Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive/developmental toxicity screening test (OECD 421, oral, rat): NOAEL (reproduction/development) >= 1000 mg/kg bw/day (read across from analogue substance propylidynetrimethanol, ethoxylated)


 


An extended one-generation reproductive toxicity study (EOGRTS) according to OECD guideline 443 in the rat by the oral route of exposure with the analogue substance ethane- 1,2-diol, propoxylated has been proposed. The decision on the testing proposal is pending. Based on the results of the EOGRTS, the hazard assessment with respect to reproductive toxicity will be updated.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Qualifier:
according to
Guideline:
other: EPA OPPTS 870.3550 (Reproduction/Developmental Toxicity Screen)
GLP compliance:
yes (incl. certificate)
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS
The test substance was applied as a solution. To prepare the solution, the appropriate amount of test substance was weighed out depending on the desired concentration. Then the vehicle (drinking water) was filled up to the desired volume, subsequently mixed using a magnetic stirrer. The test-substance preparations were prepared daily.
The daily volume administered was 10 ml/kg of body weight.
Details on mating procedure:
MATING PROCEDURES:
Each of the male and female animals was mated overnight in a 1 : 1 ratio for a maximum of 2 weeks. Throughout the mating period, each female animal was paired with a predetermined male animal from the same dose group. The animals were paired by placing the female in the cage of the male mating partner from about 4.00 p.m. until 7.00 - 9.00 a.m. of the following morning. Deviations from the specified times were possible on weekends and public holidays and were reported in the raw data. A vaginal smear was prepared after each mating and examined for sperm. If sperm was detected, pairing of the animals was discontinued. The day on which sperm was detected was denoted "day 0" and the following day "day 1" post coitum.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of the test substance in drinking water for a period of up to 4 hours at room temperature was verified.
Frequency of treatment:
Daily
Details on study schedule:
The test substance was administered orally via gavage to the F0 generation parental animals daily, at approximately at the same time in the morning(exception: no administration to animals being in labor). The treatment lasted up to one day prior to sacrifice. The animals of the control group were treated in the same way with the vehicle only (drinking water). The calculation of the volume administered was generally based on the most recent
individual body weights. At least 13 days after the beginning of treatment, males and females from the same dose group were mated overnight in a ratio of 1:1 (see details on mating procedure). All F0 males were sacrificed under Isoflurane anesthesia on study day 35 followed by necropsy. The females were allowed to litter and rear their pups until day 4 after parturition. F0 females were sacrificed under Isoflurane anesthesia on study day 49/56 followed by necropsy.
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10 animals per sex per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Doses were selected according to a preceding subacute rat study were the same doses were applied over 4 weeks by gavage.
Parental animals: Observations and examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
A cageside examination was conducted daily before and about 1 hour after application for any signs of morbidity, pertinent behavioral changes and signs of overt toxicity. Abnormalities and changes were documented for each animal.

The littering and lactation behavior of the dams was generally evaluated in the mornings in combination with the daily clinical inspection of the dams. Only particular findings (e.g., animal could not litter, umbilical cord not cut) were documented on an individual dam basis.
On weekdays (except public holidays) the littering behavior of the dams was inspected in the afternoons in addition to the evaluations in the mornings.
The day of littering was considered to be the 24-hour period from about 3.00 p.m. of one day until about 3.00 p.m. of the following day.

BODY WEIGHT: Yes
In general, the body weight of the male and female parental animals was determined once a week at the same time of the day (in the morning).
The body weight change of the animals was calculated from these results.
The following exceptions are notable for the female animals:
• During the mating period the parental females were weighed on the day of positive evidence of sperm (day 0 post coitum) and on days 7, 14 and 20 post coitum.
• Females with litter were weighed on the day of parturition (day 0 post partum) and on day4 post partum.

FOOD CONSUMPTION: Yes
Generally, food consumption was determined once a week (in a period of 7 or 6 days resp.) for male and female parental animals, with the following exceptions:
• Food consumption was not determined during the mating period (male and female F0
animals).
• Food consumption of the F0 females with evidence of sperm was determined on days 0,
7, 14 and 20 post coitum.
• Food consumption of F0 females, which gave birth to a litter was determined on days 0
and 4 post partum.
Food consumption was not determined in females without positive evidence of sperm (during the mating period of dams used in parallel) and females without litter (during the lactation period of dams used in parallel).

WATER CONSUMPTION : No
Sperm parameters (parental animals):
The following parameters were determined:
• sperm motility
• sperm morphology
• sperm head count (cauda epididymis)
• sperm head count (testis)
Sperm motility examinations and the preparation of the specimens for sperm morphology were carried out in a randomized sequence. Sperm morphology and sperm head count (cauda epididymis and testis) were evaluated forthe control and highest dose group, only.
Litter observations:
Pup number and status of delivery; pup viability/mortality; sex ratio, pup clinical observations, pup body weight data
Postmortem examinations (parental animals):
Gross pathological examination:
- Gross pathological examination was performed for all females and males at necrosy.
HISTOPATHOLOGY / ORGAN WEIGHTS
- Organ weights: Testes, Epididymides, Ovaries
- The following organs were fixed: all gross lesions, pituitary gland, prostate gland, seminal vesicles with coagulation glands, uterus, oviducts, cervix uteri, vagina, left testis, left epididymis, ovaries
Histopathological examination: all gross lesions, left testis, lefr epididymis, ovaries (all animals of the control and high dose group)
Postmortem examinations (offspring):
All surviving pups (after sacrifice on day 4 post partum by means of CO2), all stillborn pups and those pups that died before schedule, were examined externally, eviscerated and their organs were assessed macroscopically. All pups without any notable findings or abnormalities were discarded after their macroscopic evaluation.
Reproductive indices:
Reproductive indices:
- female and male mating index
- male and female fertility index
- gestation index
Offspring viability indices:
live birth index
post implantation loss
sex ratio
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: general, systemic toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: reproductive performance and fertility
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: developmental toxicity
Reproductive effects observed:
not specified
Executive summary:

Under the conditions of this reproduction/developmental toxicity screening test (OECD TG 421, gavage) the NOAEL (no observed adverse effect level) for reproductive performance and fertility is 1000 mg/kg body weight/day for the F0 parental rats. The NOAEL for general, systemic toxicity of the test substance was 1000 mg/kg body weight/day for the F0 parental animals. The NOAEL for developmental toxicity in the F1 progeny of the test-substance treated groups was found to be 1000 mg/kg body weight/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises an adequate and reliable (Klimisch score 1) reproductive/developmental toxicity study performed with the analogue substance propylidynetrimethanol, ethoxylated. Moreover, an extended one-generation reproductive toxicity study with the analogue substance ethane- 1,2-diol, propoxylated has been proposed. The decision on the testing proposal is pending. The studies are thus sufficient to fulfil the standard information requirements set out in Annexes VIII - X, Section 8.7., of Regulation (EC) No. 1907/2006.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No data on reproductive toxixity for propylidentrimethanol, propoxylated are available. Therefore, data obtained with the analogue substance propylidynetrimethanol, ethoxylated are used in a read across approach. Toxicity to reproduction of propylidynetrimethaol, ethoxylated was investigated in a reproductive/developmental toxicity screening study according to OECD guideline 421 under GLP conditions (rel 1-key, rat, gavage, OECD 421, BASF, 2010, AT02642). Groups of 10 Wistar rats per sex were dosed with 100, 300 and 1000 mg/kg bw/day by oral gavage. Since no toxicologically relevant effects were observed, the NOAEL (no observed adverse effect level) for reproductive performance and fertility was found to be 1000 mg/kg bw/day for the F0 parental rats. The NOAEL for general, systemic toxicity of the test substance was 1000 mg/kg bw/day for the F0 parental animals. The NOAEL for developmental toxicity in the F1 progeny of the test- ubstance treated groups was found to be 1000 mg/kg bw/day.


 


Moreover, an extended one-generation reproductive toxicity study (EOGRTS) according to OECD guideline 443 in the rat by the oral route of exposure with the analogue substance ethane- 1,2-diol, propoxylated has been proposed. The decision on the testing proposal is pending. A dossier update will be submitted containing the results of the EOGRTS following an appropriate decision by ECHA. Based on the results of the EOGRTS, the hazard assessment with respect to reproductive toxicity will be concluded.

Effects on developmental toxicity

Description of key information

Pre-natal development (OECD 414, oral, rat): NOAEL (maternal toxicity) = 1000 mg/kg bw/day; NOAEL (development) =1000 mg/kg bw/day

Pursuant to ECHA Decision TPE-D-2114465594-39-01/F (issued 4 July 2019) a pre-natal developmental toxicity study in a second species (oral route, rabbit) according to OECD guideline 414 is currently ongoing. The deadline for submitting the requested information in an updated registration dossier set in the decision is 12 July 2021. Based on the results of the pre-natal developmental toxicity study in rabbits, the hazard assessment with respect to developmental toxicity will be updated.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
08 Apr - 25 May 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted in 2018
Deviations:
yes
Remarks:
No histopathological examination of thyroid performed.
GLP compliance:
yes (incl. certificate)
Limit test:
no
Specific details on test material used for the study:
Batch/Lot Number: 1907170614
Expiry: 03 October 2020
Storage Conditions: Ambient room temperature
Species:
rat
Strain:
other: Han Wistar RccHan®:WIST
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS (UK) Limited, Shaw’s Farm, Blackthorn, Bicester, Oxon, UK
- Age at study initiation: 9 - 11 weeks
- Weight at study initiation: 177 - 246 g
- Housing: 3 per cage in polycarbonate cages with stainless steel grid tops, solid bottoms and sterilised white wood shavings as bedding material.
- Diet: VRF-1 breeder diet (SDS, Witham, Essex, UK), ad libitum
- Water: Water from public supply, ad libitum
- Acclimation period: From arrival until start of dosing, i.e. a minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 23
- Humidity (%): 44 - 65
- Air changes (per hr): >= 10
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 14 Apr To: 07 May 2020
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared weekly by weighing the required amount of test item and adding the required amount of the vehicle water (w/w). The final concentrations of test item in the vehicle were 10, 30 and 100 mg/mL.

VEHICLE
- Substance: Milli-Q Water (purified in house)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Duplicate top, middle and bottom samples (duplicate middle only for control) were collected for concentration and homogeneity analyses. When only concentration analysis was required, the formulations were only sampled from the middle. Concentration results were considered acceptable if they were within or equal to ± 15% of theoretical concentration. Each individual sample concentration result was considered acceptable if it was within or equal to ± 20%. Homogeneity results were considered acceptable if the relative standard deviation of the mean value at each sampling location was <= 10%. The analyses confirmed the concentration, stability and homogeneity of the dosing formulations.
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
Day 6 - 20 of gestation
Frequency of treatment:
daily, 7 days/week
Duration of test:
Until Day 20 of gestation
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
24 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were based on the results of a foregoing preliminary prenatal developmental toxicity study in which animals were orally exposed to 100, 300 and 1000 mg/kg bw/day from GD 6 to GD 20 (Charles River, 2020, study no. 490513). In the absence of any maternal toxicity findings, 100, 300 and 1000 mg/kg bw/day were selected as the dose levels for the main study.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily throughout the study for general health/mortality and moribundity.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once during pretreatment on GD 3 and weekly during the dosing period from GD 6.

BODY WEIGHT: Yes
- Time schedule for examinations: GD 0 (provided by the supplier), GD 3, GD 6, GD 9, GD 12, GD 15, GD 18 and GD 21.

FOOD CONSUMPTION: Yes
- Time schedule: GD 3 - 6, GD 6 - 9, GD 9 - 12, GD 12 - 15, GD 15 - 18 and GD 18 - 21

WATER CONSUMPTION: Yes
- Time schedule for examinations: Water consumption was monitored by visual inspection of the water bottles only. No quantitative analysis was performed.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs / tissues examined: Thyroid gland (with parathyroid), ovary, oviduct, uterus/cervix/vagina, placentae
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
- Other: Apparent non-pregnant uteri were retained, stained and examined for implantation sites.
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
Statistics:
Means, standard deviations, percentages, numbers, and/or incidences have been reported, as appropriate by dataset. Inferential statistical tests were conducted at the 5% significance level. All pairwise comparisons were conducted using two sided tests and have been reported at the 1% and 5% levels, unless otherwise noted. Analyses were performed excluding any group with less than 3 observations.
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 were conducted using Dunnett’s or Dunn’s test, respectively.
Non-parametric: The groups were compared using an overall Kruskal-Wallis test. If the overall Kruskal-Wallis test was found to be significant, then the above pairwise comparisons were conducted using Dunn’s test.
Incidence: A Fisher’s exact test was used to conduct pairwise group comparisons of interest.
Indices:
Pregnancy Rate = (No. of animals pregnant / No. of animals mated at the supplier) x 100

Pre-Implantation Loss = [(No. of corpora lutea – No. of implants) / No. of corpora lutea] x 100

Post-Implantation Loss = [(No. of implants – No. of live fetuses) / No. of implants] x 100

Sex Ratio (% males) = (No. male fetuses / Total No. of fetuses) x 100

Litter % of Fetuses with Abnormalities = (No. of fetuses in litter with a given finding / No. of fetuses in litter examined) x 100
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
9/23 animals in the high-dose group showed ploughing of the cage shavings from GD 15 onwards. This was transient and was seen immediately following dose administration only. Abnormal gait and hunched posture were observed in 2/24 animals on GD 7 or GD 8. One of these 2 animals was euthanised on GD 7 and showed decreased respiratory rate, hunched posture, eyes partly closed, uncoordinated and abnormal gait, subdued, cold to touch and head twitches as additional clinical signs. Further minor clinical observations were not treatment-related based on the type and distribution, e.g. fur thinning, and scabbing are commonly observed in rats and were therefore considered normal background findings. Increased activity was seen once in 1 animal of the low-dose group. Based on the single incidence and absence of dose response, this was considered sporadic.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One animal of the high-dose group was euthanised on GD 7 after receiving 2 doses due to the onset of adverse clinical signs at 1 - 2 h post dose administration. At necropsy, there were no abnormalities noted. The animal was not pregnant.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
A significant increase in food consumption in the high-dose group on GD 9 - 15 was observed. This was considered not treatment-related.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Description (incidence and severity):
Water consumption was not analysed quantitatively.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Maternal thyroid hormone levels (T3, T4 and TSH) on GD 21 were comparable between all groups. Slight intergroup differences did not follow a dose-related pattern and were too small to be considered treatment-related.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Number of abortions:
no effects observed
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
The mean pre- and post implantation losses were higher in the mid-dose group when compared to the controls. However, as there was no dose relationship, this was considered incidental.
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:
effects observed, non-treatment-related
Description (incidence and severity):
4, 4 and 2 animals were found to be not pregnant in the low-, mid- and high-dose groups, respectively. As there was no dose relationship, these non pregnancies were considered sporadic and unrelated to administration of the test substance.
Key result
Dose descriptor:
NOAEL
Remarks:
maternal
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: no biologically relevant effects observed
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
not examined
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 examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
In the high-dose group, the litter mean anogenital distance (AGD) was lower by 12% in male fetuses (2.90 mm vs. 3.28 mm in the controls) and by 16% in female fetuses (1.26 mm vs. 1.50 mm in the controls). However, the differences in absolute values were small, the mean AGD was within the standard deviation for the control group and within the test facility’s control values from similar assessments. Therefore, the AGD was considered to be within normal variation for all groups. There was no evidence of an effect on fetal weights.
Key result
Dose descriptor:
NOAEL
Remarks:
development
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no biologically relevant effects observed
Key result
Developmental effects observed:
no
Conclusions:
Propylidynetrimethanol, propoxylated did not exert any maternal systemic toxicity and had no effect on intrauterine development when administered at doses of up to 1000 mg/kg bw/day by oral gavage to pregnant rats on GD 6 - GD 20.
Endpoint:
developmental toxicity
Data waiving:
other justification
Justification for data waiving:
other:
Species:
rabbit
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises an adequate and reliable (Klimisch score 1) study performed with the registered substance. Moreover, pursuant to ECHA Decision TPE-D-2114465594-39-01/F (issued 4 July 2019) a pre-natal developmental toxicity study in a second species (oral route, rabbit) according to OECD guideline 414 is currently ongoing. The selected study is thus sufficient to fulfil the standard information requirements set out in Annexes VIII - X, Section 8.7., of Regulation (EC) No 1907/2006.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Developmental toxicity / teratogenicity in rats

Potential effects of propylidentrimethanol, propoxylated on pre-natal development were examined in a study conducted according to OECD guideline 414 under GLP conditions (rel 1-key, rat, gavage, OECD 414, Charles River, 2020, 490529). The test substance was administered once daily by oral gavage to groups of 24 pregnant Han Wistar RccHan®:WIST rats in doses of 100, 300 and 1000 mg/kg bw/day. The animals of the control group received the vehicle (water) only. Animals were dosed during the critical phase of organogenesis, i.e. on gestation days (GD) 6 - 20. The following parameters were evaluated: clinical observations, body weights, gravid uterus weights and corrected body weights, food consumption, clinical pathology parameters (thyroid stimulating hormone [TSH], T3 and T4), gross necropsy, organ weights (thyroid), maternal performance, ovarian and uterine findings and fetal examinations (body weights, sex, anogenital distance, external abnormalities, fixed head examinations, visceral examinations and skeletal examinations). In the dams, administration of the test substance at 1000 mg/kg bw/day was associated with transient ploughing following dose administration, which was considered not adverse. One animal given 1000 mg/kg bw/day, was euthanised due to clinical signs at 1 - 2 h following dose administration on GD 7 (decreased respiratory rate, hunched posture, partly closed eyes, uncoordinated and abnormal gait, subdued, cold to touch, and head twitches). The cause of this animal’s condition was unknown. Abnormal gait and hunched posture were seen in one other animal given 1000 mg/kg bw/day (GD 8, 0 - 1 h post dose only), but based on the single occurrence and transient nature, this was considered incidental. Given the lack of adverse findings in any other animal, the moribund condition of the unscheduled decedent was considered unlikely to be related to treatment with the test substance. For all other parameters, there were no test substance-related changes. In conclusion, administration of propylidentrimethanol, propoxylated by once daily oral gavage to pregnant rats was tolerated with no changes in maternal food consumption, body weight gains or thyroid hormone levels. Examination of pregnancies did not reveal any effect of the test substance on implantation, embryofetal survival, anogenital distance and fetal or placental weights. There were no relevant fetal morphology changes. Based on these results, the No-Observed-Adverse-Effect-Level (NOAEL) for maternal toxicity and fetal development was considered to be the high dose level of 1000 mg/kg bw/day.

Developmental toxicity / teratogenicity in a second species

In addition to the study performed in the rat, pursuant to ECHA Decision TPE-D-2114465594-39-01/F (issued 4 July 2019) a pre-natal developmental toxicity study in a second species (oral route, rabbit) according to OECD guideline 414 is currently ongoing. The hazard assessment of propylidentrimethanol, propoxylated with respect to developmental toxicity will be updated in due course when the results of this second study are available.

Justification for classification or non-classification

The available data on developmental toxicity with the registered substance in the rat do not meet the criteria for classification according to the CLP Regulation (EC) No. 1272/2008 and are therefore conclusive but not sufficient for classification. A pre-natal developmental toxicity study in a second species (oral route, rabbit) according to OECD guideline 414 is currently being performed. The endpoint toxicity to reproduction is covered by read across from the analogue substance propylidentrimethanol, ethoxylated since no study is available for the registered substance. The available data on toxicity to reproduction with propylidentrimethanol, ethoxylated do not meet the criteria for classification according to the CLP Regulation (EC) No. 1272/2008 and are therefore conclusive but not sufficient for classification. In addition, an extended one-generation reproductive toxicity study (EOGRTS) according to OECD guideline 443 in the rat by the oral route with the analogue substance ethane- 1,2-diol, propoxylated has been proposed. The decision on the testing proposal is pending.


 


In conclusion, the data currently available do not provide sufficient evidence that would imply a classification for reproductive or developmental toxicity according to the CLP Regulation (EC) No. 1272/2008 and are therefore conclusive but not sufficient for classification. However, since important studies are currently ongoing or are proposed to be performed in the future, the overall conclusion for classification of propylidentrimethanol, propoxylated regarding toxicity to reproduction and developmental toxicity / teratogenicity needs to be re-assessed once reliable study results are available.