be elevated at the highest dose of dapsone (e.g., 16% resorbed implantation sites vs. 2% for controls).
Fetal body weights (male, female or both) were significantly reduced by 25% at the highest dose of dapsone. Altered incidences of fetal morphological anomalies (malformations or variations) were noted, but patterns of effects varied across replicates.

Study 4: Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Mean implantations: reduced at 75 mg/kg/day
Body weight of live fetuses: no remarkable observations
No. of live fetuses at C-section: Slightly reduced at 30 mg/kg/day; significantly reduced at 75 mg/kg/day
No. of early resorptions: significantly increased at 75 mg/kg/day only

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
Remarks on result:
other: Not Specified

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified
Treatment related:
not specified

Applicant's summary and conclusion

Conclusions:
Study 2: From all the observations and results it was concluded that, the NOAEL for the test chemical was found to be 2500 mg/kg bw for SPF-derived Wistar rats.

Study 3: Based on all the observations and results, it was concluded that the NOAEL value for the test chemical was found to be 100 mg/kg/day for parental as well as F1 generation.

Study 4: The NOAEL value of the test chemical for the F1 generation was 12 mg/kg/day based on the reduction in number of implantations, increase in early resorption rate and reduction in mean litter size.
Executive summary:

Developmental Toxicity Study:

The data from the developmental toxicity studies are as follows:

Developmental Toxicity Study 2:

Developmental studies were performed on SPF-derived Wistar female rats. Study was conducted in two stages as the preliminary study four groups of 15 pregnant rats was administered by gavage from day 0-19 of pregnancy. In second study, 30 pregnant rats were used with same protocol. On 21 days the animals were killed and ovaries and uterus removed. The number of corpora lutea in each ovary was recorded and the foetuses examined. Live foetuses, embryonic and foetal resorptions and dead foetuses were counted and the number and position of implantation sites were recorded. In the second study, half the foetuses in the control and top dose groups were examined for skeletal malformations and half for visceral defects. No abnormalities in condition or behaviour of the dams were observed in either study. At autopsy, no signs of embryo-toxicity or teratogenicity were observed. Thus, based on all the observations and results it was concluded that, the NOAEL for the test chemical was found to be 2500 mg/kg bw for SPF-derived Wistar rats.

Developmental Toxicity Study 3:

The above experiment was performed to evaluate and assess the effect of the test chemical on the developmental parameters of the test animals. Timed-mated Swiss albino (CD-1®) mice were dosed by gavage with the test chemical 0, 50, 100 or 200 mg/kg/day. on gestational days (gd) 6 through 15. The vehicle was 0.5% aqueous methylcellulose. Total daily doses were administered in two divided doses (morning and afternoon), each with a volume of 10 ml/kg body weight. The oral route corresponds to one of the commonly used routes in human patients. Timed-mated mice (20-21 per group) were monitored at regular intervals for clinical signs of toxicity, feed consumption, and body weight. At necropsy (17), the following observations were made: clinical condition; maternal body, and gravid uterine weights; pregnancy status; and number of corpora lutea. In the gravid uterus, the numbers of prenatal deaths (resorptions and/or dead fetuses) and live fetuses were recorded. Live fetuses were weighed, sexed, and examined for morphological anomalies (external, visceral, and skeletal). For the test chemical, maternal mortality (10%) was noted at the high dose, but otherwise clinical observations were unremarkable. At scheduled necropsy (17), gross findings included enlarged spleens in 1, 12, 13 or 17 dams in the control through high dose groups, respectively. Maternal body weight, weight change, and gravid uterine weight were each reduced at the highest dose of the test chemical (200 mg/kg/day). Maternal feed consumption was usually at or above controls for subsequent measurement periods. Indices of prenatal mortality appeared to be elevated at the highest dose of the test chemical (e.g., 16% resorbed implantation sites vs. 2% for controls). Fetal body weights (male, female or both) were significantly reduced by 25% at the highest dose of the test chemical. Thus, based on all the observations and results, it was concluded that the NOAEL value for the test chemical was found to be 100 mg/kg/day for parental as well as F1 generation.

Developmental Toxicity Study 4:

The above experiment was performed to evaluate and assess the effect of the test chemical on the developmental parameters of the test animals. 25 females per group were selected in this study. The animals were dosed with the test chemical in concentration of 0, 12, 30 and 75 mg/kg/day. The maternal animals were dosed from 15 days prior to pairing upto day 17 of gestation. The maternal animals were observed for Maternal survival and body weight and Number of live, dead and resorbed fetuses were also determined. Live fetuses were weighed and examined for external, visceral and skeletal abnormalities. It was observed that no mortality was present in any of the maternal animals at any dose groups. However, increased licking, sniffing, chewing and salivation in animals were observed at 75 mg/kg/day. Significantly reduced body weight gain at 30 mg/kg/day and above during treatment period. Increased at 30 mg/kg/day and above on days 18-21 (after stopping of treatment). Slightly reduced at 30 mg/kg/day and above during treatment period. Increased at 30 mg/kg/day and above on days 18-21 (after stopping of treatment). Also, no effects on latency to mate or fertility index was observed at any dose group. Number of early resorptions were significantly increased at 75 mg/kg/day. In fetal parameters, no remarkable effects were observed on fetal body weights. Although, number of live fetuses were slightly reduced at 30 mg/kg/day; significantly reduced at 75 mg/kg/day. Thus, based on all the observations and results, it was concluded that the NOAEL value of the test chemical for the F1 generation was 12 mg/kg/day based on the reduction in number of implantations, increase in early resorption rate and reduction in mean litter size.