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EC number: 221-254-0 | CAS number: 3047-32-3
- 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)
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
No data are available. Repeated dose 28 -day and 90 -day toxicity studies do not indicate any effects relevant to fertility at the limit dose of 1000 mg/kg bw/d. A waiver is therefore provided for the EOGRTS in the absence of any triggers.
Link to relevant study records
- Endpoint:
- extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Justification for type of information:
- JUSTIFICATION FOR DATA WAIVING
At this tonnage band an EOGRTS is not required in the absence of any triggers for reproducitve toxicity in the 28-day and 90-day studies. - Reproductive effects observed:
- not specified
Reference
Effect on fertility: via oral route
- Endpoint conclusion:
- no study available
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
Based on a comparison of findings in the 28-day and 90-day toxicity studies with triggers from ECHA Guidance it is concluded that, based on the available data, there are no specific concerns for the reproductive toxicity potential of TMPO. No additional data raising concerns for reproductive toxicity are available. An EOGRTS is therefore not required for this substance at REACH Annex IX level.
Effects on developmental toxicity
Description of key information
A modern developmental toxicity study in the rat is available.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 18 March 2016 to 03 February 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes
- Specific details on test material used for the study:
- Identity TMPO
Alternative name Trimethylolpropane Oxetane
Batch no. 160100167
Purity 99.7%
Expiry date 13 January 2017
EC Name 3-ethyloxetane-3-methanol
EC No. 221-254-0
IUPAC Name (3-ethyloxetan-3-yl)methanol
CAS No. [3047-32-3]
Storage conditions Room temperature
Appearance Colourless liquid
RTC number 14802 - Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Envigo RMS srl, San Pietro al Natisone (UD), Italy
- Age at study initiation: approx. 8 weeks for females; approx. 15 weeks for males
- Weight of female rats at Day 0 of gestation: 192.2 to 251.7
- Fasting period before study: No
- Housing: in groups of up to five by sex in solid floor polysulphone cages with bedding bags and nesting material (as necessary) before and after mating. During the mating period, rats were housed on the basis of 1 male to 1 female in polysulphone cages with a stainless steel mesh lid and floor.
- Diet: ad libitum 4 RF 21
- Water: ad libitum
- Acclimation period: two weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 15
- Air changes (per hr): approximately fifteen to twenty air changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light and twelve hours darkness cycle
IN-LIFE DATES: 22 March 2016 (first day of mating) to 22 April 2016 (final day of necropsy). - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- The test item was administered orally by gavage at a dose volume of 10 mL/kg body weight. Control animals received the vehicle alone at the same dose volume.
The dose was administered to each animal on the basis of the most recently recorded body weight and the volume administered was recorded for each animal. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The proposed formulation procedure for the test item was checked in the range from 10 to 100 mg/mL by chemical analysis (concentration) in RTC Study No. A2036 to confirm that the method was suitable. Final results for all levels were within 90-110% of nominal.
Samples of the formulations prepared on Weeks 1 and 4 were analysed to check the concentration.
Results of the analyses were within 90-110% of nominal. - Details on mating procedure:
- The females were paired with male rats. Females were paired one to one in the home cage of
the male and left overnight. Vaginal smears were taken daily in the morning from the day
after pairing until a positive identification of mating was made. The day of mating, as judged
by the presence of sperm in the vaginal smear or by the presence of a copulation plug, was
considered as Day 0 of gestation (or Day 0 post coitum). - Duration of treatment / exposure:
- All animals were dosed from Day 6 through Day 19 post coitum.
- Frequency of treatment:
- Once daily
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- Vehicle control
- 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:
- Each group comprised 24 mated females.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Rationale for animal assignment: The animals were randomly allocated to treatment groups using a stratified randomisation procedure to give approximately equal initial group mean body weights.
- Recovery group: Control and high dose group included 5 additional animals per sex to be sacrificed after 4 weeks recovery - Maternal examinations:
- Mortality: Throughout the study, all animals were checked early in each working day and again in the
afternoon. At weekends and Public Holidays a similar procedure was followed except that the final check was carried out at approximately mid-day.
Clinical signs: All clinical signs were recorded for individual animals. Each animal was observed daily and any clinical signs recorded starting from allocation until sacrifice.
Bodyweights: All animals were weighed on Days 0, 6, 9, 12, 15 and 20 post coitum.
Food consumption: Food consumption was measured on Days 6, 9, 12, 15 and 20 post coitum starting from Day 0 post coitum.
The animals were euthanised with carbon dioxide on Day 20 post coitum and necropsied.
The clinical history of the animals was studied and a detailed post mortem examination was
conducted (including examination of the external surface and orifices). Changes were noted
and the abnormalities preserved in 10% neutral buffered formalin. - Ovaries and uterine content:
- The ovaries and uteri were examined to determine:
– Gravid uterine weight;
– number of corpora lutea;
– number of implantation sites;
– number, sex and weight of all live foetuses;
– number and sex of dead foetuses (foetuses at term without spontaneous movements
and breathing);
– number of intra-uterine deaths;
– gross evaluation of placentae.
Intra-uterine deaths were classified as:
– Early resorptions: only placental remnants visible.
– Late resorptions: placental and foetal remnants visible.
Uteri or individual uterine horns without visible implantations were immersed in a 20%
solution of ammonium sulphide to reveal evidence of embryonic death at very early stages
of implantation. - Fetal examinations:
- Examination of foetuses: All live foetuses were examined externally.
Euthansia: All foetuses were sacrificed by intraperitoneal injection of Sodium Thiopental followed by hypothermia.
Approximately one-half of the foetuses (i.e., routinely, every second live foetus) in each litter was preserved in Bouin’s solution for subsequent fixed-visceral examination. The remaining foetuses were eviscerated after which the carcasses were fixed in 95% (v/v) ethanol for subsequent skeletal examination. Skeletal and fixed-visceral examinations were performed in all groups.
Structural deviations were classified as follows:
Malformations - Major abnormalities that are rare and/or affect the survival or health of the species under investigation.
Anomalies - Minor abnormalities that are detected relatively frequently.
Variants -A change that occurs within the normal population under investigation and is unlikely to
adversely affect survival or health. This might include a delay in growth or morphogenesis that would have otherwise followed a normal pattern of development.
Sex ratios of the foetuses were calculated as the percentage of males per litter. All derived values (e.g., means, percentages, ratios) were first calculated within the litter and
the group values derived as a mean of individual litter values. Foetal structural deviations were expressed as the percentage of affected foetuses relative to all foetuses examined per group, as well as in terms of the mean litter percentage of affected litters. - Statistics:
- For continuous variables the significance of the differences amongst group means was
assessed by Dunnett’s test or a modified t test, depending on the homogeneity of data.
Statistical analysis of non-continuous variables was carried out by means of the Kruskal-
Wallis test. - Indices:
- Pre-implantation loss was calculated as a percentage from the formula:
Pre-implantation loss = (number of corpora lutea minus number of implantations)/ number of corpora lutea
Expressed as a percentage.
Post-implantation loss was calculated as a percentage from the formula:
Post-implantation loss = (number of implantations minus number of live foetuses)/ number of implantations
Expressed as a percentage.
Total implantation loss was calculated as a percentage from the formula:
Total implantation loss = (number of corpora lutea minus number of live foetuses)/number of corpora lutea
Expressed as a percentage. - Clinical signs:
- no effects observed
- Description (incidence and severity):
- No signs of toxicological significance were noted during the study and no signs of reaction to
treatment were noted during the dosing period. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- No animal died during the study. One female in the control group gave premature birth on
gestation Day 20. Two females in the low dose group were found not pregnant at necropsy.
The number of females with live foetuses on gestation Day 20 was 23 in the control group, 22
in the low dose group and 24 in mid- and high dose groups. - Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No differences in body weight were noted between control and treated groups. At body
weight gain, a statistically significant decrease of approximately 17% was noted on Day 12
post coitum in mid-dose females when compared to controls. The change was considered to
be without toxicological relevance.
No differences in terminal body weight were observed in treated groups compared to the control group. - Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- No differences in food consumption were noted between control and treated groups. The
statistically significant decrease of approximately 7% detected on Day 9 post coitum in high
dose females was considered to be without toxicological relevance. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No differences in gravid uterus weight and absolute weight gain were
observed in treated groups compared to the control group. - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No treatment-related changes were observed at post mortem examination in treated animals,
when compared to the controls. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- not specified
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not examined
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined - Changes in number of pregnant:
- no effects observed
- Other effects:
- not specified
- 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
- Key result
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- not examined
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined - Reduction in number of live offspring:
- not examined
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Sex ratios were not affected by treatment.
- Changes in litter size and weights:
- effects observed, non-treatment-related
- Description (incidence and severity):
- No significant effects were seen in the litter data even if a slight trend towards a decrease in mean foetal weight and in litter weight (up to 6%) was seen in the mid- and high dose groups.
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- A total of 9 small foetuses (< 2.7 g) were detected; 4 out of 325 in the mid-dose group and 5 out of 320 in the high dose group. In addition, abnormal dark red area was detected on muzzle and sacral region of one small foetus in the high dose group. These findings were considered incidental.
No others abnormalities were detected at the external examination of foetuses. - Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- Skeletal observations of the low dose foetuses were comparable to controls. An increased incidence of no ossification of metacarpals (4th), incomplete or no ossification of sternal elements (5th and 6th), as well as incomplete or no ossification of the centrum of the thoracic vertebrae, were seen in mid- and high dose groups compared to controls. In addition, incomplete or no ossification of the pubis, associated with incomplete ossification of the ischium, was seen in few small foetuses in the same treated groups. The findings noted are considered to be due to a slight foetal underdevelopment also demonstrated by the presence of small foetuses in mid- and high dose groups.
- Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Visceral observations of the low dose foetuses were comparable to controls. Single cases of malformations were detected in control, mid- and high dose groups. Extremely enlarged uterers were seen in 1 foetus each in the control, mid- and high dose groups; extreme pelvic dilatation of kidney was seen in 2 foetuses from different litters in the mid-dose group and in 1 foetus in the high dose group; 1 foetus in the high dose group showed hepatomphalocele, and another one showed hepatic lobe agenesis. No clear treatment relationship was attributed to these findings due to their low incidence. Anomalies were detected in a few foetuses in all groups, with lower or similar incidence in treated groups respect to controls. Therefore they were considered to be without toxicological significance.
- Other effects:
- no effects observed
- 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
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- skeletal: sternum
- skeletal: vertebra
- skeletal: pelvic girdle
- Description (incidence and severity):
- Minor effects on skeletal ossification, secondary to low foetal weight and not considered to be adverse.
- Developmental effects observed:
- not specified
- Conclusions:
- A NOAEL of 1000 mg/kg bw/d for maternal and developmental toxicity can be determined for this study.
- Executive summary:
In a study conducted in accordance with OECD TG 414, TMPO was dosed via oral gavage to groups of 24 mated Sprague Dawley female rats at dose levels of 100, 300 and 1000 mg/kg bw/d on GD 6 -19. A control group comprising 24 mated females was administered with the vehicle (softened water) by oral gavage. Clinical signs, bodyweight and food consumption were monitored throughout the treatment phase. All maternal animals were caesarean sectioned on Day 20 post coitum and subjected to gross necropsy, including the ovaries and uteri. All live foetuses were examined externally. Approximately half of the foetuses were preserved for subsequent fixed-visceral examination and the remaining foetuses fixed for subsequent skeletal examination. There were no unscheduled deaths during the study. One female in the control group gave premature birth on gestation Day 20 and two females in the low dose group were not pregnant at necropsy. There were no clinical signs, changes in body weight, body weight gain, food consumption, terminal body weight, uterus weight and absolute weight gain which were significant in the treated groups when compared to the control group. There was a slight trend towards a decrease in mean foetal weight and in litter weight in the mid- and high-dose groups. Some small foetuses (less than 2.7 g) were detected in the mid- and high dose groups which was considered to be incidental. There were no treatment related findings following the visceral examination of the foetuses. Some skeletal changes which were defined as variants or anomalies were observed in higher incidences in mid- and high dose groups. These changes were attributed to the decreases in mean foetal weight and litter weight or associated to growth retardation in the small foetuses. The No Observed Adverse Effect Level (NOAEL) was determined to be 1000 mg/kg bw/d.
Reference
External and skeltal examination of foetuses
Dose (mg/kg bw/d) |
0 (control) |
100 |
300 |
1000 |
Small foetuses |
0/308 |
0/306 |
4/325 |
5/325 |
Mean litter weight (g) |
50.54 |
50.54 |
48.82 |
47.49 |
Mean foetal weight (g) |
3.78 |
3.65 |
3.59 |
3.56 |
No ossification of metacarpals (4th) |
29/162 |
30/158 |
61/170 |
51/169 |
Incomplete or no ossification of sternal elements (5th) |
18/162 |
34/158 |
56/170 |
49/169 |
Incomplete or no ossification of sternal elements (6th) |
20/162 |
30/158 |
52/170 |
54/169 |
Incomplete or no ossification of the centrum of the thoracic vertebrae |
15/162 |
14/158 |
25/170 |
35/169 |
Incomplete or no ossification of the pubis |
0/162 |
0/158 |
3/170 |
7/169 |
Fate of females, maternal weight and litter data
Dose |
0 (control) |
100 |
300 |
1000 |
Mated (#) |
24 |
24 |
24 |
24 |
Non-pregnant (#) |
0 |
2 |
0 |
0 |
Premature birth (#) |
1 |
0 |
0 |
0 |
Litters examined (#) |
23 |
22 |
24 |
24 |
Terminal weight (g) |
377.94 |
379.12 |
374.63 |
373.13 |
Weight gain (g) |
72.44 |
70.53 |
70.44 |
70.50 |
|
|
|
|
|
Corpora lutea (#) |
14.26 |
14.41 |
14.50 |
14.25 |
Implantations (#) |
13.78 |
14.14 |
14.33 |
13.79 |
Early uterine death (#) |
0.39 |
0.23 |
0.75 |
0.46 |
Late uterine death (#) |
0.00 |
0.00 |
0.04 |
0.00 |
Viable young (#) |
13.39 |
13.91 |
13.54 |
13.33 |
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:
- A modern developmental toxicity study in the rat is available for the submission substance.
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Toxicity to reproduction: other studies
Additional information
In a study conducted in accordance with OECD TG 414, TMPO was dosed via oral gavage to groups of 24 mated Sprague Dawley female rats at dose levels of 100, 300 and 1000 mg/kg bw/d on GD 6 -19. A control group comprising 24 mated females was administered with the vehicle (softened water) by oral gavage. Clinical signs, bodyweight and food consumption were monitored throughout the treatment phase. All maternal animals were caesarean sectioned on Day 20 post coitum and subjected to gross necropsy, including the ovaries and uteri. All live foetuses were examined externally. Approximately half of the foetuses were preserved for subsequent fixed-visceral examination and the remaining foetuses fixed for subsequent skeletal examination. There were no unscheduled deaths during the study. One female in the control group gave premature birth on gestation Day 20 and two females in the low dose group were not pregnant at necropsy. There were no clinical signs, changes in body weight, body weight gain, food consumption, terminal body weight, uterus weight and absolute weight gain which were significant in the treated groups when compared to the control group. There was a slight trend towards a decrease in mean foetal weight and in litter weight in the mid- and high-dose groups. Some small foetuses (less than 2.7 g) were detected in the mid- and high dose groups which was considered to be incidental. There were no treatment related findings following the visceral examination of the foetuses. Some skeletal changes which were defined as variants or anomalies were observed in higher incidences in mid- and high dose groups. These changes were attributed to the decreases in mean foetal weight and litter weight or associated to growth retardation in the small foetuses. The No Observed Adverse Effect Level (NOAEL) was determined to be 1000 mg/kg bw/d.
Justification for classification or non-classification
No classification is proposed in the absence of any indication of reproductive or developmental toxicity.
Additional information
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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