Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 944-405-9 | CAS number: -
- 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
- Study period:
- 2015-12-08 till 2016-01-18
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 016
- Report date:
- 2016
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- March, 1996
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- TNO Triskelion BV, Utrechtseweg 48, 3704 HE Zeist, The Netherlands
- Limit test:
- no
Test material
- Reference substance name:
- Reaction mass of (4Z)-4-ethylidene-2-propoxycyclohexanol and (4E)-4-ethylidene-2-propoxycyclohexanol and (5Z)-5-ethylidene-2-propoxycyclohexanol and (5E)-5-ethylidene-2-propoxycyclohexanol
- EC Number:
- 944-405-9
- Molecular formula:
- C11H20O2
- IUPAC Name:
- Reaction mass of (4Z)-4-ethylidene-2-propoxycyclohexanol and (4E)-4-ethylidene-2-propoxycyclohexanol and (5Z)-5-ethylidene-2-propoxycyclohexanol and (5E)-5-ethylidene-2-propoxycyclohexanol
- Test material form:
- liquid
- Details on test material:
- - Substance name as cited in test report: FRET 13-0156
- Phystical state: clear, yellowish liquid
- Storage conditions: ambient temperature (15-25 °C), protected from light
1
- Specific details on test material used for the study:
- - Substance name in the test report: FRET 13-0156
- Physical state: clear liquid
- Storage conditions: 15-25 °C, dark
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- Outbred rats (RccHanTM:WIST)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Schulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Weight at study initiation: Males: 303.38 – 307.00 g; Females: 188.58 – 190.68 g
- Housing: Macrolon cages with a bedding of wood shavings (Lignocel) and strips of paper (Enviro-dri) and a wooden block as environmental enrichment. During the premating period, the animals were housed in groups of four per sex. For mating, one male and one female were housed together. Mated females were housed individually in macrolon cages, which were placed in another cage rack. The location of the mated females in the new cage racks was determined by the date of mating females found sperm-positive on the same date were considered a "lot") and by the animal number within each lot the mated females were housed in the order of animal number). After delivery, the cage containing the dam with litter was transferred to another cage rack, the location being determined by delivery date and animal number as described for mated females. On the day of FOB testing and motor activity assessment, animals were temporarily kept singly.
- Diet: ad libitum, from their arrival, the rats received a cereal-based (closed formula) powder rodent diet (VRF1 (FG)) from a commercial supplier (SDS Special Diets Services, Witham, England).
- Water: ad libitum
- Acclimation period: > 5 days
DETAILS OF FOOD AND WATER QUALITY: Each cage was supplied with domestic mains tap-water suitable for human consumption (quality guidelines according to Dutch legislation based on EC Council Directive 98/83/EC). The water was given in polypropylene bottles, which were cleaned weekly and filled as needed.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 45-65
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
- Rate of preparation of diet: two times during the study (on 03 December 2015 and on 04 January 2016)
- Mixing appropriate amounts with: VRF1 (FG) diet
- Storage temperature of food: ≤ -18 °C - Details on mating procedure:
- - M/F ratio per cage: 1
- Length of cohabitation: until mating occurred or 1 week had elapsed
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged: individually - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- From both batches of diets prepared in the study (03 December 2015 and 04 January 2016), samples were taken and stored in a freezer (≤ -18 °C). Analyses to determine the stability, homogeneity and content of the test substance in the test diets were conducted as indicated below.
- Content: the content of the test substance at each dietary level was determined in the batches prepared on 03 December 2015 and 04 January 2016.
- Homogeneity: the homogeneity (and content) of the test substance in the experimental diets was assessed in the first batch (03 December 2015), by analyzing five samples (taken at different locations in the feed container) of each test diet in duplicate. One sample of the control diet was analyzed.
- Stability: to demonstrate the stability of the test substance under experimental conditions, samples of the batch of test diets prepared on 03 December 2015 (low-dose diet, mid-dose diet and high dose diet) were analyzed at t=0 and reanalyzed after storage in the animal room (in an open container) for 4 days, and after storage in a freezer (<-18 °C) for at least 5 weeks. - Duration of treatment / exposure:
- Duration of study, following acclimatisation, is dependent on the female performance and is approximately 54 days, [at least 14 days pre-mating, (up to) 14 days mating, 22 days gestation, 4 days lactation].
- Frequency of treatment:
- Continously
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 500 mg/kg diet
- Remarks:
- Equivalent to at least 84.56 and 104.34 mg/kg bw/day for males and females, respectively
- Dose / conc.:
- 5 000 mg/kg diet
- Remarks:
- Equivalent to at least 279.86 and 332.8 mg/kg bw/day for males and females, respecively
- Dose / conc.:
- 15 000 mg/kg diet
- Remarks:
- Equivalent to at least 870.22 and 794.48 mg/kg bw/day for males and females, respectively
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- Dose selection rationale: the doses are based on the results of a dose-range finding study.
- Positive control:
- No.
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: in the morning hours and the afternoon. On Saturdays, Sundays and public holidays only one check per day was carried out.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to the first exposure and then once weekly until sacrifice for males, or until delivery of the first lot for females.
BODY WEIGHT: Yes
- Time schedule for examinations: one day before the start of the treatment and at the start of the study (day 0). Males were weighed weekly until sacrifice. Females were weighed once per week during the premating period. Mated females were weighed on days 0, 7, 14 and 21 during gestation and on day 0 and 4 of lactation. One non-mated female was weighed once per week after the mating period. All animals were weighed on their scheduled necropsy date in order to calculate the correct organ to body weight ratios.
FOOD CONSUMPTION AND COMPOUND INTAKE :
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to the end of the premating period (day 13)
- Anaesthetic used for blood collection: Yes, CO2/O2
- Animals fasted: Yes, overnight
- How many animals: 5 rats/sex/group
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to the end of the premating period (day 13)
- Animals fasted: Yes, overnight
- How many animals: 5 rats/sex/group
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: shortly prior to sacrifice
- Dose groups that were examined: 5 males/group and in 5 females/group with a litter
- Battery of functions tested: FOB and motor activity - Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined on days 0 and 4 in [F1] offspring: total litter size, numbers of each sex, number of stillbirths, live-and dead pups and grossly malformed pups. Mean pup weight was calculated per sex and for both sexes combined.
GROSS EXAMINATION OF DEAD PUPS:
Yes, grossly malformed pups were sacrificed and examined. A necropsy was performed on stillborn pups and pups dying during the study; macroscopic abnormalities were recorded. At necropsy of the dams, at or shortly after day 4 of lactation, pups were examined externally for gross abnormalities and sacrificed by gradual CO2 anesthesia, followed by irreversible hypothermia. - Postmortem examinations (parental animals):
- SACRIFICE
All surviving male and female parent animals were sacrificed by exsanguination from the abdominal aorta whilst under CO2/O2 anesthesia and then examined grossly for pathological changes.
GROSS NECROPSY
Gross necropsy consisted of ovaries (after counting the corpora lutea), uterus (after counting of the implantation sites), testes, epididymides, seminal vesicles (with coagulating glands), prostate, all gross lesions. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring was sacrificed on or shortly after day 4 of lactation.
- Pups were examined for gross abnormalities - Statistics:
- Tests were generally performed as two-sided tests with results taken as significant where the probability of the results was p<0.05 or p<0.01. Non-mated females were excluded from mean data tables presenting data from the gestation and lactation periods. Additional information is supplied in the "any other information on materials and methods".
- Reproductive indices:
- - mating days until Day 0 pc = time between the start of mating and successful copulation
- duration of gestation = time between gestation day 0 and day of delivery
- female mating index = (number of females inseminated/number of females placed with males) x 100
- male mating index = (number of males placed with females /number of females inseminated) x 100
- female fertility index = number of pregnant females*100/number of inseminated females
- male fertility index = number of males with pregnant females*100/number of males placed with females
- gestation index = (number of females with live pups / number of females pregnant) x 100
- pre-implantation loss = [(number of corpora lutea – number of implantation sites) / number of corpora lutea] x 100
- prenatal loss = (Total number of Implantations - Total number of pups delivered) x 100 / Total number of Implantation Sites
- perinatal loss = (Total number of pups delivered - Total number of alive pups delivered) x 100 / Total number of pups delivered. - Offspring viability indices:
- - live birth index = (number of pups born alive/number of pups born) x 100
- viability index day 0 - 4 = (number of pup surviving 4 days/number of liveborn on day 0) x100
- sex ratio day 0 = [(number of live male or female pups on day 0 / number of live pups on day 0] x 100
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One control male died during the mating period. The death of this rat was not treatment-related.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- Mean food intake in the high-dose group females was statistically significantly lower in the first week of the premating period, but recovered thereafter. This was considered to be related to the palatability of the test substance.
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- - Phospholipids were statistically significantly increased in both males and females of the highdose group and glucose plasma levels were statistically significantly decreased in females of the high dose group.
- In absence of a dose response relationship statistically significant differences in PO4 in males of the low-dose and mid-dose group were considered not related to treatment. ASAT and ALAT activity were statistically significantly decreased in males of the low-dose (ASAT) and high-dose group (ASAT and ALAT). No toxicological relevance was attached to these findings, because the results for ALAT activity were within the historical control range (see Table 7a) and for ASAT and ALAT activity an increase rather than a decrease in these parameters is considered to represent a toxic effect. - Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The control group male that was found dead during the mating period showed pelvic dilatation and tubular dilatation in the kidneys. In addition the kidneys were a bit autolytic. The stomach was moderately autolytic and the thymus was severely autolytic. The prostate showed mild mixed inflammation with hemorrhagic material in the lumina. The prostate was a bit autolytic.
As the male was not exposed to the test substance, these findings were considered incidental findings, not related to the treatment.
Reproductive function / performance (P0)
- Reproductive performance:
- no effects observed
Details on results (P0)
Effect levels (P0)
- Key result
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One pup in the control group and one pup in the high dose group showed a wound. Another pup in the control group showed cyanosis. There were no treatment-related signs in pups during the lactation period.
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No macroscopic examination could be performed on the pups that were missing during the lactation period. The one pup in the control group that was found dead was not macroscopically examined.
Effect levels (F1)
- Key result
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Any other information on results incl. tables
Analytical results - the analytical report concludes that:
- The test substance was homogeneously distributed in the diet at each dose level.
- The test substance was stable in the test diets for the low and high dose groups under the experimental conditions of 4-days storage in the animal room. In the mid dose test diets concentrations did not meet the acceptance criteria related to the actual measured t = 0 concentration. However, when related to the nominal concentration the difference is 3% and accepted.
- Upon storage in a closed container in a freezer for more than 5 weeks concentrations were 14-20% lower as compared to the actual measured concentrations and therefore FRET 13- 0156 was considered to be unstable upon storage in a freezer, resulting in a loss of maximal 20% as compared to the t=0 concentration.
- The concentration of the test substance was close to intended (90-110%) for all diets at all dose levels, except for the low dose diet (1500 mg/kg) prepared on 3 December that differed +14% from the nominal. This slight deviation from the acceptance criteria was considered acceptable.
Applicant's summary and conclusion
- Conclusions:
- Based on the absence of adverse effects on male and female fertility and reproductive performance, the NOAEL was determined to be ≥15000 mg/kg diet corresponding to an intake of at least 894 mg/kg body weight per day in females and at least 870 mg/kg body weight per day in males.
- Executive summary:
In this GLP compliant study performed according to OECD guideline 422, the possible effects of the test substance on general toxicity and reproductive performance and development of pups were examined in groups of 12 male and 12 female Wistar rats. The test substance was administered at constant concentrations in the diet at levels of 0 (control), 1500, 5000 and 15000 mg/kg diet during a premating period of 2 weeks and during mating, gestation until day 4 of lactation. These dietary levels provided an overall mean intake of at least 104, 333 and 894 mg/kg body weight per day in females of the low-, mid- and high-dose group and at least 85, 280 and 870 mg/kg body weight per day in males of the low-, mid- and high-dose group.
The content and homogeneity of the test substance in the carrier were analysed and accepted. Stability testing showed a decrease in concentration after storage of the test substance in the carrier in the freezer for more than 5 weeks and slightly lower concentrations in the mid dose group after 4 days in the animal room. There was no treatment-related mortality. Daily clinical observations did not reveal any treatment-related clinical signs. Neurobehavioral observations and motor activity assessment did not indicate any neurotoxic potential of the test substance. There were no relevant differences in body weights or food consumption during the premating period, during the post-mating period in males, or in dams during the gestation period and the lactation period.
Hematology and clinical chemistry was conducted in 5 rats/sex/group at the end of the premating period. No effects were observed on hematology parameters. In males and females of the high-dose group phospholipids were increased compared to controls, glucose plasma levels were decreased in females of the high-dose group and liver weight was increased in males of the high-dose group. In absence of macroscopic and microscopic changes, these effects were considered treatment-related, but not adverse. Macroscopic/ Microscopic examination revealed no treatment-related effects. There were no effects of the test substance on fertility and reproductive performance.
Because fertility parameters, reproductive performance and development were not affected by the test substance, the NOAEL for reproduction and developmental effects was placed at ≥ 15000 mg/kg diet (the highest concentration tested; equivalent to an overall intake of at least 894 mg/kg bw/d in females and at least 870 mg/kg bw/d in males).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.