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EC number: - | CAS number: 313644-32-5
- 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
- Remarks:
- Prenatal developmental Toxicity Study in rats by oral administration according to OECD guideline 414
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 21 Dec 2020 - 05 Oct 2021
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 021
- Report date:
- 2021
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2018
- Deviations:
- no
- GLP compliance:
- yes
Test material
- Reference substance name:
- 1,4-bis(7-methyloctyl) cyclohexane-1,4-dicarboxylate
- Cas Number:
- 313644-32-5
- Molecular formula:
- C26H48O4
- IUPAC Name:
- 1,4-bis(7-methyloctyl) cyclohexane-1,4-dicarboxylate
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- see test material information
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories Deutschland, Sulzfeld, Germany
- Age at study initiation: 11-15 weeks
- Weight at study initiation: 201-252g
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23 °C
- Humidity (%): 50-56%
- Air changes (per hr): ten or more
- Photoperiod (hrs dark / hrs light): 12h light and 12h dark
IN-LIFE DATES: From: 06 Jan 2021 To: 10 Feb 2021
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Trial preparations were performed to select the suitable vehicle and to establish a suitable formulation procedure. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dose formulation samples were collected for concentration and homogeneity analysis. Formulation analyses confirmed that formulations of test item in corn oil were prepared accurately and homogenously.
- Duration of treatment / exposure:
- From Day 6 to 20 post-coitum, inclusive
- Frequency of treatment:
- once daily
- Duration of test:
- From Day 6 to 20 post-coitum, inclusive
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- Group 1, control
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- Group 2
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Remarks:
- Group 3
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- Group 4
- No. of animals per sex per dose:
- 22
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- The dose levels in this study were selected based on the results of a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test with Diisononyl 1,4 cyclohexanedicarboxylate by oral gavage in Sprague Dawley rats, as well as the unaudited results from treatment Days 1-36 of a 90 day study with Diisononyl 1,4 cyclohexanedicarboxylate by oral gavage in Crl:WI(Han) rats (2020-0008-DGT).
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least once daily; starting on Day 6 post-coitum up to the day prior to necropsy. During the dosing period, this observation was performed post-dose.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly, animals were examined on the following time points: Pretreatment Period (prior to dosing Subgroup 1 on Day 6 post-coitum), prior to dosing Subgroup 1 on Day 13 post-coitum and on the day of necropsy corresponding to subgroup.
BODY WEIGHT: Yes
- Time schedule for examinations: On Days 2, 6, 9, 12, 15, 18 and 21 post-coitum.
FOOD CONSUMPTION: Yes
- Food consumption: Over Days 2-6, 6-9, 9-12, 12-15, 15-18 and 18-21 post coitum.
WATER CONSUMPTION: Yes
- Time schedule for examinations: Water consumption was monitored by visual inspection of the water bottles.
POST-MORTEM EXAMINATIONS: Yes / No / No data
- Sacrifice on gestation day 21
- Organs examined: thyroid gland, uterus - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes / No / No data
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
- Number and distribution of live and dead fetuses - Blood sampling:
- - Plasma: No
- Serum: Yes
- Volume collected: 1ml
- Other: analysis of thyroid hormones - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
- Anogenital distance of all live rodent pups - Statistics:
- Yes.
Parametric/non-parametric: one-way ANOVA F-test, Levene’s test or Kruskal-Wallis test
Incidence: Fisher's exact test - Indices:
- Parental Indices and Mortality
- Historical control data:
- Comparison with historical control data.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Endocrine findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Mean serum level of total triiodothyronine (T3) was decreased (0.83x of control) at 1000 mg/kg/day but remained within the historical control range .
Mean serum level of thyroid stimulating hormone (TSH) was decreased (0.81, 0.79 and 0.75x of control, not statistically significant) at 100, 300 and 1000 mg/kg/day, but remained within the historical control range .
Mean serum level of total thyroxine (T4) was considered unaffected by treatment with the test item up to 1000 mg/kg/day. - Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- There were no test item-related alterations in thyroid weight up to 1000 mg/kg/day.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no test item-related gross observations.
All of the recorded macroscopic findings were within the range of background gross observations. - Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- All of the recorded microscopic findings of the thyroid gland were within the range of background microscopic observations
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Mean pre-implantation loss was increased (107% higher than control) in the 300 mg/kg/day group. This increase was considered to be the result of two animals (Nos. 53 and 56) that had a pre implantation loss of 85 and 86%, respectively. In the absence of a dose-related trend, this increase was considered unrelated to treatment with the test item.
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- At scheduled necropsy, Female Nos. 5, 22 (control) and 61 (300 mg/kg/day) were non-gravid.
Therefore, the number of females with viable litters for evaluation was 20, 22, 21 and 22 in the control, 100, 300 and 1000 mg/kg/day groups, respectively.
The number of corpora lutea, implantation sites, viable and dead fetuses, early and late resorptions and post-implantation loss were considered unaffected by treatment with the test item up to 1000 mg/kg/day.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- Mean litter sizes were 10.7, 10.5, 9.4 and 11.5 fetuses/litter for the control, 100, 300 and 1000 mg/kg/day groups, respectively.
- Anogenital distance of all rodent fetuses:
- no effects observed
- External malformations:
- no effects observed
- Description (incidence and severity):
- There were no external malformations or variations noted among fetuses in any group.
- Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- Among skeletal variations, mean litter incidence of supernumerary short ribs at the thoracolumbar region was increased at 1000 mg/kg/day compared to control (77.38% versus 52.36%, respectively) and exceeded the upper limit of the historical control range3. Therefore, this increase was considered related to treatment with the test item. In addition, mean litter incidences of supernumerary thoracolumbar full rib and a pelvic girdle with misaligned ilium were increased at 1000 mg/kg/day compared to control (without reaching statistical significance). As these incidences were above the historical control range , a possible relation with the test item could not be excluded.
Given their low incidences and/or in the absence of a dose-related trend, all other skeletal variations were considered not to be related to treatment with the test item.
The incidence of supernumerary short ribs at the thoracolumbar region, supernumerary thoracolumbur full rib and pelvic girdle with misaligned ilium were increased at 1000 mg/kg/day, however, as all these skeletal findings are classified as variations, these were considered not adverse. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No visceral malformations or variations were noted among fetuses that were considered to be related to treatment with the test item up to 1000 mg/kg/day.
Situs inversus was observed in one fetus (24-L2) at 100 mg/kg/day. Given the single incidence and in absence of a dose-related trend, this malformation was considered not to be related to treatment with the test item.
Given the low incidences and/or group distribution, any other visceral variations that were noted (supernumerary liver lobes and convoluted ureters) were considered not to be related to treatment with the test item.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Fetal abnormalities
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- skeletal: supernumerary rib
- Description (incidence and severity):
- The incidence of supernumerary short ribs at the thoracolumbar region, supernumerary thoracolumbur full rib were increased at 1000 mg/kg/day, however, as all these skeletal findings are classified as variations, these were considered not adverse.
Overall developmental toxicity
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects in the absence of maternal toxicity effects
- Dose response relationship:
- no
- Relevant for humans:
- no
Applicant's summary and conclusion
- Conclusions:
- No maternal toxicity was observed up to the highest dose level tested (1000 mg/kg/day). Moreover, no developmental toxicity was observed up to the highest dose level tested (1000 mg/kg/day). The incidence of supernumerary short ribs at the thoracolumbar region, supernumerary thoracolumbur full rib and pelvic girdle with misaligned ilium were increased at 1000 mg/kg/day, however, as all these skeletal findings are classified as variations, these were considered not adverse.
In conclusion, based on the results of this prenatal developmental toxicity study in time mated female Wistar Han rats the following maternal and developmental No Observed Adverse Effect Levels (NOAELs) for Diisononyl 1,4-cyclohexanedicarboxylate (DINCD) were established:
Maternal NOAEL: at least 1000 mg/kg/day.
Developmental NOAEL: at least 1000 mg/kg/day.
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