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EC number: 201-222-2 | CAS number: 79-74-3
- 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:
- 18 November - 2 December 1991
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: No deviations reported. The study fully meets the reported guidelines.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 992
- Report date:
- 1992
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: EPA (40 CFR Part 792)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Details on test material:
- - Name of test material (as cited in study report): Santovar A
- Substance type: white powder
- Physical state: solid
- Analytical purity: 98%
- Impurities (identity and concentrations): not mentioned
- Lot/batch No.: NOA027
- Expiration date of the lot/batch: 06-1992
- Stability under test conditions: yes, verified
- Storage condition of test material: room temperature
- Other: stability, homogeneity and dose of the tested substance are verified
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Age at study initiation: females - 12 weeks
- Weight at study initiation: females - 227 - 276g
- Fasting period before study: not mentioned
- Housing: individually in stainless steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 11 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 -26
- Humidity (%): 40 - 70
- Air changes (per hr): not mentioned
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: prepared once weekly, daily aliquots were stored refrigerated.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Prestudy analytical chemistry evaluations indicated that Santovar A was homogeneous and stable in corn oil for up to eight days when stored refrigerated. Analysis of dosing preparations resulted in average test article recoveries ranging from 99.2 to 103.0% indicating that the mixtures were accurately prepared.
- Details on mating procedure:
- No details mentioned.
- Duration of treatment / exposure:
- From gestation day 6 - 15.
- Frequency of treatment:
- Once daily
- Duration of test:
- Until gestation day 20
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 20, 70, 175 mg/kg/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 25 females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on range finding study (3044.226)
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily and one half and two hours after dosing
BODY WEIGHT: Yes
- Time schedule for examinations: 0, 6, 9, 12, 16, and 20 days.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: thoracic, abdominal and pelvic cavities. Uterus in detail - 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: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No - Statistics:
- Continuous maternal and fetal data, including body weights, body weight gain, food consumption, number of fetuses, implantation sites and corpora lutea, were analyzed by one-way analysis of variance (ANOVA) followed by Dunnett's test. The Mann-Whitney U test was used to compare post-implantation loss and resorptions. Fetal sex ratios were analyzed using the Chi-Square test. Fisher's Exact test was used to analyze the incidence and number of fetal malformations and variations utilzing the dam (litter) as the experimental unit. All analyses were two-tailed with a minimum signifcance level of 5%.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- The toxicity was characterized by an increase in the incidence of reddish colored vaginal discharge and post-dose salivation at the 70.0 mg/kg/day.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- 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 examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not specified
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- not specified
- Dead fetuses:
- not specified
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- not specified
- Other effects:
- not specified
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Oral administration of Santovar A produced slight maternal toxicity at the 70.0 mg/kg/ day level and substantial maternal toxicity at the 175.0 mg/kg/day level. The toxicity was characterized by an increase in the incidence of reddish colored vaginal discharge and post-dose salivation at the 70.0 mg/kg/day level and more frequent and severe clinical signs, body weight loss and reduced food consumption at the 175.0 mg/kg/day level.
Effect levels (maternal animals)
open allclose all
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 20 mg/kg bw/day (actual dose received)
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 70 mg/kg bw/day (actual dose received)
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 70 mg/kg bw/day (actual dose received)
- Basis for effect level:
- other: developmental toxicity
Maternal abnormalities
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- vagina
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean fetal body weight was slightly, but statistically reduced at the 175.0 mg/kg/day level when compared to the control group.
- Reduction in number of live offspring:
- not specified
- Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not specified
- External malformations:
- not specified
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Slight, nonstatistical increases in the incidence of skull anomalies and 7th cervical ribs were observed in the 175.0 mg/kg/day group.
- Visceral malformations:
- not specified
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Mean fetal body weight was slightly, but statistically reduced at the 175.0 mg/kg/day level when compared to the control group. Slight, nonstatistical increases in the incidence of skull anomalies and 7th cervical ribs were observed in the 175.0 mg/kg/day group.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 70 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- not specified
- Basis for effect level:
- fetal/pup body weight changes
Fetal abnormalities
- Key result
- Abnormalities:
- not specified
Overall developmental toxicity
- Key result
- Developmental effects observed:
- not specified
- Lowest effective dose / conc.:
- 20 mg/kg bw/day
- Treatment related:
- yes
Any other information on results incl. tables
The increase in reddish colored vaginal discharge did not result in adverse effects in rats (e.g. no change in spontanious abortions, in litter size etc). Post-dose salivation is not considered adverse. Therefore the reviewer considers 70 mg/kg bw/day as a NOAEL.
Applicant's summary and conclusion
- Conclusions:
- Sprague-Dawley rats were treated with 0, 20, 70, and 175 mg/kg 2,5-Di-t-pentylhydroquinone once daily during gestation days 6-15. Based on the results of this study, a dosage level of 20.0 mg/kg/day was considered a no-observed-effect level (NOEL) for maternal toxicity and a dosage level of 70.0 mg/kg/day was considered a NOEL for developmental toxicity. Santovar A at a dosage level of 175.0 mg/kg/day produced substantial maternal toxicity with minimal developmental toxicity.
- Executive summary:
This study was performed to detect and evaluate the potential embryotoxic or teratogenic effects of Santovar A when administered orally to pregnant rats during the period of major organogenesis. The study design consisted of a vehicle control and three treatment groups. Each group contained twenty-five mated female Sprague-Dawley rats. The test article was mixed with corn oil and administered at dosage levels of 20.0, 70.0 and 175.0 mg/kg/day from gestation day 6 through gestation day 15. All doses were given at a constant volume of 5 ml/kg. Control animals were administered corn oil under the same experimental conditions and at an equivalent dose volume. The animals were observed daily for clinical signs of toxicity. Body weights and food consumption were measured on gestation days 0, 6, 9, 12, 16 and 20. All females were euthanized on gestation day 20 and subjected to cesarean section. Fetuses were individually weighed, sexed and examined for external, visceral and skeletal abnormalities.
Oral administration of Santovar A produced slight maternal toxicity at the 70.0 mg/kg/day level and substantial maternal toxicity at the 175.0 mg/kg/ day level.
The toxicity was characterized by an increase in the incidence of reddish colored vaginal discharge and post-dose salivation at the 70.0 mg/kg/day level and more frequent and severe clinical signs, body weight loss and reduced food consumption at the 175.0 mg/kg/day level. No adverse clinical signs were observed in the 20.0 mg/kg/day group. Similarly, no treatment-related differences in mean body weights, body weight gain or food consumption were observed at the 20.0 or 70.0 mg/kg/day levels. Mean fetal body weight was slightly, but statistically reduced at the 175.0 mg/kg/day level when compared to the control group. All other cesarean section parameters were comparable among the groups. No apparent treatment-related malformations or developmental variations were observed at the 20.0 or 70.0 mg/kg/day levels. Slight, non-statistical increases in the incidence of skull anomalies and 7th cervical ribs were observed in the 175.0 mg/kg/day group. The number of litters with sternebra(e) #5 and/or #6 unossifed was also statistically increased at this level when compared to the control group. The number of litters in the control group with unossifed sternebrae in this study is unusually low when compared to SLS historical control data.
Therefore, it is not clear if the increase in the number of litters with sternebra(e) #5 and/or #6 unossified at the 175.0 mg/kg/day level in this study was spontaneous or associated with the reduced fetal body weights observed at this level.
Based on the results of this study, a dosage level of 20.0 mg/kg/day was considered a no-observed-effect level (NOEL) for maternal toxicity and a dosage level of 70.0 mg/kg/day was considered a NOEL for developmental toxicity.
Santovar A at a dosage level of 175.0 mg/kg/day produced substantial maternal toxicity with minimal developmental toxicity.
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