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Key value for chemical safety assessment

Effects on fertility

Description of key information

No study of reproductive toxicity is available; however there is no indication of any effects on the male or female reproductive tract in a 90 -day study with the submission substance 2 -oxepanone, polymer with 1,4 -butanediol (CAPA 2043).

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

Effects on developmental toxicity

Description of key information

A developmental toxicity study in the rat is available for the submission substance 2-oxepanone, polymer with 1,4-butanediol (CAPA 2043).

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 November 2016 - 28 November 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
22 January 2001
Deviations:
no
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
Identity: CAPA 2043
Label name: CAPA(TM) 2043
Chemical name 2-oxepanone, polymer with 1,4-butanediol
Batch no. WAC000478
Purity: 100 % (UVCB)
CAS number 31831-53-5
EC number 608-670-1
Expiry date 10 May 2018
Storage conditions Cool, dry conditions in well-scaled receptacles
Appearance Clear, colourless liquid
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS srl, San Pietro al Natisone (UD), Italy
- Age at arrival: at least 11 weeks old
- Weight at arrival: 202-219 g for females and 306-344 g for males
- Housing: Before and after the pairing period, the animals were housed no more than 5 of one sex to a cage in polysulfone solid bottomed cages. Nesting material was provided inside suitable bedding bags and changed at least 3 times a week. During the pairing period, the rats were housed on the basis of 1 male to 1 female in clear polysulfone cages with a stainless steel mesh lid and floor. Each cage tray held absorbent material which was inspected and changed daily.
- Diet: commercially available laboratory rodent diet (4 RF 21, Mucedola S.r.l., Via G. Galilei, 4, 20019 Settimo Milanese (MI), Italy); ad libitum
- Water: drinking water; ad libitum
- Acclimation period: 19 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C ± 2 °C
- Humidity (%): 55% ± 15%
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
The test item was administered orally by gavage at a dose volume of 4mL/kg bw. 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.

PREPARATION OF DOSING SOLUTIONS: The required amount of CAPA 2043 was suspended in the vehicle. The formulation was prepared daily (concentrations of 50, 100 and 200 mg/mL). Concentrations were calculated and expressed in terms of test item as supplied.

VEHICLE: corn oil
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Prior to commencement of treatment, analysis was performed to confirm that the proposed formulation procedure was acceptable. Results of the analyses were within the limits of acceptance. Stability at 3 and 8 days at room temperature was verified in the range from 10 to 120 mg/mL in RTC Study No. A2242. In addition, the stability was verified in this study at 200 mg/mL and found to be 28 hours and 8 days at room temperature. Samples of the formulations prepared at Week 1 and Week 3 of the study were also analysed to check the concentration and homogeneity. Results of the analyses were within the limits of acceptance. Chemical analysis was carried out by the laboratory, according to a validated method (RTC Study no. A2242 with validation in the range from 10 to 120 mg/mL and the present RTC Study no. X0460 with validation up to 200 mg/mL.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: Females were paired 1 to 1 in the home cage of the male and left overnight.
- M/F ratio per cage: 1:1
- Length of cohabitation: overnight; vaginal smears were taken daily in the morning from the day after pairing until a positive identification of mating was made
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
Gestation Day 6-19
Frequency of treatment:
Once daily (GD 6-19)
Duration of test:
The animals were euthanised on Gestation Day 20.
Dose / conc.:
0 mg/kg bw/day
Remarks:
Vehicle (corn oil) control
Dose / conc.:
200 mg/kg bw/day
Remarks:
Low dose group
Dose / conc.:
400 mg/kg bw/day
Remarks:
Mid dose group
Dose / conc.:
800 mg/kg bw/day
Remarks:
High dose group
No. of animals per sex per dose:
Each group comprised 24 mated female rats.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were selected in consultation with the Sponsor based on information from a preliminary non GLP compliant study (RTC Study No. E0064, see IUCLID section 7.5.1, Oberto G. (2017)). This oral gavage preliminary study was carried out at dose levels of 100, 300 and 1000 mg/kg bw/day. In this study, the test item CAPA 2043 was satisfactorily tolerated by Sprague Dawley rats at the low and intermediate dose levels (100 and 300 mg/kg bw/day), while the highest dose level of 1000 mg/kg bw/day induced some toxicity (mortality or occasional clinical signs, slight reductions in body weight and food consumption). A NOEL of 300 mg/kg bw/day was determined in this preliminary study.
As the highest dose in the preliminary study (1000 mg/kg bw/day) is not considered to be safe in a subsequent toxicity of longer duration in Sprague Dawley rats, a lower dose was chosen which is higher than the NOEL of 300 mg/kg bw/day. Thus, a high dose of 800 mg/kg bw/day was used, with the aim to induce some developmental and/or maternal toxicity (clinical signs or a decrease in body weight) but not death or severe suffering, as required in the OECD guideline 414.
Furthermore, according to OECD guideline 414, at least one intermediate dose level should produce minimal observable toxic effects. The lowest dose level should not produce any evidence of either maternal or developmental toxicity. A descending sequence of dose levels should be selected with a view to demonstrating any dosage-related response and no-observed-adverse-effect level (NOAEL) or doses near the limit of detection that would allow the determination of a benchmark dose. It is stated that two to four-fold intervals are frequently optimal for setting the descending dose levels. Since a NOAEL of 300 mg/kg bw/day was determined in the 2-week preliminary study, a mid-dose of 400 mg/kg bw was chosen for the prenatal developmental study and a low dose of 200 mg/kg bw/day was selected based on the recommendations of the guideline.
- Rationale for animal assignment: On the day of allocation (Day 0 post coitum) all females were weighed and allocated to the groups by computerised stratified randomisation to give approximately equal initial group mean body weights. Each female was identified within the study by ear notch and housed no more than 4 to a cage. The cages were identified by a label recording the study number, animal numbers and details of treatment. The arrangement of cages in batteries was such that cages from each treatment group were evenly distributed across the battery to minimize possible environmental effects.
The group identification and animal numbers assigned to the treatment are summarized below:

Group 1 (0 mg/kg bw/day): Females numbers (odd only): 1-47
Group 2 (200 mg/kg bw/day): Females numbers (odd only): 49-95
Group 3 (400 mg/kg bw/day): Females numbers (odd only): 97-143
Group 4 (800 mg/kg bw/day): Females numbers (odd only): 145-191

The rat numbers listed above formed the last digits of a computer generated 8 figure animal number (the remaining digits of the animal number were different for each concurrent study and served to ensure unique animal numbering for any study employing computerised data collection). The computerised system used in this study was the Xybion Path/Tox System, Version 4.2.2.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 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.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: clinical signs were recorded for individual animals. Each animal was observed twice daily during treatment before dosing and 30 minutes -1 hour after dosing and any clinical signs recorded starting from allocation until sacrifice.

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 3, 6, 9, 12, 15, 18 and 20 post coitum

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: Days 0, 3, 6, 9, 12, 15, 18 and 20 post coitum
- Cages with at least one not pregnant female were excluded from group mean calculation
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No (no feeding study)

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on Gestation day 20
- Organs examined: Ovaries and uteri
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: 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
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: approx. half per litter
- Skeletal examinations: Yes: approx. half per litter
- Head examinations: Yes: no data

Skeletal and fixed-visceral examinations were performed in all groups. Structural deviation was classified as follows:
- Malformations: Major abnormalities that are rare and/or affect survival or health.
- 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.
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 and intergroup differences between the control and treated groups assessed by a non-parametric version of Williams test.
Indices:
Pre-implantation loss was calculated as a percentage from the formula: Pre-implantation Loss (%) = [no. corpora lutea − no. implantations / no. corpora lutea] ×100

Post-implantation loss was calculated as a percentage from the formula: Post implantation Loss (%) = [no. implantations − no. live foetuses / no. implantations] ×100

Total implantation loss was calculated as a percentage from the formula: Total implantation Loss (%) = [no. corpora lutea − no. live foetuses / no. corpora lutea] ×100

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.
Historical control data:
No data
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Signs of reaction to treatment were limited to salivation observed during the dosing period in 11 out of 24 females of the high-dose group starting on GD8 post coitum and in 1 out of 24 females of the low dose group on GD 13. Hairloss of the lower forelimb was also detected in one female of the high-dose group at the end of treatment. These signs were not to be considered of toxicological significance.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No animals died during the study.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
No differences in body weight were noted between the control and treated groups. A significant decrease in body weight gain of approximately 11% was noted on GD20 in females of the low-dose group when compared to controls. This change was considered to be without toxicological relevance in the absence of findings in other dose groups.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No changes were detected in food consumption between treated and control females.
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 significant differences in terminal body weight, 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 noted. The sporadic changes, such as marked hairloss of the forelimbs in one high-dose female or thickened mucosa, white firm contents of the urinary bladder and distended right ureter in one low-dose female, were not attributable to treatment.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
Effects were observed in clinical signs (hairloss, salivation), as well as in body weight, food consumption, gravid uterus weight and macroscopic observation of treated females when compared to controls. These effects were not considered to be treatment-related.
Number of abortions:
no effects observed
Description (incidence and severity):
No abortions were reported.
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
In the control group one female showed unilateral implantation with total resorption. Unilateral implantation was also detected in one female of the low dose group.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
No effects on total litter losses by resorption were reported.
Early or late resorptions:
effects observed, non-treatment-related
Description (incidence and severity):
In the control group one female showed unilateral implantation with total resorption.
Dead fetuses:
no effects observed
Description (incidence and severity):
No dead fetuses were observed.
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
effects observed, non-treatment-related
Description (incidence and severity):
A total of 10 females were found not pregnant at necropsy: one in the control group, four in the low-dose group, two in the mid-dose group and three in the high-dose group.
Other effects:
not examined
Details on maternal toxic effects:
In the control group one female showed unilateral implantation with total resorption. Unilateral implantation was also detected in one female of the low dose group. A total of 10 females were found not pregnant at necropsy: one in the control group, four in the low-dose group, two in the mid-dose group and three in the high-dose group. These effects were considered to be non-treatment related, since no dose-response relationship was observed.
Key result
Dose descriptor:
NOAEL
Effect level:
800 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no adverse effects observed
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Mean foetal weight was not affected by treatment.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
A reduction in the number of live offspring was not reported.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Sex ratio was not affected by treatment.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Litter data were not affected by treatment.
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
A total of 2 small foetuses (< 2.7 g) were detected, both in the mid-dose group. No abnormalities were detected in the control, low- or high-dose groups.
Skeletal malformations:
no effects observed
Description (incidence and severity):
No changes were noted at the skeletal examination of the foetuses which were considered to be treatment-related.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No changes were seen at the visceral examination of the foetuses which were considered to be treatment-related. Extreme pelvic dilatation and/or extremely enlarged ureter (malformations) were seen in a single foetus each in the low- and the mid-dose groups. These isolated cases were considered without toxicological relevance. Anomalies were seen in treated as well as control groups, with similar (testes displaced) or higher (generalised oedema, ureter moderately enlarged) incidence in the control group and, therefore, considered toxicologically unremarkable.
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
No changes were noted at the visceral foetuses examination and in relation to external malformations which were considered treatment-related.
There was no evidence of teratogenicity or developmental toxicity in this study.
Key result
Dose descriptor:
NOAEL
Effect level:
800 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

Table 1: Summary of relevant findings in the prenatal developmental toxicity study with CAPA 2043

Dose level (mg/kg bw/day) 0 200 400 800
Mated (#) 24 24 24 24
Deaths (#) - - - -
Not pregnant (#) 1 4 2 3
Dams with abortions (#) - - - -
Dams with early deliveries (#) - - - -
Dams with stillbirths (#) - - - -
Dans wutg dead foetuses (#) - - - -
Unilateral implantation and total resorption 1 0 0 0
Unilateral implantation 0 1 0 0
Dams with live fetuses on GD20 (#) 22 20 22 21
Clinical signs of females - Salivation (1/24 animals/4.2% of animals with observation during interval) - Hairloss (1/24 animals/4.2% of animals with observation during interval)
Salivation (11/24 animals/45.8% of animals with observations during interval)
Mean body weight (g) GD0 232.71 231.74 228.83 231.76
GD6 256.02 256.69 254.23 256.15
GD9 265.36 265.09 263.15 265.81
GD18 342.80 341.83 343.49 336.61
GD20 375.06 370.55 375.04 367.21
Mean body weight gain (g/day) GD6 3.422 3.652 3.367 3.269
GD9 3.115 2.832 2.974 3.222
GD20 16.132 14.363* 15.778 15.299
Mean body weight gain (g) GD6-9 9.34 8.40 8.92 9.66
GD6-20 119.04 113.86 120.81 111.06
GD0-20 142.35 138.81 146.21 135.45
Mean gravid uterus weight (g) 75.33 71.12 74.24 71.54
Mean absolute weight gain (g) 59.62 65.90 68.89 60.55
Corpora lutea (#) 13.14 12.45 12.77 12.76
Implantations (#) 13.00 12.35 12.45 12.62
Pre-implantation loss (%) 1.02 0.67 2.66 1.07
Post-implantation loss (%) 3.54 1.60 0.86 4.64
Total implantation loss (%) 4.51 2.27 3.52 5.68
Mean viable foetuses (#) 12.55 12.15 12.32 12.05
Viable foetuses (%) 100 100 100 100
Mean foetal weight (g) (sexes combined) 3.91 3.86 3.92 3.94
Mean foetal weight (g) by sex not reported
Small foetuses (#) - - 2 -
Mean litter weight (g) 48.92 46.86 48.17 47.24
Early uterine deaths (%) 0.45 0.20 0.14 0.57
Late uterine deaths (%) 0.00 0.00 0.00 0.00
Males (%) 51.37 50.19 47.73 46.41
External abnormalities in foetuses (% of foetuses) - - 0.74 -
External abnormalities in foetuses (# of foetuses) - - 2 -

*significantly different to controls (p<0.05)

Conclusions:
In this study, maternal and developmental NOAELs of 800 mg/kg bw/day can be considered.
Executive summary:

In a developmental toxicity study conducted according to OECD guideline 414, CAPA 2043 (2-oxepanone, polymer with 1,4-butanediol diluted in corn oil) was administered to 24 pregnant female Sprague-Dawley rats/dose by gavage at dose levels of 0, 200, 400 or 800 mg/kg bw/day from days 6 through 19 of gestation. Rats were terminated on gestation day 20 and the uterine contents investigated. Foetuses were assessed for external, visceral and skeletal abnormalities.

No maternal deaths occurred during the study. Clinical signs of treatment were limited to post-dosing salivation in a number of maternal rats at the highest dose level, which is not considered to be of toxicological significance. A reduction of the body weight in the low-dose group is considered to be not treatment-related, since no dose-response relationship was observed. Food consumption was unaffected by treatment. Litter parameters were unaffected by treatment. Litter size and foetal weight were comparable in all groups. There were no changes in the incidence or nature of foetal external, visceral or skeletal findings indicative of an effect of treatment. In the absence of any toxicologically significant maternal effects and in the absence of any developmental toxicity, maternal and developmental NOAELs of 800 mg/kg bw/day can be determined for this study.

The developmental toxicity study in the rat is classified acceptable and satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rats.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
800 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
A modern GLP- and Guideline-compliant rat study 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
Additional information

A developmental toxicity study in the rat is available for the submission substance 2-oxepanone, polymer with 1,4-butanediol (CAPA 2043). In this study, conducted according to OECD guideline 414, CAPA 2043 (2-oxepanone, polymer with 1,4-butanediol diluted in corn oil) was administered to 24 pregnant female Sprague-Dawley rats/dose by gavage at dose levels of 0, 200, 400 or 800 mg/kg bw/day from days 6 through 19 of gestation. Rats were terminated on gestation day 20 and the uterine contents investigated. Foetuses were assessed for external, visceral and skeletal abnormalities.

No maternal deaths occurred during the study. Clinical signs of treatment were limited to post-dosing salivation in a number of maternal rats at the highest dose level, which is not considered to be of toxicological significance. A reduction of the body weight in the low-dose group is considered to be not treatment-related, since no dose-response relationship was observed. Food consumption was unaffected by treatment. Litter parameters were unaffected by treatment. Litter size and foetal weight were comparable in all groups. There were no changes in the incidence or nature of foetal external, visceral or skeletal findings indicative of an effect of treatment. In the absence of any toxicologically significant maternal effects and in the absence of any developmental toxicity, maternal and developmental NOAELs of 800 mg/kg bw/day can be determined for this study.

Justification for classification or non-classification

In the absence of any evidence for effects on the reproductive tract from the 90 -day study and the absence of developemental toxicity seen in the rat developmental toxicity study, the submission substance 2 -oxepanone, polymer with 1,4 -butanediol (CAPA 2043) is not classified for reproductive toxicity according to the CLP criteria.