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EC number: 500-099-5 | CAS number: 37625-56-2
- 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
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Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 22nd October to 30th December 2014
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 015
- Report date:
- 2015
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- CAPA 3050
- IUPAC Name:
- CAPA 3050
- Reference substance name:
- ε-Caprolactone, oligomeric reaction products with propylidynetrimethanol
- EC Number:
- 500-099-5
- EC Name:
- ε-Caprolactone, oligomeric reaction products with propylidynetrimethanol
- Cas Number:
- 37625-56-2
- Molecular formula:
- (C6H14O3)x.C6H10O2 (x=0-6)
- IUPAC Name:
- 2-Oxepanone, polymer with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol
- Reference substance name:
- 2-Oxepanone, polymer with 2-ethyl-2-(hydroxymethyl)-1, 3-propanediol
- IUPAC Name:
- 2-Oxepanone, polymer with 2-ethyl-2-(hydroxymethyl)-1, 3-propanediol
- Test material form:
- other: liquid
- Details on test material:
- - Name of test material (as cited in study report): CAPA 3050
- Substance type: Oligomer
- Physical state: Liquid
- Analytical purity: 100%
- Lot/batch No.: WCB000999
- Expiration date of the lot/batch: 23th August 2015
- Stability under test conditions: Stable for the duration of the study
- Storage condition of test material: Ambient
Constituent 1
Constituent 2
Constituent 3
- Specific details on test material used for the study:
- Identification: Capa 3050
Alternative Name: 2-Oxepanone, polymer with 2-ethyl-2-(hydroxymethyl)-1,
3-propanediol
CAS Number: 37625-56-2
EC Number: 500-099-5
Batch (Lot) No.: WCB000999
Receipt Date: 31 March 2014
Expiration Date: 26 August 2015
Physical Description: Liquid
Purity: 100 %
Storage Conditions: Ambient
Supplier: Perstorp
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
Source: Charles River, Margate, Kent, UK
Age at study initiation: 9 weeks
Weight at study initiation: 200-262 g
Fasting period before study: not applicable
Housing: Individual in plastic cages with solid bottoms and bedding material
Diet: ad libitum
Water: ad libitum
Acclimation period: 3-5 days
ENVIRONMENTAL CONDITIONS
Temperature (°C): 19-23
Humidity (%): 40-85
Air changes (per hr): 10 (minimum)
Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES
From: 24th October 2014
To: 12th November 2014
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5% hydroxypropylmethylcellulose, 0.1% Tween 80 in water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The control item, 0.5% HPMC, 0.1% Tween 80 in Milli-Q water was prepared weekly, stored at 2-8°C, and dispensed daily. The prepared control item was stirred for at least 30 minutes before dosing and continuously during dosing.Test item dosing formulations were prepared based on a method established at the Test Facility at appropriate concentrations to meet dosage level requirements. The required amount of test item was weighed into a pre-labelled container according to instructions from the formulation computerised system (Dispense 8). The appropriate amount of the vehicle was added to the container and the formulation was mixed by means of magnetic stirring and high shear mixing until a homogenous formulation was obtained. The dosing formulations were prepared weekly, stored at 2-8°C, and dispensed daily. The dosing formulations were stirred for at least 30 minutes before dosing and continuously during dosing. Details of the preparation and dispensing of the test item have been retained in the study records.VEHICLE- Justification for use and choice of vehicle (if other than water): the vehicle was water-based, with the addition of 0.5% HPMC and 0.1% Tween 80 to ensure homogeneity of the dosing solution- Concentration in vehicle: 0, 10, 30, 100 mg/mL- Amount of vehicle (if gavage): 10 mL/kg bw (constant volume)Milli-Q water (batches MILLIQ297, MILLIQ304 and MILLIQ311; expiry dates 31 Oct 2014, 07 Nov 2014 and 14 Nov 2014 respectively), Methocel E4M Premium HPMC (batch DT357129, expiry date 17 Aug 2016) and Polysorbate 80 Ph Eur (batches BCBK8291V and BCBN2111V; expiry dates 01 Nov 2014 and 31 Mar 2016) were used during control item preparation on this study. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Formulation analysis on this study was performed using a validated analytical procedure (Charles River Study 432576). Dosing formulation samples were analysed by UPLC with UV detection for the determination of CAPA 3050. Duplicate top, bottom and middle samples were taken from each formulation pepared for Weeks 1 and 2. Triplicate back-up samples were also taken for the verification of results out of specification.
- Details on mating procedure:
- Female rats were provided time-mated and were received in the testing facility on Day 1-3 of gestation.
- Duration of treatment / exposure:
- The test and control items were administered to the appropriate animals by once daily oral gavage from Days 6-19 of gestation. The dose for each animal was based on the most recent body weight measurement.
- Frequency of treatment:
- Daily (Day 6-19 of gestation)
- Duration of test:
- Rats were terminated on Day 20 of gestation
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day
- Dose / conc.:
- 300 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- No. of animals per sex per dose:
- 24 time-mated females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected in agreement with the Sponsor following review of data from a preliminary prenatal developmental toxicity study using this test item (Charles River Study No. 496926). In that study, there was no adverse maternal toxicity at dose levels up to 1000 mg/kg bw/d however; a reduction in foetal weight of approximately 10% was noted at 1000 mg/kg bw/d. Therefore, 1000 mg/kg bw/d was chosen as the high dose level in this study to further explore toxicity.- Rationale for animal assignment: On arrival from the suppliers, the animals were allocated to cages on racks. Animals were allocated by the use of randomly sequenced numbers, in such a way that each full rack of cages contained similar numbers of representatives from all groups. It was ensured that females inseminated by the same male did not appear in the same group. Two extra females were assigned to a separate group. The disposition of all animals was documented in the study records.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS:
Time schedule: All animals were checked early morning and as late as possible each day for viability.
DETAILED CLINICAL OBSERVATIONS:
All animals were examined daily from the start of dosing; animals were removed from the cage for examination
BODY WEIGHT:
Time schedule for examinations: Pre-test – once (Day 4 of gestation); dosing period – daily on days 6 – 20 of gestation
FOOD CONSUMPTION:
Daily from Day 4 of gestation (first measured quantity given on Day 3 of gestation). Food consumption was quantitatively measured for individual animals
WATER CONSUMPTION:
Time schedule for examinations: Regularly during the study. Water consumption was monitored by visual inspection of the water bottles. It was considered that there were no intergroup differences therefore water consumption was not assessed quantitatively.
POST-MORTEM EXAMINATIONS:
Sacrifice on gestation Day 20- Organs examined: All adult animals were subjected to a complete necropsy examination, which included evaluation of the carcass and musculoskeletal system; all external surfaces and orifices; cranial cavity and external surfaces of the brain; and thoracic, abdominal, and pelvic cavities with their associated organs and tissues.: - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: YesExaminations included:- Gravid uterus weight: Yes. The gravid uterus was weighed (with the exception of Animal 27, group 2, 100 mg/kg bw/d, which was not weighed in error.- Number of corpora lutea: Yes- Number of implantations: Yes- Number of early resorptions: Yes- Number of late resorptions: YesEach implant was classified as being live, or a dead fetus (dead full term foetus that showed no sign of maceration), or a late embryonic death (macerated tissue identifiable as an embryo or foetus, with recognizable external features such as tail, limbs, mouth and nares present; attached to distinct identifiable placentae), or an early embryonic death (discrete, formless, discoloured tissue mass attached to the internal uterine wall; may have been of varying size).
- Fetal examinations:
- - External examinations: all per litter
Soft tissue examinations: half per litter
Skeletal examinations: Yes: half per litter - Statistics:
- In order to assist interpretation, tests were applied to determine the statistical significance of observed differences between Control and groups receiving test item. Unless otherwise stated, all statistical tests were two-sided and performed at the 5% significance level using in house software. Pairwise comparisons were only performed against the control group. Body weight and food consumption data was analysed for homogeneity of variance using the ‘F-Max' test. If the group variances appeared homogeneous, a parametric ANOVA was used and pairwise comparisons were made using Fisher’s F protected LSD method via Student's t test i.e. pairwise comparisons were made only if the overall F-test was significant. If the variances were heterogeneous, log or square root transformations were used in an attempt to stabilise the variances. If the variances remained heterogeneous, then a Kruskal-Wallis nonparametric ANOVA was used and pairwise comparisons were made using chi squared protection (via z tests, the non-parametric equivalent of Student's t test).
- Indices:
- Not relevant to the study type
- Historical control data:
- Not reported; not required for interpretation of any study findings
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects 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
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
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:
- no effects observed
- 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:
- no effects observed
- Details on maternal toxic effects:
- There were no premature deaths during the study. There were no clinical observations which were considered to be related to treatment with Capa 3050. All clinical observations were considered to be incidental background findings commonly observed in this species at Charles River, Edinburgh. Group mean body weights were similar between all groups throughout the study. Group mean food consumption was similar between all groups throughout the study. It was noted that there were occasional low consumption values in individual animals across all groups; however, these did not follow a treatment related pattern and were noted to be transient. These were therefore considered to be incidental and unrelated to treatment with Capa 3050. There were no gross necropsy findings which were considered to be related to treatment with Capa 3050. All findings were considered to be incidental background findings commonly observed in this species at Charles River, Edinburgh.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A slightly lower mean litter mean foetal weight was seen at 1000 mg/kg bw/d but was considered to be incidental as it was associated with a slightly higher litter size and weight in this group.
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:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Slightly higher litter size and weight in this group were observed at 1000 mg/kg bw/d but are not related to treatment.
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- At 1000 mg/kg bw/d, there were increased incidences of cervical remnant of thymus, incompletely ossified thoracic vertebral centrum, retarded sternebrae; and minimally kinked ribs. These findings could indicate a delay in foetal development; however, all incidences were within the historical control ranges at Charles River Edinburgh, and for cervical remnant of thymus, incompletely ossified thoracic vertebral centrum and retarded sternebrae, the increases were minor and generally did not correlate in individual foetuses and/or litters. Findings are often associated with low foetal weight and, as the foetuses with these findings were the smallest within their litters, it was considered that these findings were unlikely to be treatment-related. Additionally, kinked ribs are known to resolve as the foetus develops, therefore, this finding is considered not to be detrimental to the foetus and it is considered that the other findings would also likely resolve. All findings were, therefore, considered unlikely to be adverse.
- Details on embryotoxic / teratogenic effects:
- Pregnancy performance was similar between all groups. Slight intergroup variations were considered to be incidental and too small to be attributed to treatment with Capa 3050. At 1000 mg/kg bw/d, slightly increased incidences of cervical remnant of thymus, thoracic vertebral centrum incompletely ossified and retarded sternebrae were noted when compared to controls and other groups. In one foetus at 300 and 1000 mg/kg bw/d, bent scapula with minimally shortened humerus was noted, which was also associated with minimally kinked ribs in these foetuses. The type and distribution of foetal abnormalities and skeletal ossification parameters at 100 mg/kg bw/d was similar to controls.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- 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
Any other information on results incl. tables
No unscheduled deaths occurred and no signs of toxicity were observed during the study period. Group mean bodyweights and food consumption were unaffected by treatment. Gross necropsy of dams did not reveal any treatment-related findings. Litter parameters were comparable in all groups; slight variations were seen between groups but were not considered to be an effect of treatment. Mean foetal weight was slightly (~5.5%) lower at 1000 mg/kg bw/d; mean foetal weight at 100 and 300 mg/kg bw/d was comparable to controls. The slightly lower mean foetal weight at 1000 mg/kg bw/d reflects to a certain extent the higher litter size in this group (14.3) compared to controls (13.8); calculation of mean total litter weight does not reveal any dose-response relationship.
Maternal findings and litter parameters
Dose level (mg/kg bw/d) |
0 |
100 |
300 |
1000 |
Terminal bodyweight (g) |
383 |
374 |
384 |
376 |
Weight gain (g) |
129 |
123 |
125 |
121 |
Mated (#) |
24 |
24 |
24 |
24 |
Pregnant (#) |
24 |
24 |
23 |
24 |
Corpora lutea (#) |
14.3 |
14.0 |
13.9 |
14.8 |
Litter size (#) |
13.9 |
13.6 |
13.4 |
14.3 |
Live implants (#) |
13.1 |
12.0 |
12.8 |
13.8 |
Dead implants (#) |
0.8 |
1.6 |
0.6 |
0.5 |
Early embryonic deaths (#) |
0.7 |
1.4 |
0.6 |
0.5 |
Late embryonic deaths (#) |
0.1 |
0.2 |
- |
- |
Foetal weight (g) |
4.00 |
4.07 |
3.94 |
3.78 |
Litter weight (g) |
55.6 |
55.4 |
52.8 |
54.1 |
The incidence and type of malformations did not reveal any relationship to treatment with CAPA 3050. A slightly increased incidence of cervical remnant of thymus was noted in foetuses from the highest dose level; this contributed to a slightly higher incidence of total visceral variations in this group. The incidences of other visceral variations were comparable in all groups. The total number of foetal skeletal variations was comparable in all groups. At 1000 mg/kg bw/d, slightly increased incidences of thoracic vertebral centrum incompletely ossified and retarded sternebrae were noted when compared to Controls and other groups. The type and distribution of foetal abnormalities and skeletal ossification parameters at 100 mg/kg bw/d was similar to Controls.
Foetal findings
Dose level (mg/kg bw/d) |
0 |
100 |
300 |
1000 |
Total malformations (#) |
- |
1 (1) |
2 (2) |
1 (1) |
Total visceral variations (#) |
19 (11) |
21 (14) |
11 (9) |
26 (13) |
Cervical remnant of thymus (#) |
1 (1) |
3 (2) |
2 (2) |
7 (5) |
Total skeletal variations (#) |
22 (15) |
19 (14) |
21 (13) |
24 (14) |
Vestigial supernumerary rib(s) on 1st lumbar vertebra (#) |
9 (7) |
18 (7) |
5 (5) |
22 (10) |
14 complete rib(s) (#) |
- |
- |
- |
1 (1) |
Incomplete ossification: thoracic vertebral centra |
16 (11) |
12 (11) |
11 (9) |
22 (11) |
Retarded sternebrae: 0 (#) |
75 (23) |
78 (22) |
60 (17) |
41 (17) |
Retarded sternebrae: 1 (#) |
55 (23) |
52 (19 |
57 (20) |
67 (22) |
Retarded sternebrae: 2 (#) |
26 (15) |
13 (9) |
24 (12) |
53 (20) |
Retarded sternebrae: >2 (#) |
3 (3) |
2 (2) |
6 (5) |
6 (4) |
foetal incidence (litter incidence)
Applicant's summary and conclusion
- Conclusions:
- No evidence of teratogenicity was seen in this study. Based on the results of this study, it was concluded that 1000 mg/kg bw/d was the maternal no-observed-effect level (NOEL) and the foetal no-observed-adverse-effect-level (NOAEL).
- Executive summary:
The objective of this study was to determine the potential toxicity of CAPA 3050 when administered during the period of organogenesis to pregnant rats. Groups of 24 time-mated female Sprague-Dawley rats were gavaged with the test material (in 0.5% aqueous hydroxypropylmethylcellulose, 0.1% Tween 80) at dose levels of 0, 100, 300 and 1000 mg/kg bw/d on Days 6-19 of gestation, where the day of detection of mating was designated Day 0. Animals were regularly monitored for clinical signs of toxicity, body weights and food consumption and were killed on Day 20 of gestation for examination of pregnancies and embryofoetal development. Dosing with CAPA 3050 at dose levels up to 1000 mg/kg bw/d was not associated with any maternal treatment-related clinical observations, body weight or food consumption effects or gross necropsy findings. Pregnancy performance was similar between all groups. A slightly lower mean litter mean foetal weight was seen at 1000 mg/kg bw/d but was considered to be incidental as it was associated with a slightly higher litter size and weight in this group. At 1000 mg/kg bw/d, there were increased incidences of cervical remnant of thymus, incompletely ossified thoracic vertebral centrum, retarded sternebrae; and minimally kinked ribs. These findings could indicate a delay in foetal development; however, all incidences were within the historical control ranges at Charles River Edinburgh, and for cervical remnant of thymus, incompletely ossified thoracic vertebral centrum and retarded sternebrae, the increases were minor and generally did not correlate in individual foetuses and/or litters. Findings are often associated with low foetal weight and, as the foetuses with these findings were the smallest within their litters, it was considered that these findings were unlikely to be treatment-related. Additionally, kinked ribs are known to resolve as the foetus develops, therefore, this finding is considered not to be detrimental to the foetus and it is considered that the other findings would also likely resolve. All findings were, therefore, considered unlikely to be adverse. Based on the results of this study, it was concluded that 1000 mg/kg bw/d was the maternal NOEL and the developmental NOAEL.
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