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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Experimental data of a read across substance (calcium salt) are used to evaluate the reprotoxic potential of the test item. A screening assay was conducted to determine toxicity to reproduction and development (OECD guideline 421, GLP). The structural analogue did not influence fertility of parental animals or development of the offspring. The NOAEL for fertility was considered to be 1000 mg/kg bw/day.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
July 27th 1995
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Lot/batch number of test material: E0986
- Expiration date of the lot/batch: not specified
- Purity test date: not specified

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: in dry room at the temperature < 30°C
- Solubility and stability of the test substance in the solvent/dispersant/vehicle/test medium: According to the information from Sponsor the main component of the test substance is insoluble in the used vehicle (water for injection). Mixture of sample and deionised water results in yellow non-transparent suspension but undissolved particles of the test substance were easily visible in the application form and homogeneity could be checked by eye.
Stability of the test substance in the application form cannot be verified analytically. The application form was prepared just before the application and there was no indication that test substance would have been unstable in the suspension in deionised water for that short time period.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Final dilution of a dissolved solid, stock liquid or gel: The concentrations of suspensions at all dose levels were adjusted to ensure the administration of 1 mL per 100 g of body weight.

FORM AS APPLIED IN THE TEST (if different from that of starting material) : test substance suspension in water for injection (prepared daily just before administration)
Species:
rat
Strain:
Wistar
Details on species / strain selection:
The preferred rodent species according to the guidelines is the rat. The test facility has long experience with this species.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: SPF breeding, VELAZ s.r.o., Kolec u Kladna, Czech Republic, RCH CZ 21760152
- Age at study initiation: 10 weeks
- Weight at study initiation: males 307.89 - 309.22g, females: 224.33 - 226.55g
- Housing: 2 rats of the same sex in one cage; during mating period - one male and one female in one cage; pregnant females individually, offspring - with mother
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: from: 19.01.2011 To: 23.02.2011 (males); 07.03. - 14.03.2011 (females)
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg bw
Details on mating procedure:
- M/F ratio per cage: 1 to 1
- Length of cohabitation: 7d
- Proof of pregnancy: sperm in vaginal smear, referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: not specified
- After successful mating each pregnant female was caged (how): individually
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
According to the information from Sponsor the main component of the test substance is insoluble in the used vehicle (water for injection).
Mixture of sample and deionised water results in yellow non-transparent suspension but undissolved particles of the test substance were easily visible in the application form and homogeneity could be checked by eye. Stability of the test substance in the application form cannot be verified analytically. The application form was prepared just before the application and there was no indication that test substance would have been unstable in the suspension in deionised water for that short time period.
Duration of treatment / exposure:
males and females - 2 weeks prior to the mating period and during the mating period,
pregnant females - during pregnancy and till the 3rd day of lactation,
males - after mating period - totally for 28 days,
non-pregnant females (mated females without parturition) - for 25 days after the confirmed mating
Frequency of treatment:
daily, 7d/week
Details on study schedule:
- Age at mating of the mated animals in the study: 12 weeks
Dose / conc.:
160 mg/kg bw/day (nominal)
Dose / conc.:
400 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on data of 14d range finder
The dose-range finding experiment with 14-day application period was performed with 4 groups of treated animals. The doses for the dose-range finding experiment were chosen with respect to the literature
data as folIows: 125, 250, 500 and 1000 mg/kg/day.
In the dose-range finding experiment with the test substance changes of body weight increments were not observed in treated males and females. Health condition control and clinical observation did not detect adverse impact of the test substance on the health condition, clinical status and behaviour of animals at all dose levels. Results of haematological examination showed the test substance influence on white blood component in females of the dose levels 500 and 1000 mg/kg/day. Pathological examination revealed only changes related to colour of the test substance at the dose levels 500 and 1000 mg/kg/day. No animal died during the 14-day application period.
Positive control:
no
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations:
males - weekly
females - weekly in premating and mating period,
during pregnancy: day 0, 7th , 14th, 20th day, during lactation: 0. or 1st and 4th day

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule for examinations:
males - weekly
females - weekly during premating period and after mating period
during pregnancy and lactation - on the same days as bodyweight

WATER CONSUMPTION: No
Oestrous cyclicity (parental animals):
- vaginal smears: daily in mating period
Sperm parameters (parental animals):
Parameters examined in P male parental generations:
testis weight, epididymis weight, prostate gland weight, pituitary glands weight, sperm motility, sperm morphology
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, presence of gross anomalies, physical or behavioural abnormalities

Dead pups were sexed and externally examined; the stomach was examined for the presence of milk. Pups killed on the 4th day of lactation were sexed and subjected to external examination of the cranium, and to macroscopic examination of the thoracic and abdominal tissues and organs.

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: no

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: no
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals, males were killed at the end of the administration period - after 28 days of administration
- Maternal animals: All surviving animals, parental females were killed on the 4th day of lactation. Mated females without delivery were killed 26th day after confirmed mating.

GROSS NECROPSY
- macroscopically examined for any pathological changes with special attention to the organs of the reproductive systems

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated below were prepared for microscopic examination and weighed, respectively:
relevant gross lesions, pituitary gland, coagulation gland, prostate gland, seminal vesicles, epididymis and testes (fixed in Davidson's suspension), cervix of uterus, ovaries, uterus and vagina
Postmortem examinations (offspring):
SACRIFICE
- sacrificed on day 4 of lactation

GROSS NECROPSY
- examination of thoracic and abdominal tissues and organs
Statistics:
The ANOVA test - Analysis of Variance (QC.Expert 2.5) at significance level 0.05 was used for the statistical analysis. This statistical analysis was used for the results of body weight, biometry of organs and number of pups. Control group with vehicle was compared with three treated groups.
Reproductive indices:
Post-implantation loss, Pre-implantation loss, Post-natal loss, Male mating index, Female mating index, Male fertility index, Female fertility index
Offspring viability indices:
Gestation index, Survival index
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
yellow stained feces at mid and high dose groups (both sexes)
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The mean food consumption of males at the dose level 1000 mg/kg bw/day was slightly decreased against control males for the whole time of application period.

The mean food consumption of mothers at all dose levels was slightly decreased against control mothers far the whole time of pregnancy (without dependence on the dose level).
Mean food consumption of treated females was slightly lower than in control females (without dependence on the dose level).
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
atrophic changes in prostate gland of high dose males
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
- males: decrease of absolute and relative weight of prostate gland (dose independent) was recorded in males of all dose levels. Changes did not exceed range of historical control. The histological examination demonstrated the increased occurrence of atrophic changes in prostate gland of males at the dose level I000 mg/kg bw/day. This finding was not dose dependend and is not considered to be an adverse effect.

- females: Dose dependent decreased relative weight of uterus was recorded in females at the dose level 1000 mg/kg/day (connection with oestrous cycle)
Dose descriptor:
NOEL
Effect level:
400 mg/kg bw/day
Sex:
male
Basis for effect level:
other: the value is based on the incidence of atrophic changes in prostate gland
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Sex:
female
Basis for effect level:
other: No effects observed up to and including the highest tested dose.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: No adverse effects observed up to and including the highest tested dose.
Critical effects observed:
no
Clinical signs:
no effects observed
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
One still born pup (female) was detected at the dose level 1000 mg/kg bw/day - unaerial lungs, other organs were without pathological changes.
One pup (male) at the dose level 400 mg/kg bw/day died during lactation period - autolysis of GIT organs, other organs were without pathological changes.
No differences in development of pups were observed at the control and treated groups.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The mean weights of the litters and pups were relatively balanced in the control and treated groups except for the mean weight of litter at the lowest dose level on the 4th day of lactation period.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
no effects observed
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: No adverse effects observed up to and including the highest tested dose.
Critical effects observed:
no
Reproductive effects observed:
no
Conclusions:
The NOEL (No Observed Effect Level) for the toxic effect on reproduction organs of males was established as 400 mg/kg body weight/day (the value is based on the incidence of atrophic changes in prostate gland).
The NOEL (No Observed Effect Level) for the toxic effect on reproduction organs of females was established as 1000 mg/kg body weight/day.
The NOAEL (No Observed Adverse Effect Level) for reproduction was established as 1000 mg/kg body weight/day.
Executive summary:

The influence of the test substance treatment expressed mainly at the highest dose level (limit dose) - decrease of absolute and relative weight of prostate gland and occurrence of atrophic changes in prostate gland of parental males. The changes relating to prostate gland at the dose level 1000 mg/kg bw/d were considered of effect related to the test substance (without negative influence on fertility of parental males). Reproductive performance - ability of male and female animals to successfully mate and produce viable offspring was unaffected by the test substance treatment. Also development of pups was not changed in treatment groups.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The target substance (diammonium salt) was not analyzed for its potential to influence reproduction and development. Experimental data of a structural analogue (calcium-salt) are available. The substances are salts of sulphonatophenyl-pyrazol-azobenzenesulfonic acid and differ in their respective inorganic cation only. A detailed read across justification is attached in chapter 7.8.1 of the IUCLID dossier.

A Reproduction / Developmental Toxicity screen was conducted to determine possible influence on fertility and teratogenicity. Herein, the analogue substance was administered by gavage at concentrations of 0, 160, 400 and 1000 mg/kg bw/day to male and female Wistar rats (12/sex/dose). Males were treated totally for 28 d, females were treated until 3rd day of lactation.

The test material did not influence fertility or reproduction of the test animals. Atrophic changes in prostate gland of parental males of the high dose group were observed. This effect did not negatively influence fertility of parental males and is not considered as adverse effect.

Administration of an analogue test substance up to 1000 mg/kg bw did not induce mortalities, clinical signs or changes in body weight or food consumption. Mating behaviour, fertillity, gestation and laction was not influences by the test item. Therefore, the test material is not considered as toxic to reproduction, which is also assumed for the actual substance.

Effects on developmental toxicity

Description of key information

Experimental data of a read across substance (ammonium salt) are used to evaluate the reprotoxic potential of the test item. A screening assay was conducted to determine toxicity to reproduction and development (OECD guideline 421, GLP). The structural analogue did not influence fertility of parental animals or development of the offspring. Teratorgenicity or malformations were not observed. The NOAEL for developmental toxicity is considered to be 1000 mg/kg bw/day.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
July 27th 1995
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Lot/batch number of test material: E0986
- Expiration date of the lot/batch: not specified
- Purity test date: not specified

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: in dry room at the temperature < 30°C
- Solubility and stability of the test substance in the solvent/dispersant/vehicle/test medium: According to the information from Sponsor the main component of the test substance is insoluble in the used vehicle (water for injection). Mixture of sample and deionised water results in yellow non-transparent suspension but undissolved particles of the test substance were easily visible in the application form and homogeneity could be checked by eye. Stability of the test substance in the application form cannot be verified analytically. The application form was prepared just before the application and there was no indication that test substance would have been unstable in the suspension in deionised water for that short time period.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Final dilution of a dissolved solid, stock liquid or gel: The concentrations of suspensions at all dose levels were adjusted to ensure the administration of 1 mL per 100 g of body weight.

FORM AS APPLIED IN THE TEST (if different from that of starting material) : test substance suspension in water for injection (prepared daily just before administration)
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: SPF breeding, VELAZ s.r.o., Kolec u Kladna, Czech Republic, RCH CZ 21760152
- Age at study initiation: 10 weeks
- Weight at study initiation: males 307.89 - 309.22g, females: 224.33 - 226.55g
- Housing: 2 rats of the same sex in one cage; during mating period - one male and one female in one cage; pregnant females individually, offspring - with mother
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: from: 19.01.2011 To: 23.02.2011 (males); 07.03. - 14.03.2011 (females)
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
suspension
Details on exposure:
VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg bw
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
According to the information from Sponsor the main component of the test substance is insoluble in the used vehicle (water for injection).
Mixture of sample and deionised water results in yellow non-transparent suspension but undissolved particles of the test substance were easily visible in the application form and homogeneity could be checked by eye. Stability of the test substance in the application form cannot be verified analytically. The application form was prepared just before the application and there was no indication that test substance would have been unstable in the suspension in deionised water for that short time period.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1 to 1
- Length of cohabitation: 7 d
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: not specified
- After successful mating each pregnant female was caged (how): individually
Duration of treatment / exposure:
males and females - 2 weeks prior to the mating period and during the mating period,
pregnant females - during pregnancy and till the 3rd day of lactation,
males - after mating period - totally for 28 days,
non-pregnant females (mated females without parturition) - for 25 days after the confirmed mating
Frequency of treatment:
daily, 7d/week
Dose / conc.:
160 mg/kg bw/day (nominal)
Dose / conc.:
400 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on data of 14d range finder
The dose-range finding experiment with 14-day application period was performed with 4 groups of treated animals. The doses for the dose-range finding experiment were chosen with respect to the literature data as folIows: 125, 250, 500 and 1000 mg/kg/day.
In the dose-range finding experiment with the test substance changes of body weight increments were not observed in treated males and females. Health condition control and clinical observation did not detect adverse impact of the test substance on the health condition, clinical status and behaviour of animals at all dose levels. Results of haematological examination showed the test substance influence on white blood component in females of the dose levels 500 and 1000 mg/kg/day.
Pathological examination revealed only changes related to colour of the test substance at the dose levels 500 and 1000 mg/kg/day. No animal died during the 14-day application period.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly in premating and mating period,
during pregnancy: day 0, 7th , 14th, 20th day, during lactation: 0. or 1st and 4th day

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule for examinations:
females - weekly during premating period and after mating period
during pregnancy and lactation - on the same days as bodyweight

POST-MORTEM EXAMINATIONS: Yes
- Parental females were killed on the 4th day of lactation. Mated females without delivery were killed 26th day after confirmed mating.
- Organs examined: macroscopically examined for any pathological changes with special attention to the organs of the reproductive systems. The tissues indicated below were prepared for microscopic examination and weighed, respectively:
relevant gross lesions, pituitary gland, cervix of uterus, ovaries, uterus and vagina
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: No
- Head examinations: No data

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, presence of gross anomalies, physical or behavioural abnormalities

Dead pups were sexed and externally examined; the stomach was examined for the presence of milk. Pups killed on the 4th day of lactation were sexed and subjected to external examination of the cranium, and to macroscopic examination of the thoracic and abdominal tissues and organs.

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities
Statistics:
The ANOVA test - Analysis of Variance (QC.Expert 2.5) at significance level 0.05 was used for the statistical analysis. This statistical analysis was used for the results of body weight, biometry of organs and number of pups. Control group with vehicle was compared with three treated groups.
Indices:
Male mating index
number of males with confirmed mating x 100 / number of males cohabited

Female mating index
number of sperm-positive females x 100 / number of females cohabited

Male fertility index
number of males impregnating a females x 100 / number of males cohabited

Female fertility index
number of pregnant females x 100 / number of sperm-positive females

Gestation index
number of females with live born pups x 100 / number of pregnant females

Survival index
number of live pups on day 4 post partum* x 100 / number of pups born alive+

Note: * Without still born pups (dead pups with anaerial lungs)
+ with dead pups with aerial lungs

Pre-implantation loss: Number of corpora lutea - number of implantations
Post-implantation loss: Number of implantations - number of live births
Post-natal loss: Number of live births - number of alive at postuatal day 4
Historical control data:
yes, 13 control groups from Reproduction / Developmental Toxicity Screening tests
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
yellow stained feces at mid and high dose groups
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The mean food consumption of mothers at all dose levels was slightly decreased against control mothers far the whole time of pregnancy (without dependence on the dose level).
Mean food consumption of treated females was slightly lower than in control females (without dependence on the dose level).
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
In all females of the middle and the highest dose level and one female of the lowest dose level the content of intestine and stomach was test substance-coloured.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Number of abortions:
effects observed, treatment-related
Description (incidence and severity):
slightly increased number of females with abortion at the dose levels 400 and 1000 mg/kg bw/day
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
not specified
Early or late resorptions:
not examined
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
One still born pup (female) was detected at the dose level 1000 mg/kg bw/day.
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: No adverse effects observed up to and including the highest tested dose.
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
instead of fetuses pups were examined
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 examined
Visceral malformations:
no effects observed
Other effects:
no effects observed
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: No adverse effects observed up to and including the highest tested dose.
Abnormalities:
no effects observed
Developmental effects observed:
no
Conclusions:
The NOAEL (No Observed Adverse Effect Level) for development of pups was established as 1000 mg/kg body weight/day.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

The test item (diammonium salt) was not analyzed for its potential to influence reproduction and development. Experimental data of a structural analogue (calcium-salt) are available. The substances are salts of sulphonatophenyl-pyrazol-azobenzenesulfonic acid and differ in their respective inorganic cation only. A detailed read across justification is attached in chapter 7.8.2 of the IUCLID dossier.

A Reproduction / Developmental Toxicity screen was conducted to determine possible influence on fertility and teratogenicity. Herein, the analogue substance was administered by gavage at concentrations of 0, 160, 400 and 1000 mg/kg bw/day to male and female Wistar rats (12/sex/dose). Males were treated totally for 28 d, females were treated until 3rd day of lactation. As a result, the ability of male and female animals to successfully mate and produce viable offspring was unaffected by the test substance treatment. Also development of pups was not changed in treatment groups.

Administration of the analogue substance did not affect number, viability and development of the offsping, also teratogenicity was not observed. Thus, the substance is not considered to own developmental toxicity, which is also assumed for the actual substance.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. No adverse effects on fertility as well as development of offspring were observed in an screening study for reproductive / developmental toxicity with a structural analogue. As a result the actual substance is not considered to be classified for reproductive toxicity under Regulation (EC) No. 1272/2008.

Additional information