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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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: 237-580-1 | CAS number: 13846-31-6
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 05 June 2018 to 03 April 2019
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
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)
- Deviations:
- yes
- Remarks:
- These deviations are considered to have no impact on the outcome of the study or on interpretation of the results.
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Diallyl hexahydrophthalate
- EC Number:
- 237-580-1
- EC Name:
- Diallyl hexahydrophthalate
- Cas Number:
- 13846-31-6
- Molecular formula:
- C14H20O4
- IUPAC Name:
- 1,2-bis(prop-2-en-1-yl) cyclohexane-1,2-dicarboxylate
- Test material form:
- liquid
- Remarks:
- Colourless
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Osaka Soda; Bx 40201
- Expiration date of the lot/batch: 26 January 2019
- Purity test date:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room Temperature, protected from light
- Stability under test conditions: no data
- Solubility and stability of the test substance in the solvent/vehicle:
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: none
- Preliminary purification step (if any):
- Final dilution of a dissolved solid, stock liquid or gel:
- Final preparation of a solid:
FORM AS APPLIED IN THE TEST (if different from that of starting material)
TYPE OF BIOCIDE/PESTICIDE FORMULATION (if applicable)
OTHER SPECIFICS:
- measurement of pH, osmolality, and precipitate in the culture medium to which the test chemical is added:
- other information:
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- The rat is regarded as a suitable species for toxicology and reproduction toxicology studies. Wistar rat was selected due to experience with this strain of rat in toxicity and reproduction toxicity studies and known fertility. Crl:WI rats were used for Dose Range Finding study (study code: 17/277-220PE [4]).
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Commercial laboratory animal supplier.
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 13 weeks
- Weight at study initiation: Males: 429 – 494 g, females: 255 – 313 g
- Fasting period before study:
- Housing: Type II polycarbonate cage
- Diet: ssniff® SM R/M "Autoclavable complete diet for rats and mice ad libitum
- Water: ad libitum
- Acclimation period: 12 days
DETAILS OF FOOD AND WATER QUALITY: Animals received ssniff® SM R/M "Autoclavable complete diet for rats and mice –breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany (batch number: 883 29966, expiry date: 31 October 2018 and batch number: 840 33675, expiry date: 31 January 2019), ad libitum, and tap water from the municipal supply, as for human consumption from a 500 mL bottle, ad libitum.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.0 – 25.0 °C (target range 22 ± 3 °C)
- Humidity (%): 34 – 69 % (target range 30-70 %)
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.
IN-LIFE DATES: From: 03 July 2018 To: 07 August 2018
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- The dosing solutions were administered to the test item or vehicle-treated (control) animals daily on a 7 days/week basis, by oral gavage using a tipped gavage needle attached to a syringe. A constant volume of 5 mL/kg bw were administered to all animals. The actual volume to be administered were calculated and adjusted based on each animal’s most recent body weight.
- Vehicle:
- polyethylene glycol
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): Formulations were prepared up to 4 days before use and were kept at room temperature until use.
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food: room temperature
VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on the results of a short solubility test performed at the Test Facility, PEG 400 was selected as vehicle for this study in agreement with the Sponsor, based on the formulation and analytical trials. The same vehicle was used in the Dose Range Finding (DRF) study [4].
- Concentration in vehicle:
- Amount of vehicle (if gavage):
- Lot/batch no. (if required): A0378559
- Purity: - Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- Control
- Dose / conc.:
- 25 mg/kg bw/day (actual dose received)
- Remarks:
- Low dose
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Remarks:
- Mid dose
- Dose / conc.:
- 400 mg/kg bw/day (actual dose received)
- Remarks:
- High dose
- No. of animals per sex per dose:
- 11
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
The dose levels were selected by the Study Director in consultation with the Sponsor based on available acute oral toxicity data (LD50 between 300 and 2000 mg/kg bw in rats [3]) and information from a Dose Range Finding study in the rat (Citoxlab study code 17/277-220PE [4]) where test item related mortality was seen at 1000 mg/kg bw and slight toxicity was seen at 300 mg/kg bw/day.
- Rationale for animal assignment (if not random):
- Fasting period before blood sampling for clinical biochemistry: yes
- Rationale for selecting satellite groups: n/a
- Post-exposure recovery period in satellite groups:
- Section schedule rationale (if not random):
- Other: - Positive control:
- No
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations checked in table [No.?] were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- 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: No
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations:
OPHTHALMOSCOPIC EXAMINATION: Not specified
- Time schedule for examinations:
- Dose groups that were examined:
HAEMATOLOGY: Yes
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: Yes (pentobarbital) d
- Animals fasted: Yes
- How many animals: 5 male, 5 female
- Parameters checked in table [No.?] were examined.
CLINICAL CHEMISTRY: Yes / No / Not specified
- Time schedule for collection of blood:
- Animals fasted: Yes / No / Not specified
- How many animals:
- Parameters checked in table [No.?] were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: Urine sampling was performed prior to necropsy by placing the selected animals in metabolic cages for approximately 16 hours.Urine sampling was performed prior to necropsy by placing the selected animals in metabolic cages for approximately 16 hours.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Not specified
- Parameters checked in table [No.?] were examined.
NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
IMMUNOLOGY: No
- Time schedule for examinations:
- How many animals:
- Dose groups that were examined:
- Parameters checked in table [No.?] were examined.
OTHER: - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Other examinations:
- The following retained organs were also processed and microscopically examined at request of the Sponsor:
• liver and lymphoid tissues (BALT, mandibular and mesenteric lymph nodes, spleen, thymus, Peyer’s patch) of all male and female animals in all dose groups,
Special attention was paid to the evaluation of the stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure. Detailed histological examination of the ovaries covered the follicular, luteal, and interstitial compartments of the ovary, as well as the epithelial capsule and ovarian stroma.
Special attention was paid to the organ weight, appearance and histopathology of immune-system tissues for any evidence of immunotoxicity (spleen, thymus, lymph nodes, bone marrow).
Special attention was paid to the central and peripheral nervous system tissues for any evidence of neurotoxicity.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- No test item related clinical signs were observed in the Low and Mid dose groups during the study. The incidental piloerection in one Mid dose male (#3004) on Day 17 was considered as not test item-related.
In the found dead (#4006) or pre-terminally euthanized (#4002, 4007, 4009) High dose males, liquid faeces (4/4), hunched back (4/4), piloerection (4/4), slight or moderate decreased activity (3/4), red discharge at the nose or snout (3/4), noisy respiration (1/4) and red faeces (1/4) were observed. Similar findings were seen in one animal (#4003) from Day 5, but it completely recovered from Day 20. Besides these, hunched back, piloerection or noisy respiration were occasionally seen in the other surviving animals for 1-2 days. Three High dose males were completely symptom-free during the study.
In the found dead (#4503, 4504, 4505, 4512) High dose females, slightly decreased activity (1/4), hunched back (1/4) and piloerection (3/4) were seen before death. One animal (#4504) was found dead without any previous clinical symptoms. In the surviving animals, piloerection (7/8), hunched back (4/8), soft or liquid faeces (2/8) or slightly decreased activity (1/4) were recorded occasionally for 1-2 days. One High dose female (#4510) was completely symptom-free during the study. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One High dose male (#4006) was found dead on Day 17 and three High dose males (#4002, 4007, 4009) were pre-terminally euthanized between Day 14 and 20. This was around the mating period, therefore three animals had to be replaced with other males to mate the females and one male was preterminally euthanized after successful mating.
In the High dose female group, four animals (#4503, 4504, 4505, 4512) were found dead around the end of the gestation period or in the beginning of lactation period:
• 4503: Animal was found dead on PPD3 (Day 42). (The single live born pup also died.)
• 4504: Animal was found dead on GD22 (Day 39). Pregnancy was confirmed at necropsy.
• 4505: Animal was found dead on GD21 (Day 38). Pregnancy was confirmed at necropsy.
• 4512: Animal was found dead on GD22 (Day 40). Pregnancy was confirmed at necropsy.
The hepatic effects were considered as cause of death of these animals. There was no mortality in the Control, Low and Mid dose groups during the study. - Body weight and weight changes:
- no effects observed
- 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:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Significantly higher aspartate aminotransferase activity (AST/GOT) (p<0.01) and alanine aminotransferase activity (ALT/GPT) (p<0.05) were measured in the male High dose group, reflecting hepatic damage seen at histology. Several other parameters linked to liver or kidney function also changed in individual male High dose animals, but without attaining statistical significance in the High dose group mean values, most probably because of the high individual variabilities in the data (total bilirubin, urea, ALKP, GGT, etc.). The High dose females had normal values. No test item-related findings were seen in the Low or Mid dose groups.
Statistical significances recorded in the bile acid and potassium concentrations were considered to be incidental, there was no clear relationship with dose and all recorded values were within the historical control ranges. These differences were considered not to reflect an effect of the test item. - Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- At necropsy, increased liver and kidney organ weights were recorded in the male and female High dose groups, the liver of the Mid dose males and the kidney of the Mid dose females were also slightly increased. The livers were discoloured and/or enlarged in the High dose group. At histopathology, massive hepatocellular necrosis, multifocal bile duct hyperplasia and periportal fibrosis were seen in the High dose livers. Other histological changes seen only in early death animals were considered to be secondary to liver necrosis. There was no test item-related macroscopic or microscopic finding in the Low and Mid dose groups, the small differences in organ weights in these groups were not considered to reflect any adverse changes.
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- System:
- hepatobiliary
- Organ:
- kidney
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Applicant's summary and conclusion
- Conclusions:
- The NOAEL for Systemic toxicity for the adults was considered to be 100 mg/kg bw/day.
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.