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EC number: 203-187-9 | CAS number: 104-23-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
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:
- 1 981
- Bibliographic source:
- WHO Food additives Series 16- 1981 ,
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 004
- Report date:
- 2004
- Reference Type:
- secondary source
- Title:
- Pharmacology review of Dapsone
- Author:
- Centre for Drug Evaluation and Research
- Year:
- 2 005
- 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
- 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
Constituent 1
- 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.
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