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EC number: 224-632-3 | CAS number: 4432-31-9
- 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
The reproductive/developmental toxicity of the test substance was screened in a experimental study according to OECD TG 422 under GLP-conditions. The substance did not adversely affect the reproductive performance in parental males and females for doses up to 1000 mg/kg bw/day. The study was performed with the hydrate form of the substance (CAS 1266615-59-1). Taking into account a correction for the water content (7 %) the NOAEL for the anhydrous form (CAS 4432-31-9) is 930 mg/kg bw/day.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2017-03-07 to 2017-06-13
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- 29 July 2016
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: EPA Health Effects Test Guidelines: OPPTS 870.3650 Combined Repeated Dose Toxicity with the Reproduction/Developmental Toxicity Screening Test
- Version / remarks:
- July 2000
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Hsd.Han
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Toxi-Coop Zrt., 1103 Budapest, Cserkesz u. 90
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 11-12 weeks (both sexes)
- Weight at study initiation: males: 327-381 g
females: 202-244 g
- Fasting period before study: no
- Housing: before mating: 2 animals of the same sex/cage; mating: 1 male and 1 female/cage; pregnant females: individually; males after mating: 2/cage;
Type III polypropylene/polycarbonate
- Diet: ad libitum, ssniff SM R/M-Z+H complete diet
- Water: ad libitum, tap water
- Acclimation period: 19 days
DETAILS OF FOOD AND WATER QUALITY: The food is considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study. The supplier provided an analytical certificate of the standard diet for the batch used. Water quality control analysis and microbiological assessment are performed once in every six months by Government Office of Capital Budapest Department of Public Health and Medical Officer Service.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/- 3
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- distilled
- Details on exposure:
- - PREPARATION OF DOSING SOLUTIONS:
The test item was solved in distilled water in concentrations of 20, 60 and 200 mg/mL. Dosing solutions were prepared not longer than for four days before the administration and stored at room temperature until use.
- VEHICLE
- Concentration in vehicle: 20, 60 and 200 mg/mL
- Amount of vehicle: 5 mL/kg body weight
- Batch no. of Aqua purificata (distilled water): 1702-5502, 1702-5510, 1703-5503 (supplier: Parma Produkt Kft., Budapest, Hungary) - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: until copulation or 14 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individually
- Any other deviations from standard protocol: none - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical control of dosing formulations was performed by LC/MS/MS in the Analytical Laboratory of Test Facility twice during the study. Recoveries of the test item in the dosing formulations ranged from 100 - 105% of the nominal concentrations.
Stability and homogeneity in distilled water over the range of relevant concentration has been demostrated at room temperature for at least four days (recoveries from 98% to 105%), i.e. the maximum period of solutions administered. - Duration of treatment / exposure:
- females: 56-66 days (depending on mating effectiveness)
males: 56-57 days (depending on mating effectiveness) - Frequency of treatment:
- daily
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 12 male and 12 female per dose and control
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on results from a 14-day dose-range finding experiment that used the same concentrations
- Rationale for animal assignment: random - Positive control:
- none
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly (starting on Day 0)
FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
Food consumption was determined weekly by reweighing the given and non-consumed diet with a precision of 1 g during the treatment period except mating phase (pre-mating days 0, 7, 13, gestation days 0, 7, 14 and 21, lactation days 0, 4 and 13). Food consumption of male animals was also determined by weekly interval during post-mating period.
WATER CONSUMPTION AND COMPOUND INTAKE: No
OTHER: none - Oestrous cyclicity (parental animals):
- The estrous cycle was monitored by examining vaginal smears each day before treatment start for each rat being considered for the study for two weeks. The estrous cycle was evaluated and considered for randomisation. However, some animal hot showing typical 4-5 day cycles were included in the study due to the large amount of rats with irregular cycles.
Vaginal smears were prepared and estrous cycle was monitored daily from the beginning of the treatment period (2 weeks pre-mating period) and during the mating period until evidence of mating.
Vaginal smears were also prepared on the day of necropsy.
Smears were stained (1% aqueous methylene blue solution) and examined microscopically. - Sperm parameters (parental animals):
- Parameters examined in P male parental generations:
- testis weight
- epididymis (and prostate and seminal vesicles with coagulating glands) weight
- histopathology of stages of spermatogenesis in the male gonads
- histopathology of interstitial testicular cell structure - 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, postnatal mortality, presence of gross anomalies, weight gain, anogenital distance (AGD), presence of nipples/areolae in male pups
- From at least 2 pups per litter, blood samples for T4 analysis were collected at post-natal day 4 and post-natal day 13.
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 on day 55
- Maternal animals: All surviving animals 14 days post-partum
GROSS PATHOLOGY: Yes
- adrenal glands
- bone with bone marrow and joint (femur)
- brain (representative regions: cerebrum, cerebellum, pons and medulla oblongata)
- eyes (lachrymal gland with Harderian glands)
- female mammary gland
- gonads (testis with epididymides, ovaries, uterus with fallopian tube and vagina)
- gross lesions
- heart
- kidneys
- large intestines (caecum, colon, rectum, incl. Peyer's patches)
- liver
- lungs (with main stem bronchi)
- lymph nodes (submandibular, mesenteric)
- muscle (quadriceps)
- esophagus
- pancreas
- pituitary
- prostate
- salivary glands (submandibular)
- sciatic nerve
- seminal vesicle with coagulating gland
- skin
- small intestines (representative regions: duodenum, ileum, jejunum)
- spinal cord (at three levels: cervical, mid-thoracic and lumber
- spleen
- sternum
- stomach
- thymus
- thyroid + parathyroid
- trachea
- urinary bladder
HISTOPATHOLOGY : Yes (control and high dose group)
Histopathological examinations were performed on the following preserved organs and tissues of ALL animals in the control and high dose groups (12 per sex):
- Ovaries (Primodial, secondary and teriary follicles; Corpora lutea)
- Uterus
- Vagina
- Testes
- Epididymides
- Seminal vesicle with coagulating gland
- thymus (one male in low dose group due to hemorrhage)
The tissues indicated above were prepared for microscopic examination and weighed, respectively.
In particular, stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure were examined.
Full histopathological examinations were performed on the following preserved organs and tissues of selected animals in the control and high dose groups (5 per sex):
- Adrenal glands
- Aorta
- Bone marrow
- Brain
- Cecum
- Colon
- Duodenum
- Eyes + optic nerves
- Esophagus
- Harderian glands
- Heart
- Ileum
- Jejunum
- Kidneys
- Lachrymal glands
- Liver
- Lungs
- Mesenteric lymph nodes
- Muscle (quadriceps)
- Pancreas
- Pituitary
- Prostate
- Rectum
- Salivary glands (subm.)
- Sciatic nerve
- Skin
- Spinal cord
- Spleen
- Sternum
- Stomach - forestomach
- Subm. lymph nodes
- Thymus
- Thyroid + parathyroid
- Trachea
- Urinary bladder
From all parent rats, blood samples for T4 analysis were collected at termination males) or on post-partum day 13 (females). - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring were sacrificed latest at 13 days of age.
GROSS NECROPSY: Dead pups and pups euthanized at day 13 post-partum, or shortly thereafter, were carefully examined for gross abnormalities.
HISTOPATHOLOGY / ORGAN WEIGTHS: No - Statistics:
- Depending on variance homogeneity between groups (Bartlett's test), parametric or non-parametric (Kruskal-Wallis test) ANOVA was performed, with subsequent inter-group comparisons (Duncan multiple range test or Mann-Whitney U-Test) in case of significant ANOVA results. If applicable, the Chi-square test was performed.
- Reproductive indices:
- Male reproduction data:
- Male mating index
- Male fertility index
Female reproduction and delivery data:
- Female mating index
- Female fertility index
- Gestation index - Offspring viability indices:
- - Post implantation mortality
- post-natal mortality
- survival index
- sex ratio - Clinical signs:
- no effects observed
- Description (incidence and severity):
- Daily clinical observation:
No treatment-related signs of systemic toxicity were detected at any dose level at the daily clinical observations (100, 300 and 1000 mg/kg bw/day, male or female).
Detailed weekly clinical observation:
The behavior and physical condition of animals was not affected by the test item at any dose level (100, 300 or 1000 mg/kg bw/day) based on the weekly detailed clinical observations during the entire treatment period. - Mortality:
- no mortality observed
- Description (incidence):
- There was no mortality in any group during the course of study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No test item related effects were noted on the mean body weight and body weight gain values at 100, 300 or 1000 mg/kg bw/day. There were no significant differences between the control and test item treated groups in the body weight or body weight gain at any occasion.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There were no test item related differences in the mean daily food consumption in any test item treated group when compared to the control during the study. There were no significant differences between the control and test item treated groups in the mean daily food consumption at any occasion.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- There were no pathological changes in the examined hematological and blood coagulation parameters in any of the groups (male and female, 100, 300 or 1000 mg/kg bw/day). The examined hematological and blood coagulation parameters were comparable in male and female animals of control and all test item treated groups and statistical significance was not observed.
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no test item related adverse effects on the examined clinical chemistry parameters at 100, 300 or 1000 mg/kg bw/day (male or female).
Some sporadic statistically differences in some parameters were not related to dose and considered of no toxicological relevance. - Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- Functional observations did not demonstrate any test item related changes. The behavior, physical condition and reactions to different type of stimuli of animals selected for examination are considered to be normal in all groups (100, 300 and 1000 mg/kg bw/day, control).
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, non-treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- Histopathological examinations did not reveal any test item related alterations in the organs or tissues of male or female animals at 1000 mg/kg bw/day. No test item related alterations in organs and tissues and no morphological evidence of acute or subacute injury to the various organs were observed. There was no morphological evidence of acute or subacute injury (degeneration, inflammation, necrosis, etc.) of the stomach, the small and large intestines, the liver, the pancreas, the cardiovascular system, the urinary system, the immune system, the hematopoietic system, the skeleton, the muscular system, the male and female reproductive system or the central or peripheral nervous system in the animals.The cytomorphology of the endocrine glands were the same in the control and the treated animals.
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- A test item influence on the estrous cycle was not detected at any dose level (100, 300 or 1000 mg/kg bw/day). There were no significant differences between the control and treated groups in the number or percentage of animals with regular cycles, in the mean number of cycles, mean length of cycles, mean number of days in estrous or diestrous during the pre-mating period.
The mean number of days in pro-estrous was statistically significantly higher in the 300 mg/kg bw/day group compared to their control. As all females in this group had normal and regular estrous cycle during the pre-mating period and no dose-dependent differences were observed, this slight difference is considered to be unrelated to the test item. - Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- In all male animals, the investigated organs of reproductive system (testes, epididymides,prostate and seminal vesicles with coagulating gland) were histologically normal and characteristic on the sexually mature organism in all cases. The various spermatogenic cells (spermatogonia, spermatocytes, spermatids and spermatozoa), representing different phases in the development and differentiation of the spermatozoons and the interstitial cells were the same in quantity and morphologically in the testes of investigated control and treated animals. The histological picture of epididymides, seminal vesicles, and coagulating glands was normal in all animals as well.
- Reproductive performance:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The examined parameters of reproductive performance were not affected by the test item at 100, 300 or 1000 mg/kg bw/day (male and female). There was statistically significant difference between the control and test item treated groups of male animals at 100, 300 and 1000 mg/kg bw/day in copulatory indices as one pair of control failed to mate during the 14-day period resulting in lower copulatory index. Thus, these statistically significant differences with respect to the control are considered to be indicative of biological variation and not related to the test item. Statistically significantly lower fertility index was observed in the male 1000 mg/kg bw/day group when compared to the control because one male animal in this group mated however the female was not pregnant. The lower fertility index of this group just met the historical controls; therefore, it is considered to be not related to the test item.
The number of pregnant females and dams delivered, the mean number of implantations, post-implantation loss, duration of pregnancy, and pups births (total, live, still birth, viable) and live birth index were comparable in all groups. In the control group the number of viable pups on post-natal day 0 (PN0) was relatively low: 89% of the liveborns in this group were viable on PN0. In the test item treated groups this value was between 96% and 99%. This observation in the control group is considered as normal biological variability. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: highest dose tested
- Dose descriptor:
- NOAEL
- Effect level:
- 930 mg/kg bw/day (nominal)
- Sex:
- male/female
- Remarks on result:
- other: conversion to anhydrous form taking into account a correction for the water content (7%)
- Key result
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Test item related clinical signs were not detected in the offspring between postnatal days 0 and 13.
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- There was no test item related effect on offspring’s extra uterine mortality.
The highest mean number of dead offspring per litter between post-natal days 0 and 13 was observed in the control and the 300 mg/kg bw/day groups (1.3 dead pups per litter) while in the 100 and 1000 mg/kg bw/day groups it was only 0.2 per litter. The survival indices are in good correlation with the mean number of dead pups. These differences did not attain statistical significance and there is no dose dependence observed and, therefore, they are considered to have no toxicological relevance. - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- A test item related effect on the body weight development of the offspring was not found.
The mean litter weights as well as the mean litter weight gain were similar in the control and in all test item treated groups (100, 300 and 1000 mg/kg bw/day) on postnatal days 0, 4 and 13.
Slight changes with statistical significance were detected in the mean pup weights and mean pup weight gain; however, these minor differences without a relation to dose are considered to have no toxicological relevance. - 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):
- no effects observed
- Description (incidence and severity):
- The anogenital distances (AGD; absolute and normalized) were not affected by the test item at 100, 300 and 1000 mg/kg bw/day.
Statistical significances were observed for decreased or increased anogenital distances (absolute and/or normalized) in male or female pups of all dose groups. These changes were minor and are considered to be indicative of biological variations and not related to the test item. - Nipple retention in male pups:
- no effects observed
- Description (incidence and severity):
- Nipples/areoles were not visible in any of the examined male offspring in the control or 100, 300 or 1000 mg/kg bw/day groups on postnatal day 13.
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Test item related macroscopic alterations were not found in offspring subjected to gross pathological examination. There were no macroscopic changes in the organs or tissues of stillborn or dead offsprings.
- Histopathological findings:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- There were no test item related differences between the control and test item treated groups in the ratio or in the litter means of genders on postnatal days 0, 4 or 13. There were no significant differences with respect to the control in the T4 thyroid hormone levels in offspring sampled on postnatal day 13 at any dose levels.
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: highest dose tested
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 930 mg/kg bw/day
- Sex:
- male/female
- Remarks on result:
- other: conversion to anhydrous form taking into account a correction for the water content (7%)
- Key result
- Critical effects observed:
- no
- Key result
- Reproductive effects observed:
- no
- Conclusions:
- Under the conditions of the present study, the test item did not cause signs of systemic toxicity in parental male and female Hsd.Han: Wistar rats at 100, 300 or 1000 mg/kg bw/day doses administered by oral gavage.
Based on these observations the NOAEL for systemic toxicity of male/female rats was determined to be 1000 mg/kg bw/day. The NOAEL for reproductive performance of male/female rats and for F1 Offspring was 1000 mg/kg bw/day, respectively. - Executive summary:
A study according OECD TG 422 was performed to investigate possible effects of the test item on reproduction and development when repeatedly administered orally to rats compared to control animals. Four groups of Wistar rats consisting of 12 animals per group and sex were administered by gavage once daily doses of 0 (vehicle only), 100, 300 and 1000 mg/kg bw/day. The suitability of distilled water as vehicle for the test item was analytically verified up front as the test item was stable in distilled water at room temperature for at least four days. The concentration of the substance in the dosing formulations administered to the animals was confirmed twice during the study. All animals of the parent (P) generation were dosed prior to mating (14 days) and throughout mating. In addition, males received the test item or vehicle after mating up to the day before necropsy (altogether 56 or 57 days). Females were additionally exposed through the gestation period and up to lactation days 12-20, i.e. up to the day before necropsy (altogether for 56 to 66 days). Observations included mortality, clinical signs, body weight, food consumption, mating, pregnancy and delivery process, as well as development of offspring. Estrous cycle was monitored by examining vaginal smears before the treatment for two weeks and for two weeks from the beginning of the treatment period (two weeks pre-mating period) and during the mating period until evidence of mating. The dams were allowed to litter and rear their offspring up to day 13 post-partum. Litters were weighed and offspring were observed for possible abnormalities and were euthanized on post-natal day 13 or shortly thereafter. Blood samples were collected for determination of serum levels of thyroid hormones (T4) from 2-8 pups per litter on post-natal day 4, from all dams and from 4-7 pups per litter at termination on post-partum/post-natal day 13 and from all parent male animals at termination. All parental animals were subjected to gross pathology one day after the last treatment. The body weight, brain weight, weight of the testes, epididymides and prostate and seminal vesicles with coagulating glands as a whole of all adult male animals were determined. Histopathology examination was performed on ovaries, uterus, vagina, testes, epididymides, prostate and seminal vesicles with coagulating gland in the control and high dose groups (male or female). Five dams and the male mating partners were randomly selected from each group to examine further signs of toxicity such as functional observations, hematology, blood coagulation, clinical chemistry, gross necropsy, and organ weighing as well as full histopathology in the control and high dose groups.
There was no mortality in any group during the course of study. Clinical signs of systemic toxicity related to the test item were not detected at any dose level, neither at the daily nor at the detailed weekly clinical observations. At the same intervals, the behavior and physical condition of the animals was not impaired at each dose level (100, 300 or 1000 mg/kg bw/day) during the entire treatment period. Test item related changes of the body weight or body weight gain were not detected. The body weight development was not disturbed and comparable in the control and test item treated groups. The mean daily food consumption was not affected by the test item in male or female animals at all test item groups during the entire study (pre-mating, post-mating, gestation and lactation periods). There were no test item related differences between the control and test item treated groups in the examined parameters of reproductive performance, and in the delivery parameters of dams (100, 300 and 1000 mg/kg bw/day). Clinical pathology examinations (hematology, blood coagulation, clinical chemistry and thyroid hormone levels) did not reveal toxicological relevant alterations related to the test item. Specific macroscopic alterations related to the test item were not found at necropsy. There were no test item related changes in the weights (absolute and relative to body or brain weights) of selected organs in the animals at any dose level.
Histopathological examinations of the selected organs (ovaries, uterus, vagina, testes, epididymides, prostate and seminal vesicles with coagulating gland) did not reveal any test item related changes at the highest dose of 1000 mg/kg bw/day. During full histopathology, there were no changes related to the test item in organs or tissues of selected animals (male or female) at 1000 mg/kg bw/day. No adverse findings on the offspring’s development were detected (mortality, clinical signs and body weight, anogenital distance and nipple retention in male pups, necropsy).
Under the conditions of the present study, the substance did not cause signs of systemic toxicity in parental male and female Hsd.Han: Wistar rats at 100, 300 or 1000 mg/kg bw/day doses administered by oral gavage and the test item did not adversely influence the reproductive performance (gonad function, mating behavior, conception, parturition) in parental male and female rats at the doses of 100, 300 or 1000 mg/kg bw/day. The development of the F1 offspring was not impaired at any dose level from birth to post-natal day 13 after repeated oral administration of dams. Based on these observations the NOAEL were determined as follows:
NOAEL for systemic toxicity of male/female rats: 1000 mg/kg bw/day
NOAEL for reproductive performance of male/female rats: 1000 mg/kg bw/day
NOAEL for F1 Offspring: 1000 mg/kg bw/day
Reference
There were no significant differences with respect to the control in the T4 thyroid hormone levels in parental male animals at any dose levels.
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 930 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- OECD TG 422, GLP
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
A study according OECD TG 422 was performed to investigate possible effects of the test item on reproduction and development when repeatedly administered orally to rats compared to control animals. Four groups of Wistar rats consisting of 12 animals per group and sex were administered by gavage once daily doses of 0 (vehicle only), 100, 300 and 1000 mg/kg bw/day. The suitability of distilled water as vehicle for the test item was analytically verified up front as the test item was stable in distilled water at room temperature for at least four days. The concentration of the substance in the dosing formulations administered to the animals was confirmed twice during the study. All animals of the parent (P) generation were dosed prior to mating (14 days) and throughout mating. In addition, males received the test item or vehicle after mating up to the day before necropsy (altogether 56 or 57 days). Females were additionally exposed through the gestation period and up to lactation days 12-20, i.e. up to the day before necropsy (altogether for 56 to 66 days). Observations included mortality, clinical signs, body weight, food consumption, mating, pregnancy and delivery process, as well as development of offspring. Estrous cycle was monitored by examining vaginal smears before the treatment for two weeks and for two weeks from the beginning of the treatment period (two weeks pre-mating period) and during the mating period until evidence of mating. The dams were allowed to litter and rear their offspring up to day 13 post-partum. Litters were weighed and offspring were observed for possible abnormalities and were euthanized on post-natal day 13 or shortly thereafter. Blood samples were collected for determination of serum levels of thyroid hormones (T4) from 2-8 pups per litter on post-natal day 4, from all dams and from 4-7 pups per litter at termination on post-partum/post-natal day 13 and from all parent male animals at termination. All parental animals were subjected to gross pathology one day after the last treatment. The body weight, brain weight, weight of the testes, epididymides and prostate and seminal vesicles with coagulating glands as a whole of all adult male animals were determined. Histopathology examination was performed on ovaries, uterus, vagina, testes, epididymides, prostate and seminal vesicles with coagulating gland in the control and high dose groups (male or female). Five dams and the male mating partners were randomly selected from each group to examine further signs of toxicity such as functional observations, hematology, blood coagulation, clinical chemistry, gross necropsy, and organ weighing as well as full histopathology in the control and high dose groups.
There was no mortality in any group during the course of study. Clinical signs of systemic toxicity related to the test item were not detected at any dose level, neither at the daily nor at the detailed weekly clinical observations. At the same intervals, the behavior and physical condition of the animals was not impaired at each dose level (100, 300 or 1000 mg/kg bw/day) during the entire treatment period. Test item related changes of the body weight or body weight gain were not detected. The body weight development was not disturbed and comparable in the control and test item treated groups. The mean daily food consumption was not affected by the test item in male or female animals at all test item groups during the entire study (pre-mating, post-mating, gestation and lactation periods). There were no test item related differences between the control and test item treated groups in the examined parameters of reproductive performance, and in the delivery parameters of dams (100, 300 and 1000 mg/kg bw/day). Clinical pathology examinations (hematology, blood coagulation, clinical chemistry and thyroid hormone levels) did not reveal toxicological relevant alterations related to the test item. Specific macroscopic alterations related to the test item were not found at necropsy. There were no test item related changes in the weights (absolute and relative to body or brain weights) of selected organs in the animals at any dose level.
Histopathological examinations of the selected organs (ovaries, uterus, vagina, testes, epididymides, prostate and seminal vesicles with coagulating gland) did not reveal any test item related changes at the highest dose of 1000 mg/kg bw/day. During full histopathology, there were no changes related to the test item in organs or tissues of selected animals (male or female) at 1000 mg/kg bw/day. No adverse findings on the offspring’s development were detected (mortality, clinical signs and body weight, anogenital distance and nipple retention in male pups, necropsy).
Under the conditions of the present study, the substance did not cause signs of systemic toxicity in parental male and female Hsd.Han: Wistar rats at 100, 300 or 1000 mg/kg bw/day doses administered by oral gavage and the test item did not adversely influence the reproductive performance (gonad function, mating behavior, conception, parturition) in parental male and female rats at the doses of 100, 300 or 1000 mg/kg bw/day. The development of the F1 offspring was not impaired at any dose level from birth to post-natal day 13 after repeated oral administration of dams. Based on these observations the NOAEL were determined as follows:
NOAEL for systemic toxicity of male/female rats: 1000 mg/kg bw/day
NOAEL for reproductive performance of male/female rats: 1000 mg/kg bw/day
NOAEL for F1 Offspring: 1000 mg/kg bw/day
The study was performed with the hydrate form of the substance (CAS 1266615-59-1). Taking into account a correction for the water content (7%) the NOAEL for the anhydrous form (CAS 4432-31-9) is 930 mg/kg bw/day.
Effects on developmental toxicity
Description of key information
The reproductive/developmental toxicity of the test substance was screened in a experimental study according to OECD TG 422 under GLP-conditions. The development of the F1 offsprings, which was observed until post-natal day 13, was not impaired for doses up to 1000 mg/kg bw/day. The study was performed with the hydrate form of the substance (CAS 1266615-59-1). Taking into account a correction for the water content (7%) the NOAEL for the anhydrous form (CAS 4432-31-9) is 930 mg/kg bw/day.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 930 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- OECD TG 422, GLP
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Classification, Labeling, and Packaging Regulation (EC) No 1272/2008
The available data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on this data, the substance is not considered to be classified for reproductive toxicity toxicity under Regulation (EC) No 1272/2008, as amended for the fifteenth time in Regulation (EU) 2020/1182.
Additional information
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