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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
25.09.2020-22.03.2021
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2020
Report date:
2021

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
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

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
The rat was chosen as the animal model for this study as it is an accepted rodent species for chemical toxicity testing by regulatory agencies.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 6-7 weeks
- Weight at study initiation: 166-208g (m); 115-148g (f)
- Housing: Up to 5 animals of the same sex and same dosing group together.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 14d

DETAILS OF FOOD AND WATER QUALITY:
Municipal tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22°C
- Humidity (%): 31-61%
- Air changes (per hr): ten or more
- Photoperiod (hrs dark / hrs light): 12h light and 12h dark

IN-LIFE DATES: From: 21 Oct 2020 To: 21 Jan 2021

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
The oral route of exposure was selected because this is a possible route of human exposure,
during manufacture, handling or use of the test item.
Vehicle:
corn oil
Details on oral exposure:
The first day of dosing was designated as Day 1. The dose formulations were stirred continuously during dosing. The doses were given using a plastic feeding tube.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentrations analyzed in the formulations of Group 2-4 were in agreements with target concentrations and formulations of Group 2 and 4 were homogeneous.
Duration of treatment / exposure:
7 days a week for a minimum of 13 weeks.
Frequency of treatment:
Once daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
control - Group 1
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:
10
Control animals:
yes, concurrent vehicle
Details on study design:
The high-dose level should produce some toxic effects, but not excessive lethality that would prevent meaningful evaluation. The mid-dose level is expected to produce minimal to moderate toxic effects. The low-dose level should produce no observable indications of toxicity.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least once daily; from Day 1 at 0 to 1hour post-dose.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly; from Week 1 and throughout the study, and on the day of necropsy.

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly; from at least Day 1 and throughout the study.

FOOD CONSUMPTION:
- Food consumption quantitatively measured per cage; Weekly

FOOD EFFICIENCY: No

WATER CONSUMPTION: Yes
- Water consumption was monitored by visual inspection of the water bottles.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretreatment period and during week 13
- Dose groups that were examined: Group 1 and 4

HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of treatment
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked:
White Blood Cell Count (WBC), Neutrophils (absolute), Lymphocytes (absolute), Monocytes (absolute), Eosinophils (absolute), Basophils (absolute), Large unstained cells (LUC) (absolute), Red Blood Cell Count, Reticulocytes (absolute), Red Blood Cell Distribution Width (RDW), Hemoglobin, Hematocrit, Mean corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin concentration (MCHC), Platelets, Prothrombin time (PT), Activated partial thromboplastin time (APTT)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of treatment
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked: Alanine aminotransferase (ALT), Triglycerides, Aspartate aminotransferase (AST), HDL and LDL Cholesterol, Alkaline Phosphatase (ALP), Sodium, Total protein, Potassium,
Albumin, Chloride, Total Bilirubin, Calcium, Urea, Inorganic Phosphate (Inorg. Phos), Creatinine, Triiodothyronine (T3), Glucose, Thyroxine (T4), Cholesterol, Thyroid-Stimulating Hormone (TSH)

URINALYSIS: No

FUNCTIONAL TESTS: Yes
- Time schedule for examinations: during week 12-13
- Dose groups that were examined: first 5 animals per sex per group
- Battery of functions tested: sensory activity / grip strength / motor activity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table)

HISTOPATHOLOGY: Yes (see table)
Statistics:
Yes.
Parametric/non-parametric: one-way ANOVA F-test, Levene’s test or Kruskal-Wallis test
Incidence: Fisher’s exact test

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Incidental salivation was seen after dosing among a few animals of all test item groups on one or more days, which was considered not toxicologically relevant. Any other clinical signs (e.g. thin fur cover, skin lesions, scabs) noted during the Dosing Period occurred within the range of background findings to be expected for rats of this age and strain.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
In males of all treated groups, a general trend towards decreased mean body weights and body weight gains was observed from Day 1 onwards. Changes compared to the concurrent control group were very slight, i.e. statistical significance was reached for mean body weight gain at 300 and 1000 mg/kg/day over Days 36-43 only, and less than 10% decrease in body weight was observed at the end of the dosing period (Day 91). Furthermore, not always a dose-related trend was evident. Based on this, these changes were considered unrelated to treatment with the test item. Any changes observed in treated females when compared to the concurrent controls, including the statistically significantly increase in mean body weight gain at 300 mg/kg/day over Days 22-29, were considered not toxicologically relevant as these occurred in absence of a dose-response.
Food consumption and compound intake (if feeding study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
In males treated at 1000 mg/kg/day, a decrease in reticulocyte count (0.85x of control) compared to the control was observed. In absence of changes in correlating parameters, this finding was considered unrelated to treatment with the test item.
Remaining differences in hematology parameters in males and females, regardless of statistical significance, were considered not test item-related based on the absence of a dose response, general overlap of individual values with the range of control values, were of a magnitude of change commonly observed in rats under similar study conditions and/or were considered to have arisen as a result of slightly high control value (basophils in control males). The prolonged mean prothrombin time (PT) observed in females at 300 and 1000 mg/kg/day (both 1.05x of control) was considered to be unrelated to treatment with the test item as this occurred in the absence of a dose-related trend and mean values remained within the range considered normal for females of this age and strain.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
In males at 300 and 1000 mg/kg/day, increased calcium concentrations (1.07x and 1.06x of control, respectively) were observed compared to the control. In absence of changes in correlating parameters, this finding was considered unrelated to treatment with the test item.
Endocrine findings:
effects observed, non-treatment-related
Description (incidence and severity):
Triiodothyronine (T3) concentrations were decreased in all test item-treated females (0.91x, 0.90x, 0.86x of control, respectively; not statistically significant). Given the magnitude of change this finding was considered unrelated to treatment with the test item.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
No test item-related microscopic observations were observed in males at 100 mg/kg/day and females up to 1000 mg/kg/day.

Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
In males treated at 300 and 1000 mg/kg/day, test item-related microscopic findings were noted in the kidney, consisting of an increased incidence of minimal to mild tubular hyaline droplet accumulation (up to a mild degree).
Histopathological findings: neoplastic:
no effects observed

Effect levels

Key result
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
In conclusion, administration of Diisononyl 1,4-cyclohexanedicarboxylate (DINCD) by once
daily oral gavage for 90 days was well tolerated in Wistar Han rats at dose levels of up to
1000 mg/kg/day. Increased minimal to mild tubular hyaline droplets accumulation was
observed in the kidneys of males at 300 and 1000 mg/kg/day, which was considered non-adverse.
No test item-related effects were seen in females up to 1000 mg/kg/day.
Based on these results, the No Observed Adverse Effect Level (NOAEL) was established as
being at least 1000 mg/kg/day for males and females.