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EC number: 484-360-8 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- January 2018 - March 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2001
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 1998
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2008
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Test material form:
- liquid
- Details on test material:
- - Name of test material: Reaction product of fatty acids, C16-18 and C18-unsaturated and reaction mass of 1.3-alkanediol, 2-(hydroxymethyl)-2-[(methoxymethoxy)methyl]- and 1.3- heteromonocycle-5,5-dimethanol
- Physical state: Yellow to amber liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Han
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories Deutschland, Sulzfeld, Germany
- Age and weight at study initiation: The females arrived on Day 0 or Day 1 post-coitum (Day 0 post-coitum is defined as the day of successful mating). They were 11-15 weeks old and weighed between 179 and 281 g at the initiation of dosing.
- Fasting period before study: no
- Housing: individually in Macrolon plastic cages (MIII type) containing appropriate bedding.
- Diet: Pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany) was provided ad libitum throughout the study, except during designated procedures. It was considered that there were no known contaminants in the feed that would interfere with the objectives of the study.
- Water: Municipal tap water was freely available to each animal via water bottles. Periodic analysis of the water was performed. It was considered that there were no known contaminants in the water that would interfere
with the objectives of the study.
- Acclimation period: at least 5 days before the commencement of dosing.
For psychological/environmental enrichment and nesting material, animals were provided with paper (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom).
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-22
- Humidity (%): 37-53
- Air changes (per hr): Ten or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms.
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 04 Feb 2018 To: 22 Feb 2018
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- (Elix)
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item was administered as received. An adequate amount of the test item was dispensed into daily aliquots, which were stored in a controlled temperature area set to maintain 21°C until use. Test item for dosing was kept at room temperature until dosing. Adjustment was made for specific gravity of the test item. No correction was made for the purity/composition of the test item. - Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- The Sponsor provided to the Test Facility documentation of the identity, purity, composition, and stability for the test item. No Certificate of Analysis or equivalent document was provided to the Test Facility. The Sponsor has appropriate documentation on file concerning the method of synthesis, fabrication or derivation of the test item.
The stability of the bulk test item was not determined during the course of this study. Information to support the stability of each lot of the bulk test item was provided by the Sponsor.
The test item was used as received from the Sponsor; therefore, samples for dose formulation analysis were not collected by the Test Facility. - Details on mating procedure:
- Time-mated female Wistar Han Rats arrived on Day 0 or Day 1 post-coitum (Day 0 post-coitum is defined as the day of successful mating). Females which were mated on the same day were classified in the same subgroup.
- Duration of treatment / exposure:
- The test item or water (Elix) was administered to the appropriate animals by once daily oral gavage 7 days a week from Day 6 to Day 20 post-coitum, inclusive. Animals were dosed approximately at the same time each day with a maximum of 6 hours difference between the earliest and latest dose. The dose volume for each animal was based on the most recent body weight measurement.
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- 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:
- 22 females
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale:
The dose levels were selected based on the results of a 28-day study with Reaction product of fatty acids, C16-18 and C18-unsaturated and reaction mass of 1.3-alkanediol, 2-(hydroxymethyl)-2-[(methoxymethoxy)methyl]- and 1.3- heteromonocycle-5,5-dimethanol in Wistar rats by oral gavage. No toxicologically relevant effects were observed and a NOAEL of 1000 mg/kg bw/day was established in this study.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical observations were performed at least once daily, beginning on Day 2 post-coitum and lasting up to the day prior to necropsy.
BODY WEIGHT: Yes
- Time schedule for examinations: Days 2, 6, 9, 12, 15, 18 and 21 post coitum
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption was quantitatively measured for Days 2-6, 6-9, 9-12, 12-15, 15-18 and 18-21 post coitum
WATER CONSUMPTION: Yes
- Subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected
POST-MORTEM EXAMINATIONS: Yes
- All animals (including females with early delivery) were subjected to an external, thoracic and abdominal examination, with special attention being paid to the reproductive organs. No organs (except for the uterus) were weighed. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Each ovary and uterine horn of all animals were dissected and examined as quickly as possible to determine:
- The number of corpora lutea.
- The weight of the (gravid) uterus (not for animals sacrificed before planned necropsy).
- The number and distribution of live and dead fetuses.
- The number and distribution of embryo-fetal deaths.
- The sex of each fetus based on the ano-genital distance.
In case no macroscopically visible implantation sites were present, nongravid uteri were stained using the Salewski technique in order to detect any former 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:
- All statistical tests were conducted at the 5% significance level. All pairwise comparisons were conducted using two sided tests and were reported at the 1% and 5% levels.
Numerical data collected on scheduled occasions for the listed variables were analyzed as indicated according to sex and occasion. Descriptive statistics number, mean and standard deviation (or %CV or SE when deemed appropriate) were reported whenever possible.
Inferential statistics were performed according to the matrix below when possible, but excluded semi-quantitative data, and any group with less than 3 observations.
The following pairwise comparisons were made:
Group 2 vs. Group 1
Group 3 vs. Group 1
Group 4 vs. Group 1
Parametric: Datasets with at least 3 groups (the designated control group and 2 other groups) were compared using Dunnett-test (many-to-one-t-test).
Non-Parametric: Datasets with at least 3 groups were compared using a Steel-test (many-to-one rank test).
Mean litter proportions (percent of litter) of the number of viable and dead fetuses, early and late resorptions, total resorptions, pre- and post-implantation loss, and sex distribution were compared using the Mann Whitney test.
Mean litter proportions (percent per litter) of total fetal malformations and developmental variations (external, visceral and skeletal), and each particular external, visceral and skeletal malformation or variation were subjected to the Kruskal-Wallis nonparametric ANOVA test to determine intergroup differences.
Incidence: An overall Fisher’s exact test was used to compare all groups at the 5% significance level.
The above pairwise comparisons were conducted using a two-sided Fisher’s exact test at the 5% significance level if the overall test was significant.
No statistics were applied for data on maternal survival, pregnancy status, group mean numbers of dead fetuses, early and late resorptions, and pre- and post-implantation loss. - Indices:
- Maternal variables:
Body Weight Gains: Calculated between at least each scheduled interval.
Corrected Body Weight Gains: Terminal body weight minus the body weight on Day 6 postcoitum and the weight of gravid uterus.
Relative Food Consumption: Calculated against the body weight for scheduled intervals.
Reproduction and Developmental Variables:
Pre-implantation loss (%): ((number of corpora lutea - number of implantation sites) / number of corpora lutea) x100
Post-implantation loss (%): ((number of implantation sites - number of live fetuses) / number of implantation sites) x100
Viable fetuses affected/litter (%): (number of viable fetuses affected/litter / number of viable fetuses/litter) x100
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related clinical signs were noted.
Alopecia noted during the treatment period occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study and did not show any apparent dose-related trend. At the incidence observed, these were considered to be unrelated to treatment. - Mortality:
- no mortality observed
- Description (incidence):
- No mortality occurred during the study period.
Two females (one at dose 300 mg/kg bw/day and one at dose 1000 mg/kg bw/day were euthanized on Day 20 post-coitum, as they delivered their offspring early. - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Body weights, body weight gain and weight gain corrected for gravid uterus were similar to the control levels over the study period.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption before or after correction for body weight was considered unaffected by treatment.
The statistical significant reduction in relative food consumption noted at dose 300 mg/kg bw/day over Days 18-21 was considered a chance finding rather than a test-item related effect as the decrease was small and no dose related trend was observed. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- 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
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a result of treatment.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One female at dose 100 mg/kg bw/day and one female at dose 1000 mg/kg bw/day delivered their offspring on Day 20 post-coitum. Early delivery was also noted for two control females and one female at dose 1000 mg/kg bw/day at the day of scheduled necropsy on Day 21 post-coitum. This finding is occasionally seen among rats in these types of study and in the absence of maternal toxicity and a dose response relationship was considered unrelated to treatment.
- Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
- Details on maternal toxic effects:
- The numbers of pregnant females, corpora lutea and implantation sites, and pre-implantation loss in the control and test groups were similar and in the range of normal biological variation.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- There were no toxicologically relevant effects on fetal body weights (both sexes) noted by treatment up to and including 1000 mg/kg bw/day.
Mean combined (male and female) fetal body weights were 5.3, 5.2, 5.4 and 5.2 gram for the control, 100, 300 and 1000 mg/kg bw/day groups, respectively. - Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- The male:female ratio was unaffected by treatment up to and including 1000 mg/kg bw/day.
Mean sex ratios (males:females) were 46:54, 50:50, 49:51 and 49:51 for the control, 100, 300 and 1000 mg/kg bw/day groups, respectively. - Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related effects on litter size of any group.
Mean litter sizes were 10.5, 10.5, 11.9 and 10.4 fetuses/litter for the control, 100, 300 and 1000 mg/kg bw/day groups, respectively. - Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Description (incidence and severity):
- There were no treatment related effects on external morphology following treatment up to and including 1000 mg/kg bw/day.
Two externally malformed fetuses were observed in this study. One fetus from dose group 300 mg/kg bw/day had an omphalocele and in dose group 100 mg/kg bw/day, one fetus had a small lower jaw which was skeletally confirmed. Since these malformations occurred singly at the low and mid dose level, they were considered chance findings and not treatment related. Moreover, both findings were previously noted in historical control fetuses.
External variations were not seen in any group. - Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment related effects on skeletal morphology following treatment up to and including 1000 mg/kg bw/day.
Malformations occurred in 3 (2), 1 (1) and 3 (2) fetuses (litters) of the 100, 300 and 1000 mg/kg bw/day groups and not in the control group. Two littermates in the high dose group had bent limb bones (humerus and scapula) and another high dose group fetus had a vertebral anomaly. In the 300 mg/kg bw/day group, one fetus had a rib anomaly and in the 100 mg/kg bw/day group, one fetus had a costal cartilage anomaly, one fetus had polydactyly and one fetus (also malformed externally and viscerally) had a vertebral anomaly with associated rib anomaly.
The low incidence and group distribution of these malformations do not suggest a treatment relationship and all but one (polydactyly) have been seen previously in historical controls.
Therefore, all the above malformations were not considered test-item related and to be spontaneous in origin.
The variation of 14th full ribs was observed at higher incidences in the test-item treated groups than in the control group, namely at 8.3%, 5.4% and 8.2% per litter at 100, 300 and 1000 mg/kg bw/day and at 0.9% per litter in the control group. None of the higher incidences in test-item treated groups was statistically significantly increased and all were close to the historical control mean value (6.3% per litter) whereas the concurrent control value was notably lower. Therefore, the higher incidences of 14th full ribs in test-item treated groups was not considered to be toxicologically relevant.
A lower incidence (1.8%) of pelvic girdle caudal shift was noted at the highest dose group, compared to an incidence of 7.1%, 9.9%, 9.0% observed for the control, 100 mg/kg bw/day, and 300 mg/kg bw/day groups, respectively. In absence of a dose-related incidence trend, and occurrence within the range of available historical data, it was considered that the low incidence of pelvic girdle caudal shift appeared by chance and not related to treatment.
Another noteworthy variation was the one of unossified metacarpals and/or metatarsals that occurred at incidences of 6.1%, 6.7%, 0.8% and 13.3% per litter in 100, 300 and 1000 mg/kg bw/day groups, respectively. There were no significant differences from the control group and all incidences were within the historical control range (0.0% - 17.6% per litter). However, only the high dose incidence was markedly above the p95 value of 4.7% per litter. It appeared that the incidence at the high dose level was caused by two litters of which all skeletally examined fetuses had unossified metacarpals and/or metatarsals. The mean fetal body weights of these two respective litters (3.7 and 3.4 grams) were also markedly below the group mean value (5.2 grams). Therefore, it was considered that the higher incidence of unossified metacarpals and/or metatarsals (a main ossification parameter) in the high dose group was a result of the low fetal body weights of these two litters and not related to the test item.
Moreover, the occurrence of this variation was not dose related.
The other variations that were noted occurred in the absence of a dose-related incidence trend, infrequently and/or at frequencies that were within the range of available historical control data. Therefore, they were not considered treatment related. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment related effects on visceral morphology following treatment up to and including 1000 mg/kg bw/day.
Four viscerally malformed fetuses were observed in this study. In the high dose group, one fetus had a situs inversus which was also observed in two fetuses at the 100 mg/kg bw/day group. In one of the fetuses of the low dose group, who was already observed with a small lower jaw externally, situs inversus went along with abnormal lobation of the lung. The fourth affected fetus was from the 300 mg/kg bw/day group (the one with an omphalocele externally) who had no jejunum, ileum and colon. The low incidence and group distribution of the above malformations did not indicate a treatment relationship and two malformations (situs inversus and abnormal lung lobation) were also in the list of historical control data. Therefore, all were considered to be chance findings.
All visceral variations that were noted occurred in the absence of a dose-related incidence trend, occurred infrequently and/or at frequencies that were within the range of available historical control data. - Other effects:
- no effects observed
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- In conclusion, based on the results in this prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Level (NOAEL) for Reaction product of fatty acids, C16-18 and C18-unsaturated and reaction mass of 1.3-alkanediol, 2-(hydroxymethyl)-2-[(methoxymethoxy)methyl]- and 1.3- heteromonocycle-5,5-dimethanol was established as being at least 1000 mg/kg bw/day.
- Executive summary:
The potential of Reaction product of fatty acids, C16-18 and C18-unsaturated and reaction mass of 1.3-alkanediol, 2-(hydroxymethyl)-2 -[(methoxymethoxy)methyl]- and 1.3- heteromonocycle-5,5-dimethanol to induce developmental toxicity after maternal exposure during the critical period of organogenesis and to characterize maternal toxicity was studied by means of an OECD 414 study peformed under GLP conditions.
Time-mated female Wistar Han rats were treated with the testsubstance from Day 6 to 20 post-coitum, inclusive by daily oral gavage at dose levels of 100, 300 and 1000 mg/kg bw/day. The rats of the control group received the vehicle, water, alone.
No treatment-related changes were noted in any of the maternal parameters investigated in this study (i.e. mortality, clinical appearance, body weight, food consumption, macroscopic examination, and maternal pregnancy data). The observed early deliveries of pups were considered unrelated to treatment as this finding is occasionally seen among rats used in these types of study and in the absence of correlated microscopic findings.
No treatment-related changes were noted in any of the developmental parameters investigated in this study (i.e. litter size, sex ratio, fetal body weights, external, visceral (including sex) and skeletal malformations and developmental variations). Some external, visceral and skeletal malformations and variations were noted. However, findings were not considered test-item related and toxicologically relevant as no dose related trends were observed or values were within the historical control range. The observed higher incidence of unossified metacarpals and/or metatarsals (a main ossification parameter) in Group 4 was considered the result of the low fetal body weights of two litters and at this low incidence not regarded toxicologically significant.
In conclusion, based on the results in this prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Level (NOAEL) for Reaction product of fatty acids, C16-18 and C18-unsaturated and reaction mass of 1.3-alkanediol, 2 -(hydroxymethyl)-2-[(methoxymethoxy)methyl]- and 1.3- heteromonocycle-5,5-dimethanol was established as being at least 1000 mg/kg bw/day.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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