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EC number: 244-311-1 | CAS number: 21282-97-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 12 March - 11 April 2019
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 27 June 2018
- Deviations:
- no
- Principles of method if other than guideline:
- not applicable
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Test material form:
- liquid
- Details on test material:
- clear liquid, colourless to yellowish
Stored at RT, protected from light and humidity
Expiry date: 6 February 2020
Constituent 1
- Specific details on test material used for the study:
- already provided
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- Species and strain: Hannover Wistar rats (CRL:WI(Han))
Age of animals: Young adult female rats, nulliparous and non-pregnant, at least 11 weeks old at mating
Starting body weight: 189-230 g (the variation did not exceed ± 20% of the mean weight)
Acclimation period: at least 12 days
Light: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Temperature: 19.7-24.6°C (target: 22 ± 3°C)
Relative humidity: 33-56% (target: 30-70%)
Ventilation: 15-20 air exchanges/hour
Housing/Enrichment: Successfully mated animals were housed individually.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- propylene glycol
- Details on exposure:
- A constant volume of 5 mL/kg body weight was administered to all dose groups, including the controls. The individual volume of the treatment was based on the most recent individual body weight of the animals.
The control or test item dose formulations were administered to mated, sperm positive (assumed pregnant) female rats daily by oral gavage at approximately the same time each day, from gestation day 6 (GD 6) to gestation
day 19 (GD 19). - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples for test item concentration and homogeneity determination of the dosing formulations were collected four times during the treatment period. Formulation stability was established before this study. The test item concentration was analysed at the Test Site using a HPLC-UV method. The mean concentration of all measured formulations were found to be in the range of 91.8-95.6% of their nominal concentrations (20, 60 and 200 mg/mL) and were found to be homogenous.
- Details on mating procedure:
- The oestrus cycle of female animals was examined shortly before start of pairing. After acclimation, the females were paired according to their oestrus cycle with males in the morning for approximately 2-3 hours (1 male : 1 female) until at least 24 sperm positive females/group were attained. After the daily mating period, a vaginal smear was prepared and stained with 1% aqueous methylene blue solution. The smear was examined with a light microscope; the presence of a vaginal plug or sperm in the vaginal smear was considered as evidence of copulation (gestation day 0, GD 0). Sperm positive females were separated and caged individually.
- Duration of treatment / exposure:
- Days 6 - 19 of gestation
- Frequency of treatment:
- Once daily during exposure period
- Duration of test:
- Until Day 20 of gestation
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day
- Dose / conc.:
- 300 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- No. of animals per sex per dose:
- 98 female animals, 25-26 mated female animals/group, 4 groups (one control and 3 test item-treated groups)
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- The sperm-positive, assumed pregnant females were allocated to the experimental groups (on each mating day) in such a way that the group averages of the body weight were as similar as possible. A computer software (SPSS PC+4.0) was used to verify homogeneity/variation among/within groups.
Examinations
- Maternal examinations:
- Animals were inspected for signs of morbidity and mortality twice daily (at the beginning and end of each working day). Detailed clinical observations were made on all animals at the onset of treatment (GD 6) then weekly.
Parameters monitored during the study included mortality and clinical observations, body weight, body weight gain and individual food consumption. Maternal reproductive parameters associated with uterine examination were evaluated, and the foetuses were weighed and examined for external, visceral and skeletal abnormalities. Placentas were examined macroscopically. - Ovaries and uterine content:
- The ovaries and uterus were removed and the pregnancy status ascertained. The uterus including the cervix was weighed and examined for early and late embryonic or foetal deaths and for the number of live foetuses.
The dams’ viscera were examined macroscopically for any structural abnormalities or pathological changes.
The number of corpora lutea in each ovary and implantation sites in each uterine horn, the number of live foetuses, early and late embryonic death and foetal death were counted and the number and percentage of pre- and postimplantation losses were calculated. The degree of resorption was described in order to estimate the relative time of death of the conceptus. The placentas were examined macroscopically. - Fetal examinations:
- Each foetus was weighed individually (accuracy ±0.01 g) and subjected to external examination, plus an additional examination of the great arteries. The anogenital distance of each foetus was measured. The sex of the fetuses was assigned based on the external observations and was reconfirmed by examining the internal sex organs. All abnormalities (external, soft tissue and skeletal malformations, and variations) found during the foetal examinations were recorded; photographic records were made additionally.
- Statistics:
- The statistical evaluation of data was performed with the program package SAS v9.2 in case of Provantis v.9, or SPSS PC+4.0 (SPSS Hungary Kft, Budapest) in the case of data tabulated in Excel, by an appropriate statistical method.
- Indices:
- No information available.
- Historical control data:
- HC data available
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Transient signs of piloerection in some Mid and High dose animals, slightly noisy respiration in some High dose animals, and hunched back, red coloured faeces and reduced faeces for a two-days period in one
High dose animals were considered to be treatment related but not adverse. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- No test item related mortality was observed in the study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No test item related effect on body weight was observed in the test item related groups when compared to the controls.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No test item related effect on food consumption was observed in the test item related groups when compared to the controls.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related effects.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no findings note at necropsy that were considered to be related to the treatment.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- No test item related effect on the weight of the thyroid gland (with parathyroid glands) was observed in the test item related groups when compared to the controls.
No test item-related changes were observed in the thyroid hormone levels of the dams.
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- The early and the late embryonic loss values of the test item treated groups, and the number of dead foetuses were comparable with the controls. There was no statistically significant difference in the postimplantation loss or
total intrauterine mortality between the treated and control groups. - Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- There was no test item related effect on the intrauterine mortality parameters.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- There was no test item related effect on the intrauterine mortality parameters.
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- The early and the late embryonic loss values of the test item treated groups, were comparable with the controls.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- The number of dead foetuses were comparable with the controls.
- Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- The number of confirmed pregnant, evaluated dams was 24 in the Control and the Mid dose groups, and 25 in the Low and High dose groups.
- Other effects:
- no effects observed
- Description (incidence and severity):
- The mean foetal weight per litter in the test item treated groups did not differ significantly from the control mean value in any treated group.
No abnormalities were observed on the placentas of any treated or control animals. - Details on maternal toxic effects:
- As there were no maternal findings, it was considered that the test item had no maternal toxicity effect at dose levels up to 1000 mg/kg bw/day.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: No maternal toxicity observed at the highest dose level
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
- Description (incidence and severity):
- Up to 1000 mg/kg bw/day did not induce maternal toxicity
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- The mean foetal weight per litter values and the number of retarded foetuses (runts) were comparable with the control in all test item treated groups.
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- The mean number of viable foetuses was comparable with the control mean in all test item treated groups.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- There was no toxicologically significant difference in the sex distribution of foetuses between the control and treatment groups and no effect on anogenital distance of either sex.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- The mean foetal weight per litter values and the number of retarded foetuses (runts) were comparable with the control in all test item treated groups.
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Description (incidence and severity):
- Foetal malformations observed in the study were considered to be incidental. The malformations showed no dose dependency, and were not regarded as a test item related effect.
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- There was no test item related effects on external, visceral, or skeletal development of foetuses in the study.
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- There was no test item related effects on external, visceral, or skeletal development of foetuses in the study.
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- At dose levels up to 1000 mg/kg bw/day did not induce maternal toxicity, embryotoxicity, foetotoxicity, or teratogenicity.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: At dose levels up to 1000 mg/kg bw/day did not induce foetotoxicity
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
- Description (incidence and severity):
- At the highest dose levels up to 1000 mg/kg bw/day did not induce embryotoxicity or foetotoxicity.
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- The test item, when administered daily by oral gavage to pregnant Hannover Wistar rats from gestation days GD6 to GD19 at dose levels up to 1000 mg/kg bw/day did not induce maternal toxicity, embryotoxicity, foetotoxicity, or teratogenicity. There were no malformations or developmental effects attributed to the test item at any dose level.
NOAELmaternal toxicity: 1000 mg/kg bw/day
Based on the lack of any test-item related maternal toxicity effect in any treatment group.
NOAELembryotoxicity: 1000 mg/kg bw/day
Based on the lack of any test-item related intrauterine effect in any treatment group.
NOAELfoetotoxicity: 1000 mg/kg bw/day
Based on the lack of any test-item related foetotoxicity effect in any treatment group.
NOAELteratogenecity: 1000 mg/kg bw/day
Based on the lack of any developmental effects in any treatment group. - Executive summary:
The teratogenic potential of the test item was evaluated in female Hannover Wistar rats in year 2019 according to OECD 414 and GLP. The test substance was administered daily by oral gavage to pregnant rats on gestation days 6 -19, at dose levels of 100, 300 and 1000 mg/kg bw/day. The dams were sacrificed at gestation day 20 and the foetuses were examined for visceral and skeletal variations and malformations.
Up to dose level of 1000 mg/kg bw/day did not induce maternal toxicity, embryotoxicity, foetotoxicity, or teratogenicity. There were no malformations or developmental effects attributed to the test item at any dose level
The following no-observed-adverse-effect (NOAEL) levels were derived:
NOAELmaternal toxicity: 1000 mg/kg bw/day
Based on the lack of any test-item related maternal toxicity effect in any treatment group.
NOAELembryotoxicity: 1000 mg/kg bw/day
Based on the lack of any test-item related intrauterine effect in any treatment group.
NOAELfoetotoxicity: 1000 mg/kg bw/day
Based on the lack of any test-item related foetotoxicity effect in any treatment group.
NOAELteratogenecity: 1000 mg/kg bw/day
Based on the lack of any developmental effects in any treatment group.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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