Registration Dossier
Registration Dossier
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EC number: 203-187-9 | CAS number: 104-23-4
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / 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 data of the test chemical.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Study period:
- Subchronic Study
- 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 publication.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- The above experiment was performed to evaluate the effect of the test chemical on the reproductive parameters of the swiss albino mice.
- GLP compliance:
- not specified
- Justification for study design:
- No Data Available
- Specific details on test material used for the study:
- - Molecular weight (if other than submission substance): 534.3681 g/mol
- Substance type: Organic
- Physical state: NO Data
- Impurities (identity and concentrations): No Data - Species:
- mouse
- Strain:
- other: Swiss Albino
- Details on species / strain selection:
- No Data Available
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Details on test animals and env. conditions
TEST ANIMALS
- Source: No Data Available
- Age at study initiation: (P) 4 weeks old
- Weight at study initiation: (P) 20±2.01 g
- Fasting period before study: No Data Available
- Housing: No Data
- Use of restrainers for preventing ingestion (if dermal): No
- Diet (e.g. ad libitum): Standard food pellets diet was given ad libitum
- Water (e.g. ad libitum): Water was provided ad libitum.
- Acclimation period: No Data Available
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No Data Available
- Humidity (%):No Data Available
- Air changes (per hr): No Data Available
- Photoperiod (hrs dark / hrs light): No Data Available - Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The first group was given drinking water as a control, the second the drinking water containing 0.1% test chemical, the third the drinking water containing 1% test chemical and the fourth the drinking water containing 2.5% test chemical each for 13 weeks.
DIET PREPARATION
- Rate of preparation of diet (frequency): No Data Available
- Mixing appropriate amounts with (Type of food): No Data Available
- Storage temperature of food: No Data Available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Water was used as the vehicle
- Concentration in vehicle: Concentration of 0.1% (50 mg/kg bw), 1% (500 mg/kg bw) and 2.5% (1250 mg/kg bw) of test chemical for low, mid and high dose groups respectively.
- Amount of vehicle (if gavage): No data Available
- Lot/batch no. (if required): No Data Available
- Purity: No Data Available - Details on mating procedure:
- Details of mating
- M/F ratio per cage: Six males per dose group, were mated 1:1 with untreated females for 1 week.
- Length of cohabitation: 1 week
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: No Data Available
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.: No Data Available
- Further matings after two unsuccessful attempts: [no / yes (explain)] No Data Available
- After successful mating each pregnant female was caged (how): Individually
- Any other deviations from standard protocol: No Data Available - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No Data Available
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- No Data Available
- Details on study schedule:
- No Data Available
- Remarks:
- 0.1% (50 mg/kg bw), 1% (500 mg/kg bw) and 2.5% (1250 mg/kg bw) of test chemical for low, mid and high dose groups respectively.
- No. of animals per sex per dose:
- 6 males per dose group.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- No Data Available
- Positive control:
- No Data Available
- Parental animals: Observations and examinations:
- Food and water consumption, body weights, Reproductive performance, Gross necropsy and histopathology were examined.
- Oestrous cyclicity (parental animals):
- No Data Available
- Sperm parameters (parental animals):
- Evaluation of sperm motility and morphology and Assessment of sperm production was examined.
- Litter observations:
- Litter size and weight after 7, 14 and 28 days of growth were examined.
- Postmortem examinations (parental animals):
- After mating, male mice were killed by cervical dislocation. Testes, epididymides were weighed immediately. The left epididymis was excised and placed in a Petri dish containing saline solution (NaCl 0.9%). The tail region tissue was minced with scalpels. Histologic examination of testis was performed. The left testis was fixed in formalin-buffer.
- Postmortem examinations (offspring):
- No Data Available
- Statistics:
- The data is expressed as mean ± SE. Statistical test one way ANOVA was applied to find significant difference between values of various
parameters recorded for control and treated animals. p<0.05 was considered statistically significant. - Reproductive indices:
- Implantation Index, Litter Index, Male Mating Index
- Offspring viability indices:
- No Data Available
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Body weight gain was significantly increased in 1% test chemical. This increased body weight gain is not evidence related dose.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food consumption values were significantly decreased at all experimental groups compared to control. However, liquid consumption was increased at all experimental groups.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- Liquid consumption was increased at all experimental groups.
- 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, non-treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Semniferous tubules were not identical with conjunctive tissue dystrophy in animals testes treated with 0.1% test chemical. Intercellular connections were reduced and imperfect and dilation in some semniferous tubules of testis mice treated 1% test chemical. Significant damage was observed in testis mice treated with 2.5% test chemical extensive disruption in semniferous tubules, widening of the interstitial spaces and loss leydig cells. Spermatogenic cells are affected and then depleted with absence of spermatozoa in the lumen.
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- effects observed, treatment-related
- Description (incidence and severity):
- Total number of spermatids count was reduced significantly in the mice administered 2.5% test chemical. Sperm concentration in epididymides was reduced in all treated groups but sperm epididymis reserves were reduced significantly only in mice treated with 2.5% test chemical. The percentage motility was reduced in 1 and 2.5% treated groups.
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Male mating index was decreased in the 2.5% treated groups compared to the control values.
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- water consumption and compound intake
- organ weights and organ / body weight ratios
- gross pathology
- histopathology: non-neoplastic
- reproductive function (sperm measures)
- reproductive performance
- Remarks on result:
- other: Not Specified
- Critical effects observed:
- not specified
- System:
- other: Not Specified
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- not specified
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Histopathological findings:
- not specified
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 2: Weight and litter sizes were, however, decreased in comparison to litters sired from control males.
- Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 50 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Litter weights and sizes
- Remarks on result:
- other: Not Specified
- Critical effects observed:
- not specified
- System:
- other: Not Specified
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- Based on all the above observations and results, it was observed that the NOAEL for the test chemical was found to be 50 mg/kg bw.
- Executive summary:
A sub chronic experiment was performed to evaluate the effect of the test chemical on the reproductive parameters of the Swiss albino mice. The test chemical was administered to adult male mice in drinking water at doses of 0, 0.1, 1 and 2.5% for 13 weeks. After that period, the weights of testes, epididymides and seminal vesicles were determined. Sperm counts in the testis and epididymides, motility, morphology and testis histology were assessed. It was observed that body weight gain was significantly increased in 1% test chemical. This increased body weight gain is not evidence related dose. Food consumption values were significantly decreased at all experimental groups compared to control. However, liquid consumption was increased at all experimental groups. Liquid consumption was increased at all experimental groups. A decrease of relative testis and seminal vesicles weight were observed in all treated groups compared to control but not statistically significant. However, their absolute weight did not change. Seminiferous tubules were not identical with conjunctive tissue dystrophy in animals testes treated with 0.1% test chemical. Intercellular connections were reduced and imperfect and dilation in some seminiferous tubules of testis mice treated 1% test chemical. Significant damage was observed in testis mice treated with 2.5% test chemical extensive disruption in seminiferous tubules, widening of the interstitial spaces and loss leydig cells. Total number of spermatids count was reduced significantly in the mice administered 2.5% test chemical. Sperm concentration in epididymides was reduced in all treated groups but sperm epididymis reserves were reduced significantly only in mice treated with 2.5% test chemical. The percentage motility was reduced in 1 and 2.5% treated groups. Male mating index was decreased in the 2.5% treated groups compared to the control values. Weight and litter sizes were, however, decreased in comparison to litters sired from control males. Thus, based on all the above observations and results, it was observed that the NOAEL for the test chemical was found to be 50 mg/kg bw.
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- fertility, other
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- 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 publication.
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- The above study was performed to evaluate the effects of the test compound on the fertility and fecundity of male rats. Its effects on the viability of epididymal spermatozoa and their penetration into the epididymis were also studied.
- 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 - Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- No Data Available
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Laboratory Animal Unit of the University of Hong Kong
- Weight at study initiation: Male rats: 300 g
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20±1°C
- Humidity (%): 60-80% - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Test chemical was freshly suspended in corn oil
- Details on mating procedure:
- - M/F ratio per cage: 1:2
- Length of cohabitation: The second rat was introduced only after mating with the first female was confirmed
- Proof of pregnancy: Successful mating was verified on the second day by the presence of a dislodged copulatory plug, or, if absent, the presence of spermatozoa in the vaginal smear
- After successful mating each pregnant female was caged (how): The day on which mating occurred was designated Day 1 of pregnancy and the female rats were separated from the males once mating had been confirmed - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No Data Available
- Duration of treatment / exposure:
- 6 weeks
- Frequency of treatment:
- Daily
- Details on study schedule:
- The substance was administered via gastric intubation into a group of 7 male rats weighing about 300 g at the start of the treatment.
- Remarks:
- Doses / Concentrations:
0 or 50 mg/kg/day
Basis:
nominal conc. - No. of animals per sex per dose:
- Control: 6 males
50 mg/kg/day: 7 males - Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dosage used was 10 times the human dose.
- Positive control:
- No Data Available
- Parental animals: Observations and examinations:
- Body weights, Mating procedure, percentage of pregnant females in each group, mean live embryo number per pregnant female, mean resorbed embryo number per pregnancy, mean number of corpora lutea of pregnancy, mean embryo crown-rump length were assessed.
- Oestrous cyclicity (parental animals):
- No Data Available
- Sperm parameters (parental animals):
- Sperm motility assessment and Determination of sperm concentration in the epididymis was conducted
- Litter observations:
- No Data available
- Postmortem examinations (parental animals):
- On Day 21 of gestation, the females were killed to determine the following values:
(1) percentage of pregnant females in each group,
(2) mean live embryo number per pregnant female,
(3) mean resorbed embryo number per pregnancy,
(4) mean number of corpora lutea of pregnancy, and
(5) mean embryo crown-rump length. - Postmortem examinations (offspring):
- No Data Available
- Statistics:
- Differences between treated and control groups were compared by using an analysis of variance. All data are presented as mean ± s.e.m.
- Reproductive indices:
- The fecundity of each test group was represented by the 'Fecundity Index' which was calculated by: mean embryo number/mean corpus luteum number Day 21 embryo length % pregnant females.
- Offspring viability indices:
- No Data Available
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- 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:
- no effects observed
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- effects observed, treatment-related
- Description (incidence and severity):
- The capacity to initiate forward motility of the cauda epididymal spermatozoa was reduced by 30%.
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- Reduced the fecundity of male rats by significantly reducing the embryo number over corpus luteum number per pregnant female. Dapsone reduced fecundity by more than 50% compared with normal rats
- Dose descriptor:
- LOAEL
- Effect level:
- 50 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: Reduced the fecundity of male rats to 38.3% of control.
- Remarks on result:
- other: not specified
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- not specified
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Histopathological findings:
- not specified
- Other effects:
- not specified
- Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- Remarks on result:
- not measured/tested
- Remarks:
- Not Specified.
- Critical effects observed:
- no
- System:
- other: Not Specified
- Remarks on result:
- not measured/tested
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- Based on all the observation and results, it was concluded that the LOAEL value of the test chemical, for effects on male fertility was observed to be 50 mg/kg/day based on the reduction of the fecundity of male rats.
- Executive summary:
The study was performed to evaluate the effects of the test compound on the fertility and fecundity of male rats. Its effects on the viability of epididymal spermatozoa and their penetration into the epididymis were also studied. The test animals Sprague-Dawley rats were obtained from the Laboratory Animal Unit of the University of Hong Kong. They were reared and maintained under SPF conditions at an ambient temperature of 20+/- 1°C and a relative humidity of 60-80%. The test chemical was freshly suspended in corn oil and was fed via gastric intubation into a group of 6-12 male rats weighing about 300g at the start of the treatment. The dosage used was 10 times the human dose and treatment was for 6 weeks. Each trial also contained a group of 6-12 control rats to which corn oil only was fed. The body weight of each rat was taken before each feeding. In the study, body weights, Mating procedure, percentage of pregnant females in each group, mean live embryo number per pregnant female, mean resorbed embryo number per pregnancy, mean number of corpora lutea of pregnancy, mean embryo crown-rump length were assessed. Sperm motility assessment and Determination of sperm concentration in the epididymis was conducted. The fecundity of each test group was represented by the 'Fecundity Index' which was calculated by: mean embryo number/mean corpus luteum number Day 21 embryo length % pregnant females. The test chemical reduced the fecundity of male rats by significantly reducing the embryo number over corpus luteum number per pregnant female. The numbers of female rats impregnated by the males treated with the test chemical. The capacity to initiate forward motility of the caudal epididymal
spermatozoa were reduced by the test chemical by 30%. No effects on the body weights of the test animals were observed due to the treatment with the test chemicals. Thus, based on all the observation and results, it was concluded that the LOAEL value of the test chemical, for effects on male fertility was observed to be 50 mg/kg/day based on the reduction of the fecundity of male rats.
- Reason / purpose for cross-reference:
- read-across source
Reference
- Endpoint:
- fertility, other
- Remarks:
- based on test type (migrated information)
- 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 based on a secondary source literature.
- Qualifier:
- no guideline available
- Principles of method if other than guideline:
- The above experiment was performed to evaluate and assess the effects of the test chemical on the fertility and general reproduction toxicity of male rats.
- GLP compliance:
- not specified
- Justification for study design:
- No Data Available
- 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 species / strain selection:
- No Data Available
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- No details available
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 0.5%
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Dapsone was dissolved in 0.5% aq. CMC solution
- Details on mating procedure:
- Only males were treated. Untreated females were used to confirm male reproductive potential.
- Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No Data Available
- Duration of treatment / exposure:
- Approx. 100 consecutive days
- Frequency of treatment:
- Daily
- Details on study schedule:
- F0 male rats were dosed with test material begining 63 days prior to cohabitation with untreated females and continuing through the day prior to sacrifice (doses administered for approx. 100 days).
- Remarks:
- Doses / Concentrations:
0, 0.25, 0.5, 1 or 2 mg/kg/day
Basis:
nominal conc. - No. of animals per sex per dose:
- 40 males per group were treated. 20 males per group were sacrificed following the last dose, 10 males per group were sacrificed following a 4 week recovery period and 10 males per group were sacrificed following a 10 week recovery period
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Satellite groups: No, but 2 recovery groups were used.
- Positive control:
- No Data Available
- Parental animals: Observations and examinations:
- F0 male rats observed for viability and clinical signs twice daily. Body weight was recorded daily during the dosing period, then weekly for recovery animals. F0 females were monitored for body weight and clinical signs on gestation days 0, 7, 10 and 13.
- Oestrous cyclicity (parental animals):
- No Data Available
- Sperm parameters (parental animals):
- Sperm concentration and motility were evaluated.
- Litter observations:
- No Data Available
- Postmortem examinations (parental animals):
- All F0 females were sacrificed on gestational day 13, cesarean-sectioned, gross necropsied and the number of corpora lutea , implantation sites, and viable and non-viable embryos were recorded. Following complettion of cohabitation, F1 males were subjected to gross necropsy, the reproductive organs (each testis, each epididymis, seminal vesicle and prostrate) were weighed, and sperm concentration and motility were evaluated.
- Postmortem examinations (offspring):
- No Data Available
- Statistics:
- No Data Available
- Reproductive indices:
- Fertility index (no. of rats pregnant/ No. of rats mated) was noted
- Offspring viability indices:
- No Data Available
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- 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:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- no effects observed
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 2 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: No effect on fertility of male rats
- Remarks on result:
- other: not specified
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- not specified
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Histopathological findings:
- not specified
- Other effects:
- not specified
- Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- Remarks on result:
- not measured/tested
- Critical effects observed:
- not specified
- System:
- other: not specified
- Remarks on result:
- not measured/tested
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
- Conclusions:
- The NOAEL value of the test chemical for this study was found to be 2 mg/kg/day as no effect on fertility of male rats was observed at this dose level.
- Executive summary:
The above experiment was performed to evaluate and assess the effects of the test chemical on the fertility and general reproduction toxicity of male rats. In this study, male rats were treated for 63 days prior cohabitation with untreated females. The animals were treated with doses of 0, 0.25, 0.5, 1 or 2 mg/kg/day. Only males were treated. Untreated females were used to confirm male reproductive potential. No significant differences in fertility parameters and sperm parameters of F0 males were observed at any of the doses. No significant differences in the number of implantations and viable embryos in the females that did become pregnant were observed. The NOAEL value of the test chemical for this study was found to be 2 mg/kg/day as no effect on fertility of male rats was observed at the exposure levels examined in this study.
Data source
Referenceopen allclose all
- Reference Type:
- publication
- Title:
- Reproductive Toxicology of the test chemical in Swiss Albino Mice
- Author:
- Mehedi et.al
- Year:
- 2 009
- Bibliographic source:
- American Journal of Pharmacology and Toxicology 4 ( 4): 130-135, 2009
- Reference Type:
- publication
- Title:
- Antifertility effects of some sulphonamides and related compounds and their accumulation in the epididymides of male rats
- Author:
- P. Y. D. Wong, S. K. D. Lau and W. O. Fu
- Year:
- 1 987
- Bibliographic source:
- Journal of Reproduction and Fertility. Volume(issue)/page/year: 81,259,1987
- 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 Page 56-57
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Principles of method if other than guideline:
- The above experiments were performed to evaluate and assess the effects of the test chemicals on the reproductive parameters of the test animals.
- GLP compliance:
- not specified
- Justification for study design:
- No Data Available
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: mouse; Study 3: Rat; Study 4: rat
- Strain:
- other: Study 2: Swiss Albino; Study 3: Sprague-Dawley; Study 4: Crl:CD(SD)IGS BR VAF/Plus
- Details on species / strain selection:
- No Data Available
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Study 2: Details on test animals and env. conditions
TEST ANIMALS
- Source: No Data Available
- Age at study initiation: (P) 4 weeks old
- Weight at study initiation: (P) 20±2.01 g
- Fasting period before study: No Data Available
- Housing: No Data
- Use of restrainers for preventing ingestion (if dermal): No
- Diet (e.g. ad libitum): Standard food pellets diet was given ad libitum
- Water (e.g. ad libitum): Water was provided ad libitum.
- Acclimation period: No Data Available
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No Data Available
- Humidity (%):No Data Available
- Air changes (per hr): No Data Available
- Photoperiod (hrs dark / hrs light): No Data Available
Study 3: TEST ANIMALS
- Source: Laboratory Animal Unit of the University of Hong Kong
- Weight at study initiation: Male rats: 300 g
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20±1°C
- Humidity (%): 60-80%
Study 4: No details available
Administration / exposure
- Route of administration:
- other: Study 2: oral: drinking water; Study 3 and 4: oral: gavage
- Vehicle:
- other: Study 2: water; Study 3: corn oil; Study 4: 0.5% CMC (carboxymethyl cellulose)
- Details on exposure:
- Study 2: PREPARATION OF DOSING SOLUTIONS: The first group was given drinking water as a control, the second the drinking water containing 0.1% test chemical, the third the drinking water containing 1% test chemical and the fourth the drinking water containing 2.5% test chemical each for 13 weeks.
DIET PREPARATION
- Rate of preparation of diet (frequency): No Data Available
- Mixing appropriate amounts with (Type of food): No Data Available
- Storage temperature of food: No Data Available
VEHICLE
- Justification for use and choice of vehicle (if other than water): Water was used as the vehicle
- Concentration in vehicle: Concentration of 0.1% (50 mg/kg bw), 1% (500 mg/kg bw) and 2.5% (1250 mg/kg bw) of test chemical for low, mid and high dose groups respectively.
- Amount of vehicle (if gavage): No data Available
- Lot/batch no. (if required): No Data Available
- Purity: No Data Available
Study 3: PREPARATION OF DOSING SOLUTIONS: Test chemical was freshly suspended in corn oil
Study 4: PREPARATION OF DOSING SOLUTIONS: Dapsone was dissolved in 0.5% aq. CMC solution - Details on mating procedure:
- Study 2: Details of mating
- M/F ratio per cage: Six males per dose group, were mated 1:1 with untreated females for 1 week.
- Length of cohabitation: 1 week
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: No Data Available
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.: No Data Available
- Further matings after two unsuccessful attempts: [no / yes (explain)] No Data Available
- After successful mating each pregnant female was caged (how): Individually
- Any other deviations from standard protocol: No Data Available
Study 4: Only males were treated. Untreated females were used to confirm male reproductive potential. - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- Study 2, 3 and 4: No Data Available
- Duration of treatment / exposure:
- Study 2: 13 weeks
Study 3: 6 weeks
Study 4: Approx. 100 consecutive days - Frequency of treatment:
- Study 2: No Data Available
Study 3: Daily
Study 4: Daily - Details on study schedule:
- Study 2: No Data Available
Study 3: The substance was administered via gastric intubation into a group of 7 male rats weighing about 300 g at the start of the treatment.
Study 4: F0 male rats were dosed with test material begining 63 days prior to cohabitation with untreated females and continuing through the day prior to sacrifice (doses administered for approx. 100 days).
Doses / concentrations
- Remarks:
- Study 2: 0.1% (50 mg/kg bw), 1% (500 mg/kg bw) and 2.5% (1250 mg/kg bw) of test chemical for low, mid and high dose groups respectively.
Study 3: 0 or 50 mg/kg/day
Study 4: 0, 0.25, 0.5, 1 or 2 mg/kg/day
- No. of animals per sex per dose:
- Study 2: 6 males per dose group.
Study 3: Control: 6 males
50 mg/kg/day: 7 males
Study 4: 40 males per group were treated. 20 males per group were sacrificed following the last dose, 10 males per group were sacrificed following a 4 week recovery period and 10 males per group were sacrificed following a 10 week recovery period - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Study 2: No Data Available
Study 3: - Dose selection rationale: The dosage used was 10 times the human dose.
Study 4: Satellite groups: No, but 2 recovery groups were used. - Positive control:
- Study 2, 3 and 4: No Data Available
Examinations
- Parental animals: Observations and examinations:
- Study 2: Food and water consumption, body weights, Reproductive performance, Gross necropsy and histopathology were examined.
Study 3: Body weights, Mating procedure, percentage of pregnant females in each group, mean live embryo number per pregnant female, mean resorbed embryo number per pregnancy, mean number of corpora lutea of pregnancy, mean embryo crown-rump length were assessed.
Study 4: F0 male rats observed for viability and clinical signs twice daily. Body weight was recorded daily during the dosing period, then weekly for recovery animals. F0 females were monitored for body weight and clinical signs on gestation days 0, 7, 10 and 13. - Oestrous cyclicity (parental animals):
- Study 2: No Data Available
Study 3: No Data Available
Study 4: No Data Available - Sperm parameters (parental animals):
- Study 2: Evaluation of sperm motility and morphology and Assessment of sperm production was examined.
Study 3: Sperm motility assessment and Determination of sperm concentration in the epididymis was conducted.
Study 4: Sperm concentration and motility were evaluated. - Litter observations:
- Study 2: Litter size and weight after 7, 14 and 28 days of growth were examined.
Study 3: No Data available
Study 4: No Data Available - Postmortem examinations (parental animals):
- Study 2: After mating, male mice were killed by cervical dislocation. Testes, epididymides were weighed immediately. The left epididymis was excised and placed in a Petri dish containing saline solution (NaCl 0.9%). The tail region tissue was minced with scalpels. Histologic examination of testis was performed. The left testis was fixed in formalin-buffer.
Study 3: On Day 21 of gestation, the females were killed to determine the following values:
(1) percentage of pregnant females in each group,
(2) mean live embryo number per pregnant female,
(3) mean resorbed embryo number per pregnancy,
(4) mean number of corpora lutea of pregnancy, and
(5) mean embryo crown-rump length.
Study 4: All F0 females were sacrificed on gestational day 13, cesarean-sectioned, gross necropsied and the number of corpora lutea , implantation sites, and viable and non-viable embryos were recorded. Following complettion of cohabitation, F1 males were subjected to gross necropsy, the reproductive organs (each testis, each epididymis, seminal vesicle and prostrate) were weighed, and sperm concentration and motility were evaluated. - Postmortem examinations (offspring):
- Study 2: No Data Available
Study 3: No Data Available
Study 4: No Data Available - Statistics:
- Study 2: The data is expressed as mean ± SE. Statistical test one way ANOVA was applied to find significant difference between values of various parameters recorded for control and treated animals. p<0.05 was considered statistically significant.
Study 3: Differences between treated and control groups were compared by using an analysis of variance. All data are presented as mean ± s.e.m.
Study 4: No Data Available - Reproductive indices:
- Study 2: Implantation Index, Litter Index, Male Mating Index
Study 3: The fecundity of each test group was represented by the 'Fecundity Index' which was calculated by: mean embryo number/mean corpus luteum number Day 21 embryo length % pregnant females.
Study 4: Fertility index (no. of rats pregnant/ No. of rats mated) was noted - Offspring viability indices:
- Study 2: No Data Available
Study 3: No Data Available
Study 4: No Data Available
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Study 3 and 4: no effects observed
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- not specified
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Study 2: Body weight gain was significantly increased in 1% test chemical. This increased body weight gain is not evidence related dose.
Study 3: no effects observed
Study 4: no effects observed - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Study 2: Food consumption values were significantly decreased at all experimental groups compared to control. However, liquid consumption was increased at all experimental groups.
Study 3: no effects observed.
Study 4: no effects observed - Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- Study 2: Liquid consumption was increased at all experimental groups.
- 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, non-treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 2: Semniferous tubules were not identical with conjunctive tissue dystrophy in animals testes treated with 0.1% test chemical. Intercellular connections were reduced and imperfect and dilation in some semniferous tubules of testis mice treated 1% test chemical. Significant damage was observed in testis mice treated with 2.5% test chemical extensive disruption in semniferous tubules, widening of the interstitial spaces and loss leydig cells. Spermatogenic cells are affected and then depleted with absence of spermatozoa in the lumen.
Study 4: no effects observed - Histopathological findings: neoplastic:
- not specified
- Other effects:
- no effects observed
- Description (incidence and severity):
- Study 4: no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 2: Total number of spermatids count was reduced significantly in the mice administered 2.5% test chemical. Sperm concentration in epididymides was reduced in all treated groups but sperm epididymis reserves were reduced significantly only in mice treated with 2.5% test chemical. The percentage motility was reduced in 1 and 2.5% treated groups.
Study 3: The capacity to initiate forward motility of the cauda epididymal spermatozoa was reduced by 30%.
Study 4: no effects observed - Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 2: Male mating index was decreased in the 2.5% treated groups compared to the control values.
Study 3: Reduced the fecundity of male rats by significantly reducing the embryo number over corpus luteum number per pregnant female. Dapsone reduced fecundity by more than 50% compared with normal rats.
Study 4: no effects observed
Details on results (P0)
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- water consumption and compound intake
- organ weights and organ / body weight ratios
- gross pathology
- histopathology: non-neoplastic
- reproductive function (sperm measures)
- reproductive performance
- Remarks on result:
- other: Not Specified
Target system / organ toxicity (P0)
- Critical effects observed:
- not specified
- System:
- other: Not Specified
Results: F1 generation
General toxicity (F1)
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Study 2: Study 2: Weight and litter sizes were, however, decreased in comparison to litters sired from control males.
Details on results (F1)
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 50 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Weight and litter sizes were, however, decreased in comparison to litters sired from control males.
- Remarks on result:
- other: Not Specified
Target system / organ toxicity (F1)
- Critical effects observed:
- not specified
- System:
- other: Not Specified
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Study 2: Based on all the above observations and results, it was observed that the NOAEL for the test chemical was found to be 50 mg/kg bw.
Study 3: Based on all the observation and results, it was concluded that the LOAEL value of the test chemical, for effects on male fertility was observed to be 50 mg/kg/day based on the reduction of the fecundity of male rats.
Study 4: The NOAEL value of the test chemical for this study was found to be 2 mg/kg/day as no effect on fertility of male rats was observed at this dose level. - Executive summary:
Reproductive Toxicity Study:
The data from the reproductive toxicity studies are as follows:
Reproductive Toxicity Study 2:
A sub chronic experiment was performed to evaluate the effect of the test chemical on the reproductive parameters of the Swiss albino mice. The test chemical was administered to adult male mice in drinking water at doses of 0, 0.1, 1 and 2.5% for 13 weeks. After that period, the weights of testes, epididymides and seminal vesicles were determined. Sperm counts in the testis and epididymides, motility, morphology and testis histology were assessed. It was observed that body weight gain was significantly increased in 1% test chemical. This increased body weight gain is not evidence related dose. Food consumption values were significantly decreased at all experimental groups compared to control. However, liquid consumption was increased at all experimental groups. Liquid consumption was increased at all experimental groups. A decrease of relative testis and seminal vesicles weight were observed in all treated groups compared to control but not statistically significant. However, their absolute weight did not change. Seminiferous tubules were not identical with conjunctive tissue dystrophy in animals testes treated with 0.1% test chemical. Intercellular connections were reduced and imperfect and dilation in some seminiferous tubules of testis mice treated 1% test chemical. Significant damage was observed in testis mice treated with 2.5% test chemical extensive disruption in seminiferous tubules, widening of the interstitial spaces and loss leydig cells. Total number of spermatids count was reduced significantly in the mice administered 2.5% test chemical. Sperm concentration in epididymides was reduced in all treated groups but sperm epididymis reserves were reduced significantly only in mice treated with 2.5% test chemical. The percentage motility was reduced in 1 and 2.5% treated groups. Male mating index was decreased in the 2.5% treated groups compared to the control values. Weight and litter sizes were, however, decreased in comparison to litters sired from control males. Thus, based on all the above observations and results, it was observed that the NOAEL for the test chemical was found to be 50 mg/kg bw.
Reproductive Toxicity Study 3:
The study was performed to evaluate the effects of the test chemical on the fertility and fecundity of male rats. Its effects on the viability of epididymal spermatozoa and their penetration into the epididymis were also studied. The test animals Sprague-Dawley rats were obtained from the Laboratory Animal Unit of the University of Hong Kong. They were reared and maintained under SPF conditions at an ambient temperature of 20+/- 1°C and a relative humidity of 60-80%. The test chemical was freshly suspended in corn oil and was fed via gastric intubation into a group of 6-12 male rats weighing about 300g at the start of the treatment. The dosage used was 10 times the human dose and treatment was for 6 weeks. Each trial also contained a group of 6-12 control rats to which corn oil only was fed. The body weight of each rat was taken before each feeding. In the study, body weights, Mating procedure, percentage of pregnant females in each group, mean live embryo number per pregnant female, mean resorbed embryo number per pregnancy, mean number of corpora lutea of pregnancy, mean embryo crown-rump length were assessed. Sperm motility assessment and Determination of sperm concentration in the epididymis was conducted. The fecundity of each test group was represented by the 'Fecundity Index' which was calculated by: mean embryo number/mean corpus luteum number Day 21 embryo length % pregnant females. The test chemical reduced the fecundity of male rats by significantly reducing the embryo number over corpus luteum number per pregnant female. The numbers of female rats impregnated by the males treated with the test chemical. The capacity to initiate forward motility of the caudal epididymal
spermatozoa were reduced by the test chemical by 30%. No effects on the body weights of the test animals were observed due to the treatment with the test chemicals. Thus, based on all the observation and results, it was concluded that the LOAEL value of the test chemical, for effects on male fertility was observed to be 50 mg/kg/day based on the reduction of the fecundity of male rats.
Reproductive Toxicity Study 4:
The above experiment was performed to evaluate and assess the effects of the test chemical on the fertility and general reproduction toxicity of male rats.In this study, male rats were treated for 63 days prior cohabitation with untreated females. The animals were treated with doses of 0, 0.25, 0.5, 1 or 2 mg/kg/day. Only males were treated. Untreated females were used to confirm male reproductive potential.No significant differences in fertility parameters and sperm parameters of F0 males were observed at any of the doses.No significant differences in the number of implantations and viable embryos in the females that did become pregnant were observed.The NOAEL value of the test chemical for this study was found to be 2 mg/kg/day as no effect on fertility of male rats was observed at the exposure levels examined in this study.
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