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 (CAS No. 50586-59-9, EC No. 500-110-3))

 

An extended one-generation reproductive toxicity study (EOGRTS) according to OECD guideline 443 in the rat by the oral route of exposure with 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

Referenceopen allclose all

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
experimental study planned
Study period:
3 years, starting from availability of the 90 day subchronic toxicity study report (sequential testing: EOGRTS to start after the 90 day subchronic study is finalized, to include knowledge gained in the 90 day study in the planning of the EOGRTS).
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS
NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Same as substance being registered

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE
REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION
[please address all points below]:
- Available GLP studies: none available
- Available non-GLP studies: none available
- Historical human data: none available
- (Q)SAR: QSAR is not an appropriate method to address the Extended One-Generation Reproductive Toxicity endpoint
- In vitro methods: none available to address the Extended One-Generation Reproductive Toxicity endpoint
- Weight of evidence: this substance is part of a broader category and has been identified as one of the substances for which data will be generated to support the broader read-across
- Grouping and read-across: this substance is part of a broader category and has been identified as one of the substances for which data will be generated to support the broader read-across
- Substance-tailored exposure driven testing [if applicable]: technically not possible due to potential exposure to the substance
- Approaches in addition to above [if applicable]: not applicable
- Other reasons [if applicable]: not applicable

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X
(AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENE
RATE THE NECESSARY INFORMATION:
- At over 1000 tons the Extended One-Generation Reproductive Toxicity study is a mandatory requirement. The substance is not classified as a Category 1 carcinogen or mutagen nor is it classified for reproductive toxicity already. In addition, although the substance has a very low order of toxicity, it is not possible to rule out the potential for systemic exposure or potential human exposure, therefore it is not possible to waive in accordance with Column 2.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED
IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed [if relevant]: Extended One-Generation Reproductive Toxicity Study, Cohorts 1A and 1B without extension, in the rat in accordance with OECD 443. The pre-mating period will be 10 weeks.
Qualifier:
according to guideline
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
Version / remarks:
Details on study design / methodology proposed [if relevant]: Extended One-Generation Reproductive Toxicity Study, Cohorts 1A and 1B without extension, in the rat in accordance with OECD 443. The pre-mating period will be 10 weeks.
GLP compliance:
yes
Justification for study design:
SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION T
OXICITY STUDY WITH JUSTIFICATIONS:
- Premating exposure duration for parental (P0) animals: 10 weeks
- Basis for dose level selection: previously conducted 28 day subacute and 90 day subchronic toxicity study with the substance. An additional dose range-finding study may be performed if additional data are needed for dose level selection.
- Inclusion/exclusion of extension of Cohort 1B: Exclusion. The test substance has a low order of toxicity as shown in a subacute toxicity study and a developmental toxicity study and data on the analogue indicate no developmental and no reproductive toxicity in previously conducted OECD 421 and rat developmental toxicity studies. Thus, as indicated by the retrospective analysis of Piersma et al. (Reprod. Toxicol. 2011 31(4):392-401) and Rorije et al. (Regul Toxicol Pharmacol. 2011 61(2):251-60), the F2 generation is unlikely to contribute data that is needed for classification and labeling.
- Termination time for F2: not applicable
- Inclusion/exclusion of developmental neurotoxicity Cohorts 2A and 2B: Exclusion. Results from the 28-day toxicity study in rats and the developmental toxicity study in rats conducted with the substance did not indicate primary effects on the nervous system. This includes no changes in clinical observations, brain weights, neuropathology (brain, spinal cord, nerves), nor developmental effects. In addition, there was no effect on functional observational battery (FOB) nor motor or locomotor activity (MA/MLA) endpoints observed in the 28-day study.

Even without inclusion of the DNT cohort (Cohort 2) in the EOGRTS, numerous neurotoxicity and
DNT-related endpoints are examined in the P1 and F1 Cohort 1A animals in the basic EOGRTS design, including the collection of brain weights and histopathological examination of brain, peripheral nerve, muscle, spinal cord, and eye plus optic nerve. Furthermore, the brain is weighed and preserved for possible histopathology in unselected F1 weanling (i.e., weanlings not assigned to other F1 Cohorts). While these endpoints do not include all of the functional assessments included in the DNT module, it is important to note that neurobehavioral endpoints were rarely the sole determinant of the no-observed-effect-level (NOEL) in either pharmaceutical or industrial chemical studies (Middaugh et al.,2003; Toxicol. Sci. 76, 250-261). Thus, the EOGRTS provides ample opportunity to confirm the absence of a primary neurotoxicity or DNT-related effect by the test compound.
- Inclusion/exclusion of developmental immunotoxicity Cohort 3: Exclusion. Results from the 28-day toxicity study in rats and the developmental toxicity study in rats conducted with the substance did not indicate primary effects on the immune system. In the 28 day study in the spleen there was an increase in germinal centers in the white pulp follicles of 1000 mg/kg males for which a treatment-relation could not be excluded, and there were no changes in white blood cell parameters, serum globulin levels, thymus weights, nor histopathology of the thymus, lymph nodes or bone marrow.

As part of the basic EOGRTS study design, hematology will be reexamined in the Cohort 1 offspring.
The basic EOGRTS study design includes numerous endpoints in the P1 and Cohort 1a animals, which will provide additional data on immunotoxicity potential. Hematology evaluation is required in
both the P1 adults and F1 Cohort 1A offspring. Spleen and thymus weights also are collected in P 1 adults, F1 unselected weanlings (i.e., weanlings not assigned to other Cohorts), and F1 Cohort 1A
animals; these organ weights also could be examined in the Cohort 1B animals if desired. In the F1
Cohort 1A animals, lymph nodes associated with and distant to the route of exposure are weighed
and splenic lymphocyte subpopulations (CD4+ and CD8+ T lymphocytes, B lymphocytes, and natural
killer cells) are enumerated to examine whether there is an exposure-related shift in the distribution
of CD4+ (helper) or CD8+ (cytotoxic) lymphocytes, or natural killer (NK) cells. The spleen, thymus
and bone marrow in both P1 and Cohort 1A adults are examined histopathologically. The spleen and
thymus are preserved in unselected weanlings for possible histopathological examination. Thus, the
EOGRTS also provides ample opportunity to confirm the absence of a primary immunotoxicity or DIT related effect by the test compound.
Species:
rat
Strain:
other:
Remarks:
TBD (should be the same strain as the 90 day toxicity study)
Route of administration:
oral: feed
Reproductive effects observed:
not specified
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
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
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: EPA OPPTS 870.3550 (Reproduction/Developmental Toxicity Screen)
GLP compliance:
yes (incl. QA statement)
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.
Remarks:
Doses / Concentrations:
0
Basis:
actual ingested
Remarks:
Doses / Concentrations:
100
Basis:
actual ingested
Remarks:
Doses / Concentrations:
300
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000
Basis:
actual ingested
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 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 (REACH).
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 ethane-1,2-diol, propoxylated (CAS No.31923-84-9, EC No. 500-078-0) are available. Therefore, data obtained with the analogue substance propylidynetrimethanol, ethoxylated (CAS No. 50586-59-9, EC No. 500-110-3) 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 no-observed-adverse-effect level (NOAEL) 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 substance-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 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-2114465593-41-01/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:
30 Apr 2009 - 17 Mar 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
(2001)
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Qualifier:
according to guideline
Guideline:
other: Japanese MAFF guidelines: Guideline on the Compiling of Test Results on Toxicity “Teratology Study”, 12-Nousan No. 8147 of November 24, 2000, amended June 26, 2001
GLP compliance:
yes (incl. QA statement)
Remarks:
Ministerium für Arbeit, Gesundheit und Soziales des Landes Nordrhein-Westfalen, Düsseldorf, Germany
Limit test:
no
Species:
rat
Strain:
Wistar
Remarks:
Hsd Cpb:WU (SPF-bred)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain: Hsd Cpb:WU (SPF-bred)
- Source: Harlan-Nederlands, 5960 AD Horst, The Netherlands
- Age at study initiation: 12-17 weeks
- Weight at study initiation: 220 - 265 g (females); 428 - 536 g (males)
- Housing: Starting from gestation day 0 individually in Type IIIh Makrolon cages on low-dust wood shavings.
- Diet and water: ad libitum
- Acclimation period: at least 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): approximately 55 %
- Air changes (per hr): > 10 per hour
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: demineralised water
Details on exposure:
Administration volume: 10 mL/kg bw

PREPARATION OF DOSING SOLUTIONS: The formulations were prepared as needed taking into account the analytically determined stability.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test substance was administered as a solution in the vehicle. The formulations were stored at room temperature. Before the start of treatment, the suitability of the formulation was confirmed by the analysis of concentration and stability of dosage forms prepared in the same way as it was done in the study (0.5 and 300 mg/mL, covering the concentration range used after 8 days of storage). Analyses were carried out before the start of the study. Content checks of the active ingredient in samples with concentrations of 10, 30, and 100 mg/mL were carried out twice during the study.
Details on mating procedure:
The animals were mated by placing two females overnight into a Type IIIh cage together with one male rat. If sperm was detected in the vaginal smear taken on the morning following mating, this day was regarded as day 0 of gestation.
Duration of treatment / exposure:
Day 6 - 20 post coitum
Frequency of treatment:
once daily, 7 days/week
Duration of test:
from days 0 to 21 post coitum
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:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were selected based on the results of a previous dose toleration study in rats, which revealed no treatment related findings after 1000 mg/kg.
Maternal examinations:
CLINICAL EXAMINATIONS: Yes
- Time schedule: The females were inspected from days 0 to 21 post coitum twice daily (once daily only on weekends, on public holidays, and on day 21 post coitum), and all findings were recorded. Attention was paid to disturbances in the general condition of the rats (appearance, behavior), and any alterations concerning their excretory products.

BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of the females was determined on day 0 and daily from day 6 to day 21 post coitum. Corrected body weight gain was determined by subtracting the uterus weight on day 21 from the body weight gain from days 0 to 21.

FOOD CONSUMPTION: Yes
- The food intake of the animals was determined from the difference in weight between the food offered and the food not consumed for the following days of gestation: Days 0 - 3, 3 - 6, 6 - 9, 9 - 12, 12 - 15, 15 - 18, and 18 - 21.

WATER CONSUMPTION: Yes
- Water intake was assessed daily by visual estimation of the quantities left over and reported together with clinical findings.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Cesarean sections were performed on day 21 post coitum without knowledge of treatment groups.
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 of dead and live fetuses: Yes
- Other: individual weight and appearance of the placentas
Fetal examinations:
- Sex of live fetuses
- Individual weights of live fetuses
- External examinations: Yes: (findings in alive and dead fetuses are included)
- Soft tissue and head examinations : Yes: (evaluation of about half of alive fetuses per litter)
- Skeletal and cartilage abnormalities : Yes: (evaluation in about half of alive fetuses per litter)
Statistics:
Differences between the control and test item treated groups were considered to be significant when p < 0.05. Significant differences from the control group are indicated with * for p < 0.05 and ** for p < 0.01. Statistical evaluation was performed on an Alpha 800 5/500 computer using the following methods:
Analysis of Variance (ANOVA); in case of significance Dunnett's test for feed intakes, body weights, body weight gains, and corrected body weight gains, uterine weights, number of corpora lutea per female, number of implantations per female, number of live fetuses per female and as percentage of implantations per female, placental weights per female, fetal weights per female.
2 by N CHI2 test; in case of significant differences Fisher's exact test with Bonferroni correction for fertility rate, gestation rate, number of implantations per group, number of preimplantation losses per group, number of postimplantation losses, early resorptions, late resorptions or dead fetuses per group, number of live fetuses per group as percentage of implantations per group, number of male or female fetuses or fetuses with indeterminable sex per group, number of placentas with findings or litters with placental findings per group, number of fetuses or litters with external, visceral or skeletal findings, with malformations or with external or visceral deviations per group.
Kruskal-Wallis test and in case of significant differences Dunn's test for number of preimplantation losses per female, number of postimplantation losses, early resorptions, late resorptions or dead fetuses per female, number of male or female fetuses or fetuses with indeterminable sex per female, number of placentas with findings per female, number of fetuses with external or visceral findings, with malformations or with external or visceral deviations per female.
CHI2 test (correction according to yates) for number of fetuses or litters with cartilaginous tissue observations.
Indices:
gestation rate
Details on maternal toxic effects:
Maternal toxic effects: no effects

BODY WEIGHTS:
Statistically significantly decreased body weight gain occurred from days 6-7 post coitum at the 1000 mg/kg bw/day level, for which a treatment-related adverse effect is not assumed, as only this single interval revealed a decreased body weight gain, and because absolute body weight gain during treatment and gestation periods as well as corrected body weight gain were unaffected at this dose level. Statistically significantly increased body weight gain at the 100 mg/kg bw/day and 1000 mg/kg bw/day levels from days 20-21 is caused by the incidentally lower body weight gain of the current control group within this interval. Thus, absolute and corrected body weight gains were unaffected by treatment at dose levels up to and including 1000 mg/kg bw/day. A treatment-related adverse effect is not assumed for transiently decreased body weight gain from days 6-7 post coitum at the 1000 mg/kg bw/day level.

NECROPSY:
One female of the 1000 mg/kg bw/day group showed a slight dilation of the left renal pelvis, for which a treatment related effect is not assumed due to its single occurrence, and since this finding is known as a spontaneous finding in the rat strain used. Furthermore, one female without implantation sites at the 1000 mg/kg bw/day level revealed a uterus tightly filled with clear fluid, for which a treatment related effect is not assumed, as this finding was also evident in one female of the current control group, and because this finding is known as a spontaneous finding in the rat strain used.
Key result
Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no adverse effects observed
Key result
Abnormalities:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: no effects

WEIGHT and APPEARANCE of PLACENTAS:
Two double placentas out of one litter occurred at the 1000 mg/kg bw/day level, for which a treatment related effect is not assumed, as the incidence of this finding lay within the range of historical control data. Furthermore, one pale placenta was shown at the 300 mg/kg bw/day level, for which a treatment related effect is not assumed due to its single occurrence, because of a lacking dose dependency, and since this finding is known as a spontaneous finding in the rat strain used.

FETAL MALFORMATIONS:
The overall incidences of fetuses with malformations showed no dose dependency at dose levels up to and including 1000 mg/kg bw/day and revealed the highest values on a fetal and a litter basis in the 100 mg/kg bw/day group. The overall incidences of affected fetuses and litters lay well within the range of historical control data of the rat strain used.

Number of fetuses per group/number of fetuses with malformations/malformed fetuses per group (%)/number of litters per group/number of litters with malformations/malformed litters per group (%)
Vehicle control: 262/0/0.0/21/0/0.0
100 mg/kg bw/day: 261/6/2.3/20/4/20.0
300 mg/kg bw/dayday: 288/4/1.4/21/4/19.0
1000 mg/kg bw/day: 262/3/1.1/20/3/15.0

FETAL EXTERNAL and VISCERAL DEVIATIONS
Circumscribed hard whitish areas in different localisations of the head occurred in all groups, without showing a dose dependency. Histopathological evaluation of this finding was performed in a recently conducted prenatal developmental toxicity study with the same rat strain and revealed calcium concrements without connection to the underlying tissue in the affected localisations. Calcium might have been dissolved from the fetal bones by the Wilson fixative and precipitated so that these findings were regarded as artifacts. The finding of a small hollow structure in different localisations of the head also occurred in all groups, without showing a dose dependency, and is also considered as a fixation artifact. The remaining findings of the dose groups revealed no dose dependency in most of the cases or were isolated findings. The incidences were comparable with the current control group and/or lay within the range of historical control data.

FETAL SKELETAL DEVIATIONS INCLUDING CARTIÖAGINOUS DEVIATIONS
Sporadic statistically significant skeletal findings (increased incidence of an unossified round area right at the exoccipital bone at the 100 mg/kg bw/day level, decreased incidence of asymmetrical 5th sternebrae at the 300 mg/kg bw/day level) showed no dose dependency so that a treatment related effect was not evident.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Additional data supporting the information provided are attached as pdf documents below under 'Attached background material'.

Executive summary:

A developmental toxicity study was performed with the test substance according to OECD TG 414. Twenty-five inseminated female Wistar rats each were treated daily orally by gavage with the test substance in deminaralized water from day 6 to day 20 p.c. in the following doses: 0, 100, 300, and 1000 mg/kg body weight (bw), respectively. The fetuses were delivered by cesarean section on day 21 of gestation. Investigation was performed on general tolerance of the test substance by the females as well as on its effect on intrauterine development.

Appearance, behavior, mortality, absolute and corrected body weight gains, food intake, water intake, and fecal and urinary excretions were unaffected at dose levels up to and including 1000 mg/kg bw.

No treatment related gross pathological findings occurred at dose levels up to and including 1000 mg/kg.

The gestation rate, appearance and weights of placentas, postimplantation loss and correspondingly the number of fetuses, fetal sex distribution, and fetal weights were unaffected by treatment at dose levels up to and including 1000 mg/kg.

A treatment related effect on malformations, external, visceral, and skeletal (including cartilage) deviations was not evident at dose levels up to and including 1000 mg/kg.

Summarizing and evaluating all data investigated the following no-observed-adverse-effect levels (NOAELs) were determined: for maternal toxicity 1000 mg/kg bw, for developmental toxicity 1000 mg/kg bw.

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-2114465593-41-01/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 (REACH).
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

A developmental toxicity study was performed with ethane-1,2-diol, propoxylated (CAS No.31923-84-9, EC No. 500-078-0) according to OECD guideline 414 under GLP conditions (rel 1-key, rat, gavage, OECD 414, Bayer Schering Pharma, 2010d, T7078264). Twenty-five inseminated female Wistar rats each were treated daily orally by gavage with the test substance in deminaralized water from day 6 to day 20 post coitum (p.c.) with doses of 100, 300, and 1000 mg/kg bw/day. The fetuses were delivered by cesarean section on day 21 of gestation. Investigation was performed on general tolerance of the test substance by the females as well as on its effect on intrauterine development. Appearance, behavior, mortality, absolute and corrected body weight gains, food intake, water intake, and fecal and urinary excretions were unaffected at dose levels up to and including 1000 mg/kg bw/day. No treatment related gross pathological findings occurred at dose levels up to and including 1000 mg/kg bw/day. The gestation rate, appearance and weights of placentas, postimplantation loss and correspondingly the number of fetuses, fetal sex distribution, and fetal weights were unaffected by treatment in all groups. A treatment related effect on malformations, external, visceral, and skeletal (including cartilage) deviations was not evident at all doses investigated. In conclusion, evaluating all data investigated the no-observed-adverse-effect levels (NOAELs) of ethane-1,2-diol, propoxylated for maternal toxicity and for developmental toxicity were both determinted to be 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-2114465593-41-01/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

ethane-1,2-diol, 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 Regulation (EC) No. 1272/2008 (CLP) 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 (CAS No. 50586-59-9, EC No. 500-110-3) 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 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 Regulation (EC) No. 1272/2008 (CLP) 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 ethane-1,2-diol, propoxylated regarding toxicity to reproduction and developmental toxicity / teratogenicity needs to be re-assessed once reliable study results are available.

Additional information