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Diss Factsheets

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:
2021
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

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
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.