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EC number: 202-589-1 | CAS number: 97-53-0
- 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:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- June 16, 1998 to August 18, 1998
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study design is considered to follow OECD guideline Test Guideline No 414 (2001). The study was fully reliable (Klimisch score = 1), however the reliability score was lowered to 2 which is the maximum score for read-across.
Cross-reference
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 999
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Isoeugenol
- EC Number:
- 202-590-7
- EC Name:
- Isoeugenol
- Cas Number:
- 97-54-1
- Molecular formula:
- C10H12O2
- IUPAC Name:
- 2-methoxy-4-prop-1-en-1-ylphenol
- Details on test material:
- - Name of test material (as cited in study report): Isoeugenol
- Analytical purity: 97.9%
- Lot/batch No.: 46928
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Age at study initiation: Not reported
- Weight at study initiation: 232-275 g on gestational day 0
- Fasting period before study: Not reported
- Housing: Sani-Chip hardwood cage litter
- Diet (e.g. ad libitum): Purina Certified Roden Chow ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 10 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.5-23.3
- Humidity (%): 39.8-59.9
- Air changes (per hr): Not reported environmental conditions monitored and controlled by computer
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: Not reported
Administration / exposure
- Route of administration:
- oral: gavage
- Type of inhalation exposure (if applicable):
- other: not applicable
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Not reported
- Concentration in vehicle: Not reported
- Amount of vehicle (if gavage): 5 ml/kg (administered dose volume) - Analytical verification of doses or concentrations:
- no
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility: not reported
- Further matings after two unsuccessful attempts: not reported
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy:sperm found in vaginal lavage referred to as day 0 of pregnancy
- Any other deviations from standard protocol: not reported - Duration of treatment / exposure:
- Day 6 through day 19 of gestation
- Frequency of treatment:
- Daily
- Duration of test:
- 13 days
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
250 mg/kg bw/day
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
500 mg/kg bw/day
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
1000 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 25 pregnant females/group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on screening study
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily at dosing, and at 0.5 and 2 hours after dosing
BODY WEIGHT: Yes
- Time schedule for examinations: Gestational Day 0, 6 through 19, 20 and immediately following termination at day 20
FOOD CONSUMPTION: Yes
- Time schedule for examinations: Gestational Day 0, 6, 9, 12, 15, 18, 19, and 20
WATER CONSUMPTION: Yes
- Time schedule for examinations: Gestational Day 0, 6, 9, 12, 15, 18, 19, and 20
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined: liver, gravid uterus, thoracic and abdominal cavities - 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: number of dead and live fetuses - Fetal examinations:
- - External examinations: Yes: all live fetuses
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter - Statistics:
- SAS software
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Compared to control, findings included lower maternal body weight (4.6%, 11.6%, and 9.9% lower at dose levels of 250, 500, and 1,000 mg/kg body weight/day, respectively) when measured on GD 20 and statistically significant and dose-dependent lower gestation body weight gain (13.6%, 22.6%, and 30.5% lower at dose levels of 250, 500, and 1,000 mg/kg body weight/day, respectively) when measured over GD 0 to 20 . Other notable changes included clinical signs of piloerection and sedation at 500 and 1,000 mg/kg body weight/day, and lower gravid uterine weight (statistically significant values of 8.54% and 10.5% at 500 and 1,000 mg/kg body weight/day, respectively) and lower maternal relative food intake (statistically significant values of 15.3% at 1,000 mg/kg body weight/day). There were no treatment-related group mean differences for the following reproductive parameters: number of corpora lutea per dam, number of implantation sites per dam, percent preimplatation loss per dam, percent preimplantation loss per litter, resorptions, late foetal deaths, average litter size, and percentage of male foetuses per litter
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- LOAEL
- Effect level:
- 250 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 500 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Dose descriptor:
- LOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
The only developmental effect noted was a 7 to 9% decrease in body weight in high-dose foetuses when compared with control group. There were no statistically significant differences among groups for the incidences of foetal malformations (i.e., total, external, or skeletal); however, the incidence of skeletal variations (i.e., unossified sternebrae) was significantly increased in high-dose foetuses. Incidental occurrences of visceral malformations were noted in one mid-dose and one high-dose foetus; however, these did not occur in a dose-related manner and were therefore considered not to be relate to the test article; these variations included enlarged lateral ventricle, enlarged nasal sinus, agenesis of the innominate artery, and distended ureter.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 500 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: based on intra-uterine growth retardations mildly delayed skeletal ossification observed at 1000 mg/kg bw/day. However, this finding is likely secondary to maternal toxicity and not indicative of a teratogenic effect.
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- LOAEL maternal toxicity = 250 mg/kg bw/day, based on dose-dependent reduced body weight gain.
NOAEL developmental toxicity = 500 mg/ kg bw/day, based on intra-uterine growth retardations mildly delayed skeletal ossification observed at 1000 mg/kg bw/day. However, this finding is likely secondary to maternal toxicity and not indicative of a teratogenic effect. - Executive summary:
A read-across strategy is used for the endpoint of developmental toxicity, with justification provided below.
Justification for Read-Across
The use of isoeugenol (CAS No. 97-54-1) as a structural surrogate for eugenol (CAS No. 97-53-0) is justified on the basis of structural similarity; both substances are 2-methoxy-4-propenylphenol isomers, whose chemical structures are identical except for the position of the double bond in the propenyl substituent. The difference in the position of the double bond is expected to exert little or no effect on the physical-chemical properties of the two substances with respect to biological activity, and their absorption and distribution profiles are therefore also expected to be essentially identical. Based on data from studies in rats, the pharmacokinetic profiles of isoeugenol and eugenol appear to be similar; the major route of elimination of these compounds isviathe urine and the major metabolites are glucuronic acid and sulphate conjugates.
Summary of Study
The teratogenic potential of isoeugenol was evaluated in a key oral embryo-foetal developmental study; administration of the isoeugenol to CD rats on Gestation Days (GD) 6 to 19 at dose levels up to 1,000 mg/kg body weight/day resulted in a number of test article-related maternal effects beginning at the low dose level (including, but not limited to, decreases in maternal body weight and body weight gain and significant decreases in gravid uterine weight and maternal relative food intake at the higher dose levels). A significant increase in the incidence of skeletal variations (i.e., unossified sternebrae) was noted in high-dose foetuses; however, this finding is likely secondary to maternal toxicity and not indicative of a teratogenic effect.
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