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EC number: 619-290-0 | CAS number: 97780-06-8
- 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:
- supporting study
- 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:
- 1 991
- Report date:
- 1991
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Reference substance 002
- Cas Number:
- 97780-06-8
- Test material form:
- solid
- Details on test material:
- -Purity: 96.8%
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD®BR
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc., Kingston, New York
- Age at study initiation: Range from 69 days old to 80 days old depending on when they became pregnant
- Weight at study initiation: Mean of 198.1 ± 10.89g (Range 168.0 to 218.1g)
- Fasting period before study: Not specified
- Housing: in suspended, stainless steel, wire mesh cages. Nesting material was not provided because dams were scheduled to be sacrificed before expected parturition
- Diet (e.g. ad libitum): Purina® Certified Rodent Chow #5002
- Water (e.g. ad libitum): Water was from the Wilmington Suburban Water Corp.
- Acclimation period: At least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.9-23.3°C (66-74°F)
- Humidity (%): 40-60%
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12 hours (6 a.m. to 6 p.m.) of artificial illumination daily
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: Methyl cellulose
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The vehicle was prepared (according to standard procedures) at least every two weeks and used as needed to prepared suspensions of the test material. Suspensions of the test material in the vehicle were prepared on the morning of each dosing day by mechanical mixture of the
test material with the vehicle followed by use of a Polytron® homogenizer until the test suspension appeared uniform. Based on a dosage volume of 10 mL/kg, nominal concentrations (pure test substance) of 0 (vehicle only), 6, 25, 100, and 400 mg/mL were prepared for the control, 60, 250, 1000, and 4000 mg/kg groups, respectively.
Two samples (10 mL each) of the test suspension for each dose level were taken at the beginning, twice during and at the end of the treatment period. For each sampling period, one sample was stored at ≤ 16°C just after mixing (fresh frozen) and the other sample was kept at room temperature for 5 hours before being stored at ≤ 16°C. Since dosing could be completed within 5 hours of preparation of the test substance suspensions, the 5-hour room temperature sample was used for comparison with the fresh frozen samples to verify stability of test substance suspensions over the time necessary for completion of dosing on each day.
On the first sampling day, an additional 10 mL sample (unscheduled) of each test substance concentration was taken just prior to dosing (as opposed to the other samples which were taken after mixing the prepared suspensions with a Polytrone homogenizer) and was fresh frozen. This extra sample was taken to see if air, put into the suspension by the homogenizer, might be affecting sampling and concentration analyses. - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: Each female will be mated by overnight cohabitation with a male.
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: Copulation will be verifed each morning by detection of a copulation plug in the vagina or on the cageboard (day 1 of gestation or Day 1G) - Duration of treatment / exposure:
- 10 days (Days 7-16 of gestation)
- Frequency of treatment:
- Daily on Days 7-16 of gestation
- Duration of test:
- 22 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 60 mg/kg bw/day
- Dose / conc.:
- 250 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- Dose / conc.:
- 4 000 mg/kg bw/day
- No. of animals per sex per dose:
- 25 females and 25 males
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Pilot study results
- Rationale for animal assignment: Females selected for the study were ranked by their gestation day 1 body weight and assigned to control or test substance groups by random sampling from strata established within the ranked list.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Clinical signs were recorded within one day of arrival, before breeding initiation, on the mornings of Days 1-22G and on the afternoons of Days 7-16G (dosing period)
BODY WEIGHT: Yes
- Time schedule for examinations: Weights were recorded within one day of arrival, before breeding initiation, and on the mornings of Days 1, 7-17, and 22G
FOOD CONSUMPTION: Yes
- Food consumption: Feeders were weighed each morning on Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 22G to determine food consumption for intervals 1-3, 3-5, 5-7, 7-9, 9-11, 11-13, 13-15, 15-17, 17-19, and 19-22G. Food consumption for the interval was determined by subtracting the partial feeder weight (feeder with remaining food) and any spillage from the initial feeder weight (feeder filled with food).
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 22
- Organs examined: Viscera, liver, uterus, ovary - 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 - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: The first live fetus and, thereafter, every other live fetus of each litter were examined
- Skeletal examinations: Yes: [all per litter]
- Head examinations: Yes: [all per litter] - Statistics:
- The litter (i.e., the proportion of affected fetuses/litter or the litter mean) was considered the experimental unit for the purpose of statistical evaluation. The level of significance selected was p≤0.05. When appropriate, the following parameters were analyzed by the indicated statistical tests:
Parameter Test for Linear Trend Pairwise Test Between Control
and Test Substance Groups
Incidence of pregnancy Cochran-Armitage Fisher's Exact
Clinical signs
Maternal death
Litters with total resorptions
Maternal body weight Orthogonal polynomial Dunnett's test when
Maternal body weight change of dose rank one-way ANOVA
Feed consumption was significant*
Liver weights (absolute & relative)
Nidations Jonckheere's Mann-Whitney U**
Live fetuses
Dead fetuses
Resorptions
Corpora lutea
Fetal weight
Percent resorptions
Incidence of fetal alterations
Mean eye measurements Mann-Whitney U
* When Bartlett's test was significant (p≤0.005), analyses were conducted on the ranks of the original values
** When more than 75% ties occurred in reproductive and fetal parameters, the Cochran-Armitage test was used to detect trends and the Fisher's exact test was applied to detect significant differences between groups.
The use of the words "significant" or "significantly" indicates a statistically significant difference between the control and test substance groups unless otherwise noted.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- For gestation days 1-6 (prior to treatment initiation), a trend was indicated for red discharge from the vaginal opening. This observation was made only for two high dose females on gestation day 1. For the remainder of gestation, no significant trends or increases in clinical signs were observed in the test substance groups (exclusive of signs associated with injuries and/or infections in animals).
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Two females died during the course of the study. Postmortem examination revealed dosing injuries to be the cause of death. One female delivered her pups on the afternoon of gestation day 21 and was sacrificed that day. The remaining females survived until scheduled sacrifice on gestation day 22.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Significant trends were observed for gestation days 7-9, 15-17, and 7-17 (entire treatment interval), but no significant differences in mean body weight changes were observed when the test substance groups were compared to the control group.
For the treatment period (7-17G), the high-dose group had a slightly lower mean weight gain than that of the control group, while mean gains of the other test substance groups were comparable to that of the control group. After treatment cessation, weight gains of all the test substance groups were comparable to those of the control group.
No differences were seen in the mean maternal adjusted body weights. However, these weights and weight changes calculated with these weights for Days 1-22 and 7-22, showed significant trends. The trends were not evident when data from the high-dose group was omitted from the analysis. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Significant trends were observed for gestation days 7-9, 9-11, 11-13, 15-17, and 7-17 (entire treatment interval), and mean food consumption values of the high-dose group were lower than that of the control group for all treatment period intervals (except for those of the 13-15 and 15-17G intervals, all reductions were statistically significant).
Mean food consumption values of the other test substance groups were not significantly different from the control group for any treatment period interval. After treatment cessation, mean food consumption values of all groups were comparable. - Food efficiency:
- 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
- Description (incidence and severity):
- No significant differences in absolute or relative liver weights were found.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No pathological conditions which were regarded as test substance related were observed during the postmortem examination of females.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- There were no abortions in any group.
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One animal in the high-dose had total resorptions at sacrifice, but postmortem examination revealed a puncture wound of the esophagus and white cheesy-appearing material in the thoracic cavity. As no other animals in the group had total resorptions and the resorption rate (mean number of resorptions per litter) was not increased for the high dose group, the embryo/fetal deaths for this female were attributed to the dosing injury and apparent infection.
- Early or late resorptions:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Mean incidence of Resorptions (Standard deviation)
Group Total Early Late
Control 0.8 ± 0.28 0.8 ± 0.28 0.0 ± 0.00
60 mg/kg 0.5 ± 0.16 0.5 ± 0.16 0.0 ± 0.00
250 mg/kg 0.3 ± 0.13 0.3 ± 0.13 0.0 ± 0.00
1000 mg/kg 1.0 ± 0.29 1.0 ± 0.29 0.0 ± 0.00
4000 mg/kg 0.6 ± 0.19 0.5 ± 0.17 0.0 ± 0.05 - Dead fetuses:
- no effects observed
- Description (incidence and severity):
- There were no dead fetuses in any group
- Changes in pregnancy duration:
- not specified
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified - Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- Group Number pregnant
Control 21/25
60 mg/kg 23/25
250 mg/kg 20/25
1000 mg/kg 21/25
4000 mg/kg 22/25
Effect levels (maternal animals)
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Group Mean fetal weight (± Standard deviation)
Control 5.30 ± 0.05 g
60 mg/kg 5.43 ± 0.09 g
250 mg/kg 5.36 ± 0.11 g
1000 mg/kg 5.29 ± 0.08 g
4000 mg/kg 5.16 ± 0.07 g
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- Group Mean Number of Live Fetuses (± Standard deviation)
Control 13.1 ± 0.73
60 mg/kg 13.5 ± 0.41
250 mg/kg 12.9 ± 0.80
1000 mg/kg 13.3 ± 0.61
4000 mg/kg 14.1 ± 0.33 - Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Group Females (± Standard deviation) Males (± Standard deviation)
Control 7.1 ± 0.65 6.0 ± 0.45
60 mg/kg 6.5 ± 0.38 7.0 ± 0.45
250 mg/kg 6.3 ± 0.67 6.6 ± 0.52
1000 mg/kg 6.1 ± 0.61 7.2 ± 0.58
4000 mg/kg 7.3 ± 0.44 6.8 ± 0.48 - Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no external malformations in the Control or 60, 250, or 1000 mg/kg groups. There was one external malformation in the 4000 mg/kg group. This was not was not statistically different.
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no skeletal malformations in the Control or 60, 1000, or 4000 mg/kg groups. There was one skeletal malformation in the 250 mg/kg group. This was not was not statistically different.
- Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The mean percent affected in the Control, 60, 250, 1000, and 4000 mg/kg groups (1.0, 1.2, 1.3, 0.6, and 0.6, respectively) was not statistically different.
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- The percentage of fetuses per litter with variations due to retarded development in the high-dose group was significantly higher than that of the control group and a significant trend was indicated for this parameter. No differences were seen in the overall incidence of variations.
Group Variations due to retarded development [Mean % affected/litter (± Standard deviation)]
Control 22.8 ± 23.04
60 mg/kg 20.3 ± 21.75
250 mg/kg 28.4 ± 26.40
1000 mg/kg 25.6 ± 20.00
4000 mg/kg 35.5 ± 21.09*
* Significantly different from control values (Dunnett's test); p≤0.05
Effect levels (fetuses)
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- fetal/pup body weight changes
- other: Increased incidence of variations due to retarded development in the high-dose group (4000 mg/kg/day)
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of the study, the apparent no effect level for the dam and fetus was 1000 mg/kg/day. Thus, the test substance was not uniquely toxic to the conceptus.
- Executive summary:
Groups of 25 pregnant Crl:CD®BR rats were administered by gavage 0, 60, 250, 1000, or 4000 mg/kg/day of the test substance in a 0.5% aqueous suspension of methyl cellulose on Days 7-16 of gestation.
Among the dams of the groups given the test substance, no compound-related mortality or clinical abnormalities were observed. For the treatment period, the high-dose group had a lower weight gain and significantly decreased food consumption compared to the control group. No other significant differences in body weight changes or food consumption were observed.
No pathological conditions which were regarded as compound related were observed during the postmortem examinations and no significant differences in liver weights were observed.
No adverse effects on reproductive parameters or significant differences in mean fetal weight were observed. However, a significant trend was indicated for mean fetal weight and the mean fetal weight of the high-dose group was lower than that of the control group. No significant differences were observed in the rates of malformations or developmental variations. The percentage of fetuses per litter with variations due to retarded development in the high-dose group was significantly higher than that of the control group and a significant trend was indicated for this parameter. No differences were seen in the overall incidence of variations.
Under the conditions of the study, the apparent no effect level for the dam and fetus was 1000 mg/kg/day. Thus, the test substance was not uniquely toxic to the conceptus.
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