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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Qualifier:
according to guideline
Guideline:
other: Japan 12 NohSan No 8147, (24 November 2000)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Cyclohex-1,4-ylenedimethanol
EC Number:
203-268-9
EC Name:
Cyclohex-1,4-ylenedimethanol
Cas Number:
105-08-8
Molecular formula:
C8H16O2
IUPAC Name:
cyclohexane-1,4-diyldimethanol
Test material form:
other: Off white solid
Details on test material:

Batch number :
Label : 1, 4-cyclohexanedimethanol Batch TP12008082
Storage conditions : Ambient, in the dark

- Name of test material (as cited in study report):1, 4-cyclohexane dimethanol
- Substance type: solid, easily melted
- Analytical purity: 100.0%
- Lot/batch No.:TP12008082
- Expiration date of the lot/batch: Not determined
- Storage condition of test material: Ambient, in the dark
- Other: Test item was received as an off white solid and warmed to produce a clear colourless liquid prior to use. It remained a clear colourless liquid after heating.
Specific details on test material used for the study:
Sponsor’s Identification : 1, 4-cyclohexane dimethanol
Description : Off white solid/clear colourless liquid*
Chemical name : cyclohex-1, 4-ylenedimethanol
CAS number : 105-08-8
Purity : 100%
Batch number : TP12008082
Label : 1, 4-cyclohexanedimethanol
Batch TP12008082
Date received : 16 April 2012
Storage conditions : Ambient, in the dark
Expiry date : not supplied

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent
- Weight at study initiation: 216-299
- Housing: Individually in solid-floor polypropylene cages with stainless steel lid
- Diet (e.g. ad libitum):Yes, Rodent 2018C Teklad Global Certified Diet, Harlan UK, Oxon, UK
- Water (e.g. ad libitum):Yes
- Acclimation period: No

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 50 +/- 20
- Air changes (per hr): ~15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Oral gavage was chosen as the route of exposure

Dose levels were chosen in collaboration with the Sponsor based on available toxicity data including a preliminary rat pre-natal development toxicity study. In the preliminary study, there were no effects observed for the pregnant females and developing offspring at 1000 mg/kg bw/day that was considered to preclude this dosage from use as the high dosage in this main study. Dosing formulations using distilled water were successfully used on the preliminary study, therefore distilled water as a vehicle and a treatment volume of 5 ml/kg bw/day will be employed on this main study.

As no increase in pre-implantation loss had been observed in the rat preliminary prenatal development study dosing on this
main study commenced on Day 3 of gestation. The test item was therefore administered daily, from Day 3 to 19 of gestation (the day prior to necropsy), by gavage. Control animals were treated in an identical manner with the vehicle only. The volume of test and control item administered to each animal was based on the most recently recorded individual scheduled body weight and adjusted accordingly.


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:

The concentration of 1,4–cyclohexane dimethanol in the test item formulations was determined by gas chromatography (GC) using an external standard technique. The test item formulations were diluted with acetonitrile to give a final, theoretical test item concentration of approximately 0.05 mg/ml. Standard solutions of test item were prepared in acetonitrile at a nominal concentration of 0.05 mg/ml. The standard and sample solutions were analysed by GC using the following conditions:

GC system : Agilent Technologies 5890, incorporating autosampler and workstation
Column : DB-5 (30 m x 0.53 mm id x 5 μm film)
Oven temperature program : initial 50 ºC for 1 mins rate 10 ºC/min final 260 ºC for 5 mins
Injection temperature : 250 ºC
FID temperature: 250 ºC
Injection volume : 1 μl
Retention time : ~ 13 mins

The test item formulations were assessed visually for homogeneity. The stability of the test item in the vehicle matrix during storage at approximately +4 °C
in the dark was confirmed to be at least fourteen days. Results from analysis of dosing formulations used during the study were 99-105% of
nominal concentration confirming the accuracy of the formulation procedure.
Details on mating procedure:
Animals were purchased already mated
Duration of treatment / exposure:
Days 3-19 of gestation
Frequency of treatment:
Once/day
Duration of test:
Aprroximately 17 days
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
24
Control animals:
yes, concurrent vehicle
Details on study design:
Dose levels were chosen in collaboration with the Sponsor based on available toxicity data including a preliminary rat pre-natal development toxicity study. In the preliminary study, there were no effects observed for the pregnant females and developing offspring at 1000 mg/kg bw/day that was considered to preclude this dosage from use as the high dosage in this main study.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once daily, Additionally, during the dosing period observations were recorded immediately before and soon after dosing and one hour post dosing. An additional observation was also performed five hours after dosing during the normal working week (excluding weekend and
public holidays).


DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded on Day 3 (before the start of treatment) and on Days 4, 5, 8, 11, 14 and 17 of gestation. Body weights were also recorded for animals at terminal kill (Day 20).

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- 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 consumption was recorded for each individual animal for the Days 3 to 5, 5 to 8, 8 to 11, 11 to 14, 14 to 17 and 17 to 20.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice: All animals were killed by carbon dioxide asphyxiation followed by cervical dislocation on Day 20 of gestation.
- Organs examined: All animals were subjected to a full external and internal examination and any macroscopic abnormalities were recorded. The
adrenals were removed from all animals, dissected free from fat and weighed before fixation in 10% buffered formulin.

OTHER:
Ovaries and uterine content:
The ovaries and uteri of pregnant females were removed, examined and the folllowing data recorded:
i) Number of corpora lutea
ii) Number, position and type of intrauterine implantation
iii) Foetal sex
iv) External foetal appearance
v) Foetal weight
vi) Placental weight
vii) Gravid uterus weight

The uteri of any apparently non-pregnant females were immersed in 10% ammonium sulphide to reveal evidence of implantation.
Fetal examinations:
The foetuses were killed by subcutaneous injection of sodium pentobarbitone. Foetuses from each litter were divided into two groups and examined for skeletal alterations and soft tissue alterations. Alternate foetuses were identified using an indelible marker and placed in Bouin’s fixative. Foetuses were transferred to 70% industrial methylated spirits (IMS) in distilled water and examined for visceral anomalies under a low power binocular
microscope. The remaining foetuses were identified using colour coded wires and placed in 70% IMS in distilled water. The foetuses were eviscerated, processed and the skeletons stained with alizarin red. The foetuses were examined for skeletal development and anomalies. Following examination
foetuses that were examined for skeletal development were placed in 100% glycerol.
Statistics:
The following parameters were analysed statistically, where appropriate, using the test methods outlined below:
Female body weights and body weight change, food consumption, adrenal weights and gravid uterus weight: Initially, homogeneity of the data was assessed using Levene’s Test. Where Levene’s Test is found to be non-significant (P>0.05) parametric assessment of the data was performed;
analysis of variance (ANOVA) followed by (if significant (p,<0.05)) pair-wise comparisons using Dunnett’s test. Where Levene’s Test was
significant, non-parametric assessments of the data was applied; Kruskal-Wallis test followed by (if significant (p<0.05)) Mann-Whitney U test. All caesarean necropsy parameters and foetal parameters, including skeletal and visceral findings: Kruskal-Wallis non-parametric analysis of
variance; and a subsequent pairwise analysis of control values against treated values using the Mann-Whitney ‘U’ test, where significance was seen.
Indices:
All data was summarised in tabular form, including reproductive incides. Where appropriate group mean values were calculated to includes data from all females with live foetuses on Day 20 of gestation. For terminal body weight and overall body weightgain during treatment this included adjustment for the contribution of the gravid uterus. For adrenal weights both absolute and body weight-relative values are presented The litter was considered to represent the standard unit of assessment, therefore individual litter values including mean foetal weights, mean placental weight, pre- and post implantation losses, sex ratio and foetal visceral and skeletal findings were first calculated for each litter and then group values calculated from these individual litter values.

Pre and Post Implantation Loss

Percentage pre-implantation loss was calculated as:
[(number of corpora lutea - number of implantations) / number of corpora lutea] x 100

Percentage post-implantation loss was calculated as:
[(number of implantations - number of live foetuses) / number of implantations] x 100

Sex Ratio
Sex ratio was calculated for each litter using the following formula:
% male foetuses (sex ratio) = (Number of male foetuses/ Total number of foetuses) x 100
Historical control data:
Historical control data on placental weights from 6 studies was supplied. The control values inclueded the previous 3 studies, the present study and the subsequent 2. The average weights for the control placentals was 0.53 grams with a range of (0.51 - 0.57).

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
There were no clinical signs observed that were considered to be associated with treatment at 100, 300 or 1000 mg/kg bw/day. At 1000 mg/kg bw/day, one female showed chromodacryorrhoea or staining around the eyes throughout most of the study from Day 11 of gestation. In isolation this finding was considered incidental and unrelated to treatment.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weights and body weight gain, including values adjusted for the contribution of the gravid uterus, were unaffected by treatment at 100, 300 and 1000 mg/kg bw/day
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption was unaffected by treatment at 100, 300 and 1000 mg/kg bw/day.
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Description (incidence and severity):
At 1000 mg/kg bw/day higher body weight-relative adrenals weights attained statistical significance when compared to control; no statistically significant differences from control were apparent for absolute adrenal weights.
There was no obvious effect of treatment on absolute or body weight relative adrenal weights at 100 or 300 mg/kg bw/day.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No macroscopic abnormalities were detected for adult animals at Day 20 of gestation
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
There was no effect of treatment on in-utero offspring survival, as assessed by the mean numbers of early or late resorptions, live litter size and pre and post-implantation losses
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
There was no effect of treatment on in-utero offspring survival, as assessed by the mean numbers of early or late resorptions, live litter size and pre and post-implantation losses
Early or late resorptions:
no effects observed
Description (incidence and severity):
There was no effect of treatment on in-utero offspring survival, as assessed by the mean numbers of early or late resorptions, live litter size and pre and post-implantation losses
Dead fetuses:
no effects observed
Description (incidence and severity):
There was no effect of treatment on in-utero offspring survival, as assessed by the mean numbers of early or late resorptions, live litter size and pre and post-implantation losses
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Not valid in an OECD 414
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
There was no effect of treatment on in-utero offspring survival, as assessed by the mean numbers of early or late resorptions, live litter size and pre and post-implantation losses
Other effects:
not specified
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
THere were no mortalities
There were no clinical signs of toxicity
There was no effects on body weight or weight gain
There was no effect on food consumption
There were no post mortem macroscopic abnormalities

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
mortality
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
NOAEL was high dose

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There was no effect of treatment on mean placental foetal or litter weight at 100, 300 or 1000 mg/kg bw/day. At 1000 mg/kg bw/day mean placental weight was slightly higher than control with differences attaining statistical significance. However, the mean value at this dosage was within the control range of four contemporary pre-natal studies performed within these laboratories, while the mean control value was slightly lower than this control range. It is considered that the statistical differences in placental weights observed at 1000 mg/kg bw/day most probably reflect slightly lower values for control litters and therefore are a result of normal biological variation, unrelated to treatment.
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
Changes in postnatal survival:
not specified
Description (incidence and severity):
not relevant for an OECD 414
External malformations:
no effects observed
Description (incidence and severity):
Neither the type, incidence or distribution of findings observed externally at necropsy examination and subsequently during detailed visceral and skeletal assessment indicated any effect of treatment on foetal development.
Skeletal malformations:
no effects observed
Description (incidence and severity):
Neither the type, incidence or distribution of findings observed externally at necropsy examination and subsequently during detailed visceral and skeletal assessment indicated any effect of treatment on foetal development.
Visceral malformations:
no effects observed
Description (incidence and severity):
Neither the type, incidence or distribution of findings observed externally at necropsy examination and subsequently during detailed visceral and skeletal assessment indicated any effect of treatment on foetal development.
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
THere was no effects on foetal or litter weight No external or skeletal effects were observed in the developing foetus All foetal parameters were similar to controls The developmental NOEL was 1000 mg/kg

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
external malformations
skeletal malformations
visceral malformations
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Relative adrenal weights were significantly increased in the 1000 mg/kg/day dose group compared to controls. There was no change in the absolute adrenal weight, nor was there a significant change in the absolute or relative adrenal weights in the 100 or 300 mg/kg/day groups. There were no morphologic changes to the adrenals, and no clinical signs found. The increase in adrenal weights was not considered to be an adverse event.

At 1000 mg/kg bw/day mean placental weight was slightly higher than control with differences attaining statistical significance. However, the mean value at this dosage was within the control range of four contemporary pre-natal studies performed within these laboratories, while the mean control value was slightly lower than this control range. It is considered that the statistical differences in placental weights observed at 1000 mg/kg bw/day most probably reflect slightly lower values for control litters and therefore are a result of normal biological variation, unrelated to treatment.

Summary table are attached as a single .PDF in the "attached full study report" section

Applicant's summary and conclusion

Conclusions:
The oral administration of 1,4-cyclohexane dimethanol to pregnant rats at 1000 mg/kg bw/day was well tolerated with only an increase in body weight-relative adrenals weights preventing this dosage from being considered the ‘No Observed Effect Level’ (NOEL) for the pregnant female. This dosage represents a clear No Observed Adverse Effect Level (NOAEL) for the pregnant female with the NOEL being 300 mg/kg bw/day. The NOEL for the survival, growth and morphological development the conceptus was considered to be 1000 mg/kg bw/day.
Executive summary:

The study was was designed to investigate the effects of the test item on embryonic and foetal development following repeated administration by gavage to the pregnant female including the period of organogenesis.

The test item was administered by gavage to three groups each of twenty-four time mated Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, between Days 3 and 19 of gestation at dose levels 100, 300, and 1000 mg/kg bw/day. A further group of twenty-four time mated females was exposed to the vehicle only (Distilled Water) to serve as a control over the same treatment period. Clinical signs, body weight change and food consumptions were monitored during the study. All surviving females were terminated on Day 20 of gestation and subjected to gross necropsy including adrenal organ weights and examination of the uterine contents. The number of corpora lutea, number, position and type of implantation, placental weights, foetal weight, sex and external and internal macroscopic appearance were recorded. Half of each litter were examined for skeletal development. The remaining half were examined viscerally.

There were no unscheduled deaths or clinical signs observed that were associated with treatment. There were no effects of treatment on body weight or body weight gain during gestation nor was there a chage in food intake. No macroscopic abnormalities were detected for adult animals at necropsy. At 1000 mg/kg bw/day there was a statistically significant increase in body weight-relative adrenals weights compared to control although there was no change in the absolute adrenal weights. There was no effect of treatment on numbers of early or late resorptions, live litter size or pre and post-implantation losses at any dose. There was no effect of treatment on mean placental, foetal or litter weight at 100, 300 or 1000 mg/kg bw/day, and external necropsy examination and subsequent detailed visceral and skeletal assessment did not indicate any effect of treatment on foetal development.

The oral administration of 1,4-cyclohexane dimethanol to pregnant rats at 1000 mg/kg bw/day was well tolerated with only an increase in body weight-relative adrenal weights preventing this dosage from being considered the ‘No Observed Effect

Level’ (NOEL) for the pregnant female. This dosage represents a clear No Observed Adverse Effect Level (NOAEL) for the pregnant female with the NOEL being 300 mg/kg bw/day. The NOEL for the survival, growth and morphological development the conceptus was considered to be 1000 mg/kg bw/day.