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EC number: 269-027-5 | CAS number: 68171-38-0
- 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:
- 19 Jun 2006 - 01 Feb 2007
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 007
- Report date:
- 2007
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2001
- Deviations:
- yes
- Remarks:
- Exposure gestational days 6-17 only
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Reference substance 001
- Cas Number:
- 85883-73-4
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Remarks:
- Crl:CD(SD)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC, USA
- Age at study initiation: 70 days
- Weight at study initiation: 222-295 g (females)
- Housing: upon arrival and until pairing, all rats were individually housed in clean, stainless steel wire-mesh cages suspended above cage-board; the rats were paired for mating in the home cage of the male; following positive evidence of mating, the females were returned to individual suspended wire-mesh cages.
- Diet: basal diet Certified Rodent LabDiet 5002 (PMI Nutrition International, LLC), ad libitum
- Water: municipal water (reverse osmosis-purified, on-site), ad libitum
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50 ± 20
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The daily aliquots were prepared weekly, stored refrigerated under nitrogen when not in use, and allowed to stand at room temperature for at least 1 h prior to administration.
- Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- The test article was administered neat. Therefore, no analyses were conducted by the Analytical Chemistry Department of the testing laboratory (WIL Research Laboratories, LLC).
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Proof of pregnancy: vaginal plug/sperm in vaginal smear referred to as Day 0 of pregnancy - Duration of treatment / exposure:
- Day 6 -17 of gestation
- Frequency of treatment:
- daily, 7days/week
- Duration of test:
- Day 20 of gestation
Doses / concentrationsopen allclose all
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 500 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 2 500 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 25 females
- Control animals:
- other: Yes, administration of water at 2.65 mL/kg (highest dose volume).
- Details on study design:
- - Dose selection rationale: dosage levels were selected based on the results of previous studies and were selected by the sponsor following consultation with the WIL study director. A high-dose of 2500 mg/kg/day was chosen as it meets or exceeds the amount expected to be used for clinical purposes.
- The dosage volumes used to obtain the desired dosage levels were based on the specific gravity of the test article at approximately 20ºC (0.942 g/mL); 0.53, 1.59 and 2.65 mL of neat test substance were administered.
- Individual dosages were based on the most recently recorded body weights to provide the correct mg/kg/day dose.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked: signs of toxicity, moribundity and mortality
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at the time of dose administration and approximately 1 h following dose administration from gestation Days 0 through 20
BODY WEIGHT: Yes
- Time schedule for examinations: gestation Days 0, 6-18 (daily) and 20
FOOD CONSUMPTION: Yes
- Food consumption for each animal calculated as g/animal/day and g/kg/day for the corresponding body weight change intervals
- Time schedule for examinations: on gestation Days 0, 6-18 (daily) and 20
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 20
- Organs examined: placenta, uterus and ovaries
- 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: Yes
- Number of late resorptions: Yes
- Other: Maternal tissues were preserved in 10% neutral-buffered formalin for possible future histopathologic examination only as indicated by the gross findings. Representative sections of corresponding organs from a sufficient number of control animals were retained for comparison. - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter - Statistics:
- Analyses were conducted using two-tailed tests (except as noted otherwise) for minimum significance levels of 1% and 5%, comparing each test article-treated group to the control group. Each mean was presented with standard deviation (S.D.) and the number if animals (N) used to calculated the mean. In addition, percent difference from control was presented for body weights. Data obtained from nongravid animals were excluded from statistical analyses. Due to the different rounding conventions inherent in the types of software used, the means and standard deviations on the summary and individual tables may differ by ± 1 in the last significant figure. Where applicable, the litter was used as the experiment unit.
Mean maternal body weights (absolute and net), body weight changes (absolute and net) and food consumption, gravid uterine weights, numbers of corpora lutea, implantation sites and viable fetuses, and fetal body weights (separately by sex and combined) were subjected to a parametric one-way analysis of variance (ANOVA) (Snedecor and Cochran, 1980) to determine intergroup differences. If the ANOVA revealed statistically significant (p < 0.05) intergroup variance, Dunnett's test (Dunnett, 1964) was used to compare the test article-treated groups to the control group. Mean litter proportions (percent per litter) of prenatal data (viable and nonviable fetuses, early and late resorptions, total resorptions, pre- and postimplantation loss, and fetal sex distribution), total fetal malformations and developmental variations (external, visceral, skeletal and combined) and each particular external, visceral and skeletal malformation or variation were subjected to the Kruskal-Wallis nonparametric ANOVA test (Kruskal and Wallis, 1952) to determine intergroup differences. If the ANOVA revealed statistically significant (p < 0.05) intergroup variance, Dunn’s test (Dunn, 1964) was used to compare the test article-treated groups to the control group. - Indices:
- Intrauterine data were summarized using 2 methods of calculation:
1) Group Mean Litter Basis: Postimplantation Loss/Litter = No. Dead Fetuses, Resorptions (Early/Late)/Group/No. Gravid Females/Group
2.) Proportional Litter Basis:
Summation Per Group (%) = ∑ Postimplantation Loss/Litter (%)/No. Litters/Group
Where:
Postimplantation Loss/Litter (%) = (No. Dead Fetuses, Resorptions (Early/Late)/Litter/No. Implantation Sites/Litter) x 100
The fetal developmental findings were summarized by: 1) presenting the incidence of a given finding both as the number of fetuses and the number of litters available for examination in the group; and 2) considering the litter as the basic unit for comparison and calculating the number of affected fetuses in a litter on a proportional basis as follows:
Summation per Group (%) = ∑ Viable Fetuses Affected/Litter (%)/No. Litters/Group
Where:
Viable Fetuses Affected/Litter (%) = (No. Viable Fetuses Affected/Litter/No. Viable Fetuses/Litter) x 100
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Effects were non-adverse. In the 1500 and 2500 mg/kg bw/day groups, test article-related salivation was noted for 8 and 6 females, respectively (1-2 occasions each), immediately prior to dose administration on gestation Days 15-17. In addition, salivation-related findings (clear material on various body surfaces) were noted for 2 and 3 females in these same respective groups (1-2 occasions each) approximately 1 h following dose administration, primarily on gestation Days 6-7 and 14-15.
Other findings noted in the treated groups including hair loss, scabbing and red material on various body surfaces, as well as rales and soft stool, occurred infrequently, at similar frequencies in the control group, and/or in a manner that was not dose-related. - Mortality:
- no mortality observed
- Description (incidence):
- All females in the control, 500, 1500 and 2500 mg/kg bw/day groups survived to the scheduled necropsy on gestation Day 20.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Mean maternal body weights, body weight gains, net body weights, net body weight gains in the 500, 1500 and 2500 mg/kg bw/day groups were unaffected by test article administration. Differences from the control group were slight and not statistically significant.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- A slightly lower food consumption observed in the 2500 mg/kg/day group during gestation Days 6-9, 9-12, 12-18 and when the entire treatment period was evaluated. This finding was not considered adverse based on the lack of an effect on mean body weights.
- 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:
- not examined
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- maternal toxicity
- Effect level:
- >= 2 500 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: no adverse effects observed
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- The numbers of fetuses (litters) available for morphological evaluation were 336(23), 361(24), 358(25) and 357(24) in the control, 500, 1500 and 2500 mg/kg bw/day groups, respectively.
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Description (incidence and severity):
- Malformations observed in 1(1), 2(2), 1(1) and 0(0) foetuses (litters) in the control, 500, 1500 and 2500 mg/kg bw/day group, respectively, were considered spontaneous in origin. A malformation was also noted for 1 late resorption in the 500 mg/kg bw/day group.
One foetus in the 1500 mg/kg bw/day group had localized foetal oedema (head) and one foetus in the 500 mg/kg bw/day group had microphthalmia (unilateral); skeletally, the left orbit appeared smaller than normal. Vertebral agenesis (all vertebrae posterior to lumbar vertebra no. 2 absent) was noted for a single foetus in the 500 mg/kg bw/day group, and 1 late resorption in the 500 mg/kg/day group had foetal oedema. One foetus in the control group had anophthalmia. - Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- embryotoxicity/teratogenicity rat
- Effect level:
- >= 2 500 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects observed
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Fetal malformations and developmental variations, when observed in the test article-treated groups, occurred infrequently or at a frequency similar to that in the control group, did not occur in a dose-related manner and/or were within the historical control data ranges. Based on these data, no fetal malformations or developmental variations were attributed to the test article.
Applicant's summary and conclusion
- Conclusions:
- The substance had no effect on intrauterine development.
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