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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2022-07-11 to 2022-08-12
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2023
Report date:
2023

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:
August 1998
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Version / remarks:
May 2008
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
June 2018
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
4-(1,1-dimethylethyl)cyclohexyl acrylate
EC Number:
282-104-8
EC Name:
4-(1,1-dimethylethyl)cyclohexyl acrylate
Cas Number:
84100-23-2
Molecular formula:
C13H22O2
IUPAC Name:
4-tert-butylcyclohexyl prop-2-enoate

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl: WI(Han)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld
- Age at study initiation: 11-15 weeks old
- Weight at study initiation: 184 – 274 g
- Fasting period before study: no
- Housing: individually housed in Polycarbonate cages (Makrolon type MIII)
- Diet: ad libitum, pellets, SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany
- Water: ad libitum, Municipal tap water
- Acclimation period: 5-6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-21
- Humidity (%): 51-73
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 06 Jul 2022 To: 29 Jul 2022

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Test material dosing formulations were kept at room temperature until dosing.

VEHICLE
- Justification for use and choice of vehicle: solubility
- Concentration in vehicle: 0, 15, 45 and 135 mg/mL
- Amount of vehicle: 4 mL/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentrations analyzed in the formulations of Groups 2, 3 and 4 were in agreement with target concentrations. No test material was detected in the Group 1 formulation. The formulations of Groups 2 and 4 were homogeneous (i.e., coefficient of variation ≤ 10%).
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
Duration of treatment / exposure:
Day 6 to Day 20 post-coitum
Frequency of treatment:
once daily
Duration of test:
14 days
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Group 1
Dose / conc.:
60 mg/kg bw/day (actual dose received)
Remarks:
Group 2
Dose / conc.:
180 mg/kg bw/day (actual dose received)
Remarks:
Group 3
Dose / conc.:
540 mg/kg bw/day (actual dose received)
Remarks:
Group 4
No. of animals per sex per dose:
22
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The doses have been selected based on a dose range finding study (see supporting study).

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least once daily 1 to 2 hours post-dose, starting on Day 6 post coitum up to and including the day prior to necropsy.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: On Days 2, 6, 15 and 21 post-coitum
BODY WEIGHT: Yes
- Time schedule for examinations: On Days 2, 6, 9, 12, 15, 18 and 21 post-coitum.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Over Days 2-6, 6-9, 9-12, 12-15, 15-18 and 18-21 post-coitum

WATER CONSUMPTION AND COMPOUND INTAKE:
Water consumption was monitored by visual inspection of the water bottles.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: ovaries and uterus, thyroid
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
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
Blood sampling:
- Serum: Yes
- Volume collected: 1 mL
- T3, T4 and TSH analysis in serum
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: Yes
Statistics:
Parametric/Non-Parametric:
Levene’s test was used to assess the homogeneity of group variances. The groups were compared using an overall one-way ANOVA F-test if Levene’s test was not significant or the Kruskal-Wallis test if it was significant. If the overall F-test or Kruskal-Wallis test was found to be significant, then pairwise comparisons was conducted using Dunnett’s or Dunn’s test, respectively.

Non-Parametric:
The groups will be compared using an overall Kruskal-Wallis test. If the overall Kruskal-Wallis test was found to be significant, then the above pairwise comparisons was conducted using Dunn’s test.
Indices:
See "Any other information on materials and methods incl. tables"

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No test material-related clinical signs were noted at 60 mg/kg/day.
At 540 mg/kg/day, tremors (slight) were observed in 5/22 females on one or multiple days between Days 14-16 post-coitum and generalized twitches (slight to moderate) were noted in 13/22 females between Days 16-20 post-coitum. Moreover, erected fur was observed in 10/22 females on various days mainly during the second week of treatment. Hunched posture was observed for a single female on Day 10 post-coitum.
Slight salivation was seen on one or multiple days after treatment among animals of the 180 and 540 mg/kg/day dose groups. Taking into account the nature and in general minor severity of the effect and its time of occurrence (i.e., after treatment), this sign was considered to be a physiological response rather than a sign of systemic toxicity.
Any other clinical signs noted during the treatment period occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study and did not show any apparent dose-related trend. At the incidence observed, these were considered to be unrelated to treatment with the test material.
Mortality:
no mortality observed
Description (incidence):
No mortality occurred during the study period.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weights, body weight gain and gravid uterus adjusted body weight gain of test material treated animals remained in the same range as control over the treatment period at 180 mg/kg/day.
At 540 mg/kg/day, mean body weight loss was observed over Days 6-9 post-coitum (-6.4 vs. +12.3 grams in control), followed by normal body weight gain over Days 9-18 post-coitum and a lower body weight gain over Days 18-21 post-coitum (35.0 vs 39.6 grams in control). The combination of body weight loss early during gestation and lower body weight gain towards the end of gestation resulted in a lower overall body weight gain over Days 6-21 post coitum (89.3 vs. 114.4 gram in control) and lower mean body weights between Days 9 21 post-coitum (up to 7% lower than control). Also, body weight gain corrected for gravid uterus weight was lower (12.99 vs. 35.61 gram in control).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
No test material-related changes in food consumption were recorded at 180 mg/kg/day.
At 540 mg/kg/day, lower mean food consumption was observed over the whole treatment period (not reaching statistical significance over Days 18-21 post-coitum). Changes compared to control were highest during the first days of treatment (46% lower than control over Days 6-9 post-coitum), followed by partial recovery. Overall mean food consumption was 22% lower than control.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
effects observed, non-treatment-related
Description (incidence and severity):
Serum levels of TSH and T4 were considered to be unaffected by treatment with the test material.
T3 serum levels were considered to be unaffected by treatment with the test material at 60 mg/kg/day.
At 180 and 540 mg/kg/day, mean T3 serum levels were lower compared to control (0.87 and 0.73x of control, respectively). Mean values remained within the central 95% range of the historical control data.

Historical Control Data for pregnant Han Wistar Rats (2020-2022):
T3 (ng/mL); mean (central 95% range): 0.424 (0.270-0.683); n=347
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
No test material-related changes in thyroid gland weight (absolute and relative to body weight) were observed up to 180 mg/kg/day.
At 540 mg/kg/day, mean absolute thyroid weight was 7% lower compared to control, without reaching statistical significance. This was ascribed to the lower terminal body weight at the high dose (6.7% below control), as mean thyroid weight relative to body weight was comparable to control.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Macroscopic observations at necropsy did not reveal any alterations that were considered to be related to treatment with the test material up to 180 mg/kg/day.
At 540 mg/kg/day, 2/22 females were observed with a small-sized thymus. As this was observed at the high dose only, a test material-relation could not be excluded.
Other findings that were noted, including those in the thyroid gland were considered to be unrelated to treatment with the test material, as they occurred in control animals only, or in the absence of a dose response.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test material-related microscopic observations in the thyroid glands.
In one female at 60 mg/kg/day, hypertrophy of the follicular cell epithelium was observed at a minimal degree. This was the only recorded microscopic finding and regarded unrelated to treatment in the absence of a dose response and single occurrence at the 60 mg/kg/day.
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
The numbers of pre- and postimplantation loss in the control and test material-treated groups were comparable and in the range of normal biological variation.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
The numbers of pregnant females in the control and test material-treated groups were comparable and in the range of normal biological variation. In total, 20/22, 20/22, 17/22 and 21/22 females of the control, 60, 180 and 540 mg/kg/day groups, respectively, were pregnant and therefore available for ovarian and uterine examination at scheduled necropsy.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Remarks:
materal
Effect level:
180 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Mean fetal weights (both sexes) were considered to be unaffected by treatment with the test material up to 180 mg/kg/day.
At 540 mg/kg/day, mean fetal weights (male, female and combined) were 2.22, 3.63 and 2.84% lower, respectively, when compared to the control group (only reaching statistical significance for females).
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The male:female ratio was considered to be unaffected by treatment with the test material.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
There were no test material-related effects in litter size.
Anogenital distance of all rodent fetuses:
no effects observed
Description (incidence and severity):
Anogenital distance (absolute and corrected for body weight) in male and female fetuses was considered not to be affected by treatment with the test material.
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No test material-related external malformations and variations were recorded.
External malformations were observed in two fetuses originating from two litters at 180 mg/kg/day. Fetus No. 53-R10 had a malpositioned eye bulge, cleft lip, meningoencephalocele and absent palatal rugae. Fetus No. 64-L4 presented with a curled tail. As these malformations were each observed only once and in the mid-dose group only, they were considered to be unrelated to treatment with the test material.
External variations or incidental findings were not observed.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No test material-related skeletal malformations and variations were recorded.
Skeletal malformations were observed in a single fetus at 60, 180 and 540 mg/kg/day each. Due to the single occurrences of all recorded malformations, they were considered unrelated to treatment with the test material.
The skeletal malformations observed for Fetus No. 53-R10 corresponded to the external malformations noted for this fetus.
Skeletal variations were observed in the forelimb, pelvic girdle, (supernumerary) rib, scapula, skull, sternebra and vertebra. All were observed either infrequently, at instances comparable to the control group, in the absence of a dose response or were limited to a control fetus only. Therefore, they were considered not to be related to treatment with the test material.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No test material-related visceral malformations and variations were recorded.
Visceral malformations were observed in a single fetus at 60 mg/kg/day (Fetus No. 41-10). This fetus was observed with a malpositioned testis and epididymis. As this occurred in a single low-dose fetus, these occurrences were considered to be unrelated to the treatment with the test material.
Visceral variations in this study were infrequently observed. They were found in the carotid artery, thoracic wall, liver and ureter. As these variations were observed at low incidences, within the available historical control data and/or in the absence of a dose response, these were considered not related to treatment with the test material.
The incidental findings of discolored liver and spleen, not otherwise classified as malformation or variation, were observed in a single fetus at 540 mg/kg/day and deemed to be a chance discovery.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Remarks:
developmental
Effect level:
> 540 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose without effects

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion