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EC number: 214-254-7 | CAS number: 1117-86-8
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Octane-1,2-diol
- EC Number:
- 214-254-7
- EC Name:
- Octane-1,2-diol
- Cas Number:
- 1117-86-8
- Molecular formula:
- C8H18O2
- IUPAC Name:
- octane-1,2-diol
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Wistar rats, strain: Hsd:HanWIST with appropriate range of bodyweight at study start.
- Source: Advinus Therapeutics Ltd. in-house random bred (conventionally bred)
- Age at treatment start: 11-12 weeks old, both sexes
- Weight at treatment start: 241-294 g for males, 185-210 g for females
- Housing in polysulfone cages with stainless steel top grill
during pre-pairing dosing period: In groups of 2 by sex
during pairing: 1 male+1 female/cage
males after pairing: In groups of 2 by sex
females during gestation and lactation: Females housed individually (+litter).
- Bedding material (in polysulfone cages): steam sterilised clean corn cob
- Diet (ad libitum): Teklad certified Global 14% protein Rodent maintenance diet - pellets, Harlan, 5800 AN Venray, The Netherlands
- Water (ad libitum): Deep bore-well water passed through activated charcoal filter and UV irradiated, regular quality control
- Acclimation period: 5 days before treatment start, after examination for health and suitability.
ENVIRONMENTAL CONDITIONS
The animal room was maintained at (target ranges for temperature and relative humidity):
- Temperature (°C): 19 - 24°C
- Relative Humidity (%): 57 - 67 %
- Photoperiod (artificial lighting): 12 hrs day / 12 hrs night
- Ventilation: 12-15 times/h
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Remarks:
- PEG 300
- Details on exposure:
- - Concentration in vehicle: The concentration of the test material in vehicle varied between dose groups thus allowing constant dosage volume in terms of mL/kg bw/day. Concentrations amounted to 15, 30, and 100 mg/ml vehicle, accordingly.
- Amount (dose volume by gavage): 10 mL/kg bw/day.
Actual dose volumes were calculated at about weekly or shorter intervals accounting for the latest bodyweight.
- Frequency of preparation of dose formulations: Once a week
Treatment of parental animals by oral gavage administration. Test substance was not directly administered to F1 animals, as these pups were sacrificed on Day 4 post partum, i.e. Day 4 of lactation. - Details on mating procedure:
- - Male/female ratio per cage: 1/1
- Length of cohabitation: At the most 14 days, until proof of pregnancy was confirmed.
- Proof of pregnancy: Formation of vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- For analysis of the test substance in the vehicle GC / FID was used with a DB-35 column (30 m long, 0.53 mm i.d., 0.5 μm film thickness). The analytical method was validated. The mean contents of the test substance in dose formulations were found to be well within the acceptance limit (within +/- 15%) of dose theoretical concentration; the relative standard deviation was equal to or less than 10%.
- Duration of treatment / exposure:
- - Treatment period, parental males: 42 days (14 days before mating and 28 days including up to 14 days for mating)
- Treatment period, parental females (dams): approx. 40-45 days (from 14 days prior to mating to Lactation Day 4)
- Pups were not treated directly (possibly via milk): until Lactation Day 4. - Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 150 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Positive control:
- Not included in the study.
Examinations
- Parental animals: Observations and examinations:
- Clinical observations performed and frequency:
- Clinical signs: Daily (covering external appearance, motor activity & morbidity in each animal)
- Body weight, Males: Weekly from Treatment Day 0 to 42 (i.e. from the first treatment day until the day before necropsy).
Body weight, Females: Weekly for pre-pairing & pairing period, Gestation Days 0, 7, 14, 20 & Lactation Days 0 (i.e. the day post partum) & 4
- Food consumption, Males: Weekly for pre-pairing period
Food consumption, Females: Weekly for pre-pairing period (Days 0-7 & 7-14) and for Gestation (Days 0-7, 7-14, 14-20) & Lactation (Days 0-4, i.e. the day post partum until the day of necropsy). - Oestrous cyclicity (parental animals):
- not observed
- Sperm parameters (parental animals):
- Parameters examined in male parental animals: testis weight, epididymis weight, histopathology with special emphasis on stages of spermatogenesis in male gonads and of interstitial testicular cell structure
- Litter observations:
- LITTER PARAMETERS EXAMINED
- Delivery or post-implantation survival index (Total no. of pups born / Total no. of implantation sites) x 100
- Total no. of pups (alive and dead), sex
- Body weight of live pups (on Lactation Days 1 and 4)
- No. of pups alive, dead or cannibalised on Lactation Days 1, 2, 3, 4
- Live birth index (No. of live pups on Lactation Day 1 / Total no. of pups born) x 100
- Viability index (No. of live pups on Lactation Day 4 / No. of live pups on Lactation Day 1) x 100
- Sex ratio (Nos. of male pups and Nos. of female pups)
- Clinical signs, on each day after birth - Postmortem examinations (parental animals):
- GROSS PATHOLOGY: Yes, see below
WEIGHING OF ORGANS: Yes, see below
HISTOPATHOLOGY: Yes, see below
Terminal sacrifice
- Males: Killed on the day after the 42-day treatment period.
- Terminal sacrifice, Females (dams): Killed on Lactation Day 4
- Terminal sacrifice, unmated Female: 1 mid dose female (300 mg/kg/day) which had failed to mate was killed on the day after 26 daily doses
Gross pathology: Necropsy with tissue collection.
The number of implantation sites and corpora lutea was recorded for all dams
Organs Weights: The following organs were weighed at necropsy and their ratios to terminal bodyweight determined:
testes, epididymides.
Histopathology: The following organs were microscopically observed for the control and 1000 mg/kg bw/day groups:
testes, epididymides, prostate, seminal vesicles and coagulating glands, ovaries.
- Postmortem examinations (offspring):
- On Lactation Day 4 external macroscopic examination of all survivors for gross abnormalities.
- Statistics:
- The statistical analysis of the experimental data was carried out using the validated package in Excel and also using licensed copies of SYSTAT Statistical package ver.12.0. All quantitative variables like body weight, food consumption, organ weights and organ weight ratios were tested for normality (Shapiro-Wilk test) and homogeneity of variances (Levene’s test) within the group before performing a one-factor ANOVA modeling by treatment groups. Non-optimal (non-normal or heteroschedastic) data were transformed, before using ANOVA. Means between treatment and control groups were compared using Dunnett’s test if the overall ‘F’ test was found to be significant.
Pre-implantation loss (%), post implantation loss (%), no. of corpora lutea, implantations, pre-coital interval and gestation length (days) were analyzed after suitable transformation (√ x + ½) of the data. One-way analysis of variance (ANOVA) was carried out for the transformed data. Dunnett’s pairwise comparison of the treated means with the control mean was done for the significant group differences.
Z test was performed for testing the differences in proportions for mating and fertility indices.
All analyses and comparisons were evaluated at the 5% (P≤0.05) level. - Reproductive indices:
- - Pre-coital interval (pairing days until detection of mating)
- No. of animals mating (evidence of successful copulation, i.e. at least one copulation plug or a sperm positive vaginal smear)
- No. of animals achieving pregnancy
- Percentage mating or copulation index (No. of animals mating/No. of animals paired) x 100
- Conception rate or fertility index (No. of animals achieving pregnancy/No. of animals mated) x 100
- Gestation length (time elapsing from detection of mating until the day prior to confirmation of parturition)
- No. of pregnant animals
- No. of pregnant animals with parturition
- Gestation Index (No. of animals achieving pregnancy with parturition/No. of animals achieving pregnancy) x 100
- No. of corpora lutea
- No. of implantation sites
- Implantation index (No. of implantation sites/No. of corpora lutea) x 100 - Offspring viability indices:
- - Mean litter size per group (number of implantations - number of live fetuses / number of implantations) x 100
- Day 4 survival index (No. of live pups on Lactation Day 4 / No. of live pups born) x 100.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- semi-solid feces in 2/10 males at 1000 mg/kg/day from Day 5 to 9.
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- one dam from the 1000 mg/kg/d group was found dead on treatment day 37 (GD21); attributed to spontaneous dystocia thus not related to treatment.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Significantly lower mean body weight was observed in males at 1000 mg/kg Bwt/day on Day 43; mean body weight gain was lower in males between Days 1-8, 36-43 and 1-43. Reduced body weight gain in females at 1000 mg/kg/day between Day 1-8 and 11-15. See attached Tables in "Attached background material".
- Food consumption and compound intake (if feeding study):
- no effects observed
- 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
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- only reproduction organs were examined
- Other effects:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- represented by testes & epididymis weights and absence of histopathological findings.
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- See attached Tables in "Attached background material".
Effect levels (P0)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- reproductive toxicity
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- parental toxicity
- Effect level:
- > 300 - < 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- other: with regard to parental toxicity the NOAEL was derived at the dose level of 300 mg/kg/d based on reduction in body weight gain primarily in males of the high dose group
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- System:
- other: body weight gain
- Organ:
- other: body weight gain
- Treatment related:
- yes
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- See attached Table on survival data of pups in "Attached background material".
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- See attached Table on body weight of pups in "Attached background material".
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
Details on results (F1)
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- developmental toxicity
- Generation:
- F1
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: NOAEL = highest dose tested.
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- In this screening study there were no treatment related effects on reproduction or developmental toxicology parameters. The no-observed-adverse- effect-levels (NOAEL) for parental toxicity regarding reprotoxic endpoints and for foetal toxicity are 1000 mg/kg bw/day. The NOAEL for general parental toxicity was derived at 300 mg/kg bw/day based on reduction of weight gain at the highest dose.
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