2-Oxepanone, polymer with 1,6-hexanediol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No specific studies of reproductive toxicity are available; there is no evidence of any effects on tissues or organs of the male or female reproductive tract from a 90-day study performed with the submission substance CAPA 2047A (2-oxepanone polymer with 1,6-hexanediol) at dose levels of up to 1000 mg/kg bw/d.

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

No specific studies of reproductive toxicity are available; there is no evidence of any effects on tissues or organs of the male or female reproductive tract from a 90-day study performed with the submission substance CAPA 2047A (2-oxepanone polymer with 1,6-hexanediol) at dose levels of up to 1000 mg/kg bw/d.

Effects on developmental toxicity

Description of key information

A modern, GLP- and guideline-compliant developmental toxicity study in the rat is available for the submission substance CAPA 2047A (2-oxepanone polymer with 1,6-hexanediol).

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

15 March 2017 - 27 November 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

adopted 22 January 2001

Deviations:

no

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

Identity: CAPA(TM) 2047A
Chemical name: 2-Oxepanone polymer with 1,6-hexanediol
Batch number: WAD000129
Purity: 100 % (UVCB)
CAS number: 36609-29-7
EC number: 609-271-5
Expiry date: 19 July 2018
Storage conditions +18 °C (+14 - 22 °C), protected from light

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo RMS, Italy
- Age at study initiation: at least 11 weeks after arrival
- Weight at study initiation: 178-234 g for females and 287-303 g for males after arrival
- Fasting period before study: not specified
- Housing: Before and after the pairing period, the animals were housed no more than 5 of one sex in polysulfone solid bottomed cages, measuring 59.5×38×20 cm. Nesting material was provided inside suitable bedding bags and changed at least twice a week. In addition, suitable nesting material was provided as necessary and changed at least twice a week. During the pairing period, the rats were housed on the basis of 1 male to 1 female in clear polysulfone cages measuring 42.5×26.6×18.5 cm with a stainless steel mesh lid and floor.
- Diet (e.g. ad libitum): commercially available laboratory rodent diet (4 RF 21, Mucedola S.r.l., Via G. Galilei, 4, 20019 Settimo Milanese (MI), Italy); ad libitum

- Water (e.g. ad libitum): drinking water; ad libitum
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C ± 2 °C
- Humidity (%): 55% ± 15%
- Air changes (per hr): 15 to 20 air changes
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

The required amount of CAPATM 2047A was suspended in the vehicle (corn oil) and maintained under magnetic stirring up to dosing. The formulations were prepared daily or up to weekly intervals according to the stability data at concentrations of 25, 75 and 250 mg/mL. Concentrations were calculated and expressed in terms of test item as supplied.
The proposed formulation procedure for the test item was checked in the range from 1 to 500 mg/mL by chemical analysis (concentration and homogeneity) in RTC Study no. A2298 to confirm that the method of preparation was suitable. Final results for all levels were within the acceptability limits stated in internal RTC SOPs for concentration (80-120% of the intended concentration) and homogeneity (CV <10%). In addition, in RTC Study no. A2298, the stability of the formulations at 28 hour and 8 days at room temperature was verified in the range from 1 to 500 mg/mL.
Samples of the formulations prepared on Week 1 and Week 3 of the study were also analysed to check the homogeneity and concentration. Results of the analyses were within the acceptability limits stated in RTC SOPs for suspensions (80-120% for concentration and CV <10% for homogeneity).
Chemical analysis was carried out by the Analytical Chemistry Department at RTC and the software used for this activity was Analyst 1.6.2.
The test item was administered orally by gavage to the females at the dose volume of 4 mL/kg body weight. 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. Control females received the vehicle alone at the same dose volume.
All animals were dosed once a day from Day 6 through Day 19 post coitum.

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 1-500 mg/mL by chemical analysis (concentration and homogeneity) in RTC Study no. A2298 to confirm that the method was suitable. Final results for all levels were within the acceptability limits for concentration (80-120%) and homogeneity (CV < 10%). In addition, a 28 hour and 8 day stability at room temperature was verified in the range from 1-500 mg/mL. Suspensions were considered to be stable if concentration and homogeneity, after the defined period of storage, are still acceptable (80%-120% for concentration and CV < 10% for homogeneity). Samples of the formulations prepared on Weeks 1 and 3 of the study were also analysed to check the homogeneity and concentration. Results of the analyses were within the acceptability limits (80-120% for concentration and CV < 10% for homogeneity).

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused: Females were paired one to one in the home cage of the male and left overnight.
- M/F ratio per cage: 1:1
- Length of cohabitation: 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). Full mating records were maintained.
- Verification of same strain and source of both sexes: not specified
- 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:

From Gestation Day 6 to 19 post coitum

Frequency of treatment:

Once daily

Duration of test:

Rats were terminated on Gestation Day 20.

Dose / conc.:

0 mg/kg bw/day

Remarks:

Vehicle control (corn oil)

Dose / conc.:

100 mg/kg bw/day

Remarks:

Low dose group

Dose / conc.:

300 mg/kg bw/day

Remarks:

Mid dose group

Dose / conc.:

1 000 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. E0088, see IUCLID section 7.5.1; Eileraas, 2017). This oral gavage preliminary study was carried out at dose levels of 100, 300 and 1000 mg/kg bw/day in which Sprague Dawley rats were treated by oral gavage for 2 weeks. Since no treatment-related effects were observed at any dose level, it was decided to use the same dose levels for the present study.
According to the Guideline OECD 414, a dose of 1000 mg/kg bw/day is considered to be the highest dose to be used for a limit test, except when human exposure indicates the need for a higher dose level to be used.
Furthermore, a descending sequence of dose levels should be selected with a view to demonstrating any dosage related response and a NOAEL with respect to the dose selection based on OECD 414 (NOAEL) at the lowest dose level. It is stated that two to four-fold intervals are frequently optimal for setting the descending dose levels. According to this requirement, a mid-dose of 300 mg/kg bw/day and a low dose of 100 mg/kg bw/day was chosen for the dose-range finding test as well as for the main study.
- 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 5 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 summarised below:

Group 1 (0 mg/kg bw/day): Females numbers (odd only): 1-47
Group 2 (100 mg/kg bw/day): Females numbers (odd only): 49-95
Group 3 (300 mg/kg bw/day): Females numbers (odd only): 97-143
Group 4 (1000 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

- 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; the animals were euthanised with carbon dioxide on Day 20 post coitum and necropsied as detailed below. All foetuses were sacrificed by intraperitoneal injection of sodium thiopental followed by hypothermia.
- 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: 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:

Group mean values for body weight of pregnant females, food consumption, gravid uterus weight, absolute weight gain (terminal body weight minus body weight at Day 0 post coitum minus gravid uterus), litter size, intra-uterine deaths, corpora lutea count, number of implantations, total implantation loss and pre- and post-implantation loss were calculated. Data from non-pregnant animals (with the exception of food consumption phase) were not included in group mean calculations of maternal body weight. 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. 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 the 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):

No signs of toxicological significance were noted during the study. Hunched posture and emaciated aspect were recorded in one rat at 300 mg/kg bw/day between Gestation Days 8 and 13. No animals died during the study. For details please see Table 1 below.

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 control and treated groups. A slight (but statistically significant) decrease in weight gain of approximately 15% was noted on Gestation Days 15-18 in females at 1000 mg/kg bw/day compared to controls. Considering that these changes were occasionally, in magnitude and associated with a trend of recovery, they were considered to be without toxicological relevance.
No significant differences in terminal body weight were observed in treated groups compared to the control group. For details please see Table 1 below.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No differences 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:

effects observed, non-treatment-related

Description (incidence and severity):

No significant differences in gravid uterus weight were observed in treated groups compared to the control group. At absolute weight gain, a slight statistically significant decrease, of approximately 13%, was noted in females receiving 1000 mg/kg/day, when compared to controls. This change was considered to be without toxicological relevance. For details please see Table 1 below.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No changes of toxicological relevance were noted at necropsy.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Details on results:

Clinical signs in females (hunched posture, emaciated aspect) observed were considered to be not treatment-related, since no dose-response relationship has been observed. The statistical significant decrease in weight gain observed in the high-dose group were occasionally, in magnitude and associated with a trend of recovery. Thus, these effects were without toxicological significance. Also the observed significant decrease in weight gain at the high dose at GD15-18 is not considered to be treatment-related, since this effect was also occasionally. For details please see Table 1 below.

Number of abortions:

no effects observed

Description (incidence and severity):

Abortions were not reported.

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

No effects on pre- and post-implantation loss were reported.

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Litter data were not affected by treatment.

Early or late resorptions:

no effects observed

Description (incidence and severity):

No effects on early or late resorptions were reported.

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 4 females were found not pregnant at necropsy: one receiving 100 mg/kg/day, two receiving 300 mg/kg/day and one receiving 1000 mg/kg/day.
The number of females with live foetuses on gestation Day 20 was: 24 in the control, 23 in the low, 22 in the mid- and 23 in the high dose groups. For details please see Table 1 below.

Details on maternal toxic effects:

A total of 4 females were found not pregnant at necropsy: one receiving 100 mg/kg/day, two receiving 300 mg/kg/day and one receiving 1000 mg/kg/day. The number of females with live foetuses on gestation Day 20 was: 24 in the control, 23 in the low, 22 in the mid- and 23 in the high dose groups. These effects were considered to be not-treatment related, since no dose-response relationship was observed.

For the summary of relevant findings see table 1 in box "Any other information on results incl. tables".

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: no adverse effects observed

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

The mean foetal weight was not affected by treatment and mean foetal weight (for each sexes as well as for both sexes) and sex ratios of treatment groups were comparable to the control group. For details please see Table 1 below.

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Description (incidence and severity):

Sex ratios were not affected by treatment. For details please see Table 4.

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

Litter size was not affected by treatment. For details please see Table 1 below.

Changes in postnatal survival:

not examined

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

A total of 7 small foetuses (<2.7 g) were detected, 1 out of 356 in the control group, 1 out of 333 in the low dose group, 4 out of 306 in the medium group and 1 out of 324 in the high dose group. This indicated that the small foetuses were distributed according to the groups without the dose-relationship. For details please see Table 1 below.

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

No relevant differences between control and treated group were observed at skeletal examination (anomalies and variants). In a few cases, some alterations were noted only in treated groups, but the incidence, in terms of foetuses affected, were similar or observed without a dose-response relationship. For details please see Table 2 below.

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

A total of eight foetuses showed malformations: generalized oedema, extreme in five control foetuses, in one foetus at 300 mg/kg bw/day and in one foetus at 1000 mg/kg bw/day. Persistent truncus arteriousus was observed for one foetus at 300 mg/kg bw/day. These findings are considered to be incidental. The other alterations (anomalies and variations) recorded were noted both in control and treated groups, with similar incidence. For details please see Table 3 below.

Other effects:

no effects observed

Details on embryotoxic / teratogenic effects:

A total of 7 small foetuses (< 2.7 g) were detected, 1 out of 356 in the control group, 1 out of 333 in the low dose group, 4 out of 306 in the mid-dose group and 1 out of 324 in the high dose group.
Furthermore, some alterations were noted only in treated groups, but the incidence, in terms of foetuses affected, were similar or observed without a dose-response relationship.
A total of eight foetuses showed malformations: generalized oedema, extreme in five control foetuses, in one foetus at 300 mg/kg bw/day and in one foetus at 1000 mg/kg bw/day. Persistent truncus arteriousus was observed for one foetus at 300 mg/kg bw/day.
The findings on skeletal, visceral and external malformation in fetuses are observed without a dose-response relationship. Thus, these effects are considered to be non-treatment related.

For the summary of relevant findings see tables in box "Any other information on results incl. tables".

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Table 1: Summary of relevant findings in the prenatal developmental toxicity study with CAPA 2047A

Dose level (mg/kg bw/day)		0	100	300	1000
Mated (#)		24	24	24	24
Deaths (#)		-	-	-	-
Not pregnant (#)		-	1	2	1
Dams with abortions (#)		-	-	-	-
Dams with early deliveries (#)		-	-	-	-
Dams with stillbirths (#)		-	-	-	-
Dams with dead foetuses (#)		-	-	-	-
Dams with live fetuses on GD20 (#)		24	23	22	23
Clinical signs of females		-	-	1 animal: Hunched posture (GD8-13), Emaciated (10-12)	-
Mean body weight (g)	GD0	227.37	228.48	225.62	229.58
	GD6	252.66	254.57	253.51	253.51
	GD9	262.72	265.72	261.71	263.88
	GD18	350.25	340.32	343.13	340.94
	GD20	386.41	386.55	376.86	373.73
Mean body weight gain (g/day)	GD6	4.340	4.402	4739	4.198
	GD9	3.358	3.717	2733	3.454
	GD18	16.423	15.846	15.047	14.223**
	GD20	18.080	18.118	16.866	16.397
Mean body weight gain (g)	GD6-9	10.06	11.15	8.20	10.37
	GD6-20	133.75	131.98	123.35	120.22
	GD0-20	159.04	158.07	151.24	144.15
Mean gravid uterus weight (g)		85.94	83.30	75.30	80.30
Mean absolute weight gain (g)		37.84	69.86	71.46	29.01*
Mean corpora lutea (#)		15.21	15.13	14.68	14.70
Mean implantations (#)		15.04	14.96	14.55	14.61
Pre-implantation loss (%)		1.21	1.17	0.97	0.54
Post-implantation loss (%)		1.36	3.27	4.40	3.41
Total implantation loss (%)		2.57	4.43	5.30	3.95
Mean viable foetuses (#)		14.83	14.48	13.91	14.09
Mean viable foetuses (%)		97.5	95.6	94.7	95.9
Mean foetal weight (g) (sexes combined)		3.81	3.78	3.65	3.76
Mean foetal weight (g) (males)		3.89	3.86	3.76	3.91
Mean foetal weight (g) (females)		3.70	3.66	3.55	3.63
Small foetuses (#/total assessed)		1/356	1/333	4/306	1/324
Small foetuses (%)		0.28	0.30	1.31	0.31
Mean litter weight (g)		56.59	54.70	50.78	52.67
Early uterine deaths (%)		0.21	0.48	0.64	0.52
Late uterine deaths (%)		0	0	0	0
Males (%)		54.05	52.72	47.39	48.65
External abnormalities in foetuses (# of foetuses)		1	1	4	1
External abnormalities in foetuses (% of foetuses)		0.28	0.30	1.31	0.31

*significantly different to controls (p<0.05); **p<0.01

 

Table 2: Summary of skeletal examination of foetuses (group incidences) in the prenatal developmental toxicity study with CAPA 2047A

			Dose	No. foetuses			No. litters
Organ	Cat	Observation	mg/kg	Observed	Affected	%	Observed	Affected	%
Cervical vertebrae	AN	Metacarpal(s) no ossification 4^th	0	184	0	0	24	0	0
			100	172	0	0	23	0	0
			300	159	0	0	22	0	0
			1000	169	1	0.59	23	1	4.35
Forepaw(s)	AN	Metacarpal(s) no ossification 4^th	0	184	16	8.70	24	11	45.83
			100	172	13	7.56	23	9	39.13
			300	159	21	13.21	22	14	63.64
			1000	169	10	5.92	23	7	30.43
Hindpaw(s)	AN	Metacarpal(s) no ossification 4^th	0	184	0	0	24	0	0
			100	172	1	0.58	23	1	4.35
			300	159	0	0	22	0	0
			1000	169	1	0.59	23	1	4.35
	VA	Metacarpal(s) incomplete ossification 4^th	0	184	0	0	24	0	0
			100	172	1	0.58	23	1	4.35
			300	159	2	1.26	22	2	9.09
			1000	169	1	0.59	23	1	4.35
Pelvic girdle	AN	Pubis incomplete ossification	0	184	0	0	24	0	0
			100	172	1	0.58	23	1	4.35
			300	159	1	0.63	22	1	4.55
			1000	169	1	0.59	23	1	4.35
Ribs	AN	Wavy	0	184	0	0	24	0	0
			100	172	0	0	23	0	0
			300	159	1	0.63	22	1	4.55
			1000	169	0	0	23	0	0
	VA	Short 14^th	0	184	1	0.54	24	1	4.17
			100	172	1	0.58	23	1	4.35
			300	159	1	0.63	22	1	4.55
			1000	169	0	0	23	0	0
	VA	Rudimentary 14^th	0	184	25	13.59	24	15	62.50
			100	172	12	6.98	23	9	39.13
			300	159	18	11.32	22	11	50.00
			1000	169	18	10.65	23	10	43.48
	VA	14 ribs	0	184	1	0.54	24	1	4.17
			100	172	0	0	23	0	0
			300	159	0	0	22	0	0
			1000	169	2	1.18	23	2	8.70
Sacral vertebrae	AN	Arch(es) incomplete ossification	0	184	0	0	24	0	0
			100	172	1	0.58	23	1	4.35
			300	159	0	0	22	0	0
			1000	169	1	0.59	23	1	4.35
Skull	AN	Temporal incomplete ossification	0	184	25	13.59	24	12	50.00
			100	172	22	12.79	23	12	52.17
			300	159	19	11.95	22	13	59.09
			1000	169	16	9.47	23	11	47.83
	AN	Palatine incomplete ossification	0	184	0	0	24	0	0
			100	172	1	0.58	23	1	4.35
			300	159	0	0	22	0	0
			1000	169	1	0.59	23	1	4.35
	VA	Supraoccipital incomplete ossification	0	184	2	1.09	24	1	4.17
			100	172	3	1.74	23	3	13.04
			300	159	4	2.52	22	4	18.18
			1000	169	4	2.37	23	4	17.39
	VA	Interparietal incomplete ossification	0	184	0	0	24	0	0
			100	172	0	0	23	0	0
			300	159	1	0.63	22	1	4.55
			1000	169	0	0	23	0	0
	VA	Parietal incomplete ossification	0	184	0	0	24	0	0
			100	172	0	0	23	0	0
			300	159	1	0.63	22	1	4.55
			1000	169	0	0	23	0	0
Sternebrae	AN	Bipartite 5^th	0	184	0	0	24	0	0
			100	172	0	0	23	0	0
			300	159	0	0	22	0	0
			1000	169	1	0.59	23	1	4.35
	AN	Asymmetrical ossification	0	184	4	2.17	24	3	12.50
			100	172	3	1.74	23	3	13.04
			300	159	4	2.52	22	4	18.18
			1000	169	2	1.18	23	2	8.70
	AN	Asymmetrical ossification 5^th	0	184	0	0	24	0	0
			100	172	3	1.74	23	3	13.04
			300	159	5	3.14	22	5	22.73
			1000	169	3	1.78	23	3	13.04
	AN	No ossification	0	184	1	0.54	24	1	4.17
			100	172	2	1.16	23	2	8.70
			300	159	1	0.63	22	1	4.55
			1000	169	1	0.59	23	1	4.35
	VA	No ossification 5^th	0	184	6	3.26	24	3	12.50
			100	172	3	1.74	23	3	13.04
			300	159	8	5.03	22	5	22.73
			1000	169	2	1.18	23	2	8.70
	VA	No ossification 6^th	0	184	0	0	24	0	0
			100	172	1	0.58	23	1	4.35
			300	159	2	1.26	22	2	9.09
			1000	169	1	0.59	23	1	4.35
	VA	Incomplete ossification	0	184	7	3.80	24	6	25.00
			100	172	1	0.58	23	1	4.35
			300	159	6	3.77	22	5	22.73
			1000	169	5	2.96	23	5	21.74
	VA	Incomplete ossification 5^th	0	184	17	9.24	24	12	50.00
			100	172	16	9.30	23	10	43.48
			300	159	22	13.84	22	12	54.55
			1000	169	21	12.43	23	12	52.17
	VA	Incomplete ossification 6^th	0	184	25	13.59	24	13	54.17
			100	172	19	11.05	23	10	43.48
			300	159	25	17.72	22	13	59.09
			1000	169	13	7.69	23	8	34.78
	VA	Dumb-bell shaped 5^th	0	184	2	1.09	24	2	8.33
			100	172	2	1.16	23	2	8.70
			300	159	1	0.63	22	1	4.55
			1000	160	0	0	23	0	0
Thoracic vertebrae	AN	Centrum no ossification	0	184	0	0	24	0	0
			100	172	1	0.58	23	1	4.35
			300	159	0	0	22	0	0
			1000	169	1	0.59	23	1	4.35
	VA	Centrum incomplete ossification	0	184	4	2.17	24	3	12.50
			100	172	6	3.49	23	4	17.39
			300	159	5	3.14	22	4	18.18
			1000	169	5	2.96	23	5	21.74
	AN	Centrum bipartite	0	184	0	0	24	0	0
			100	172	2	1.16	23	2	8.70
			300	159	0	0	22	0	0
			1000	169	1	0.59	23	1	4.35
	VA	Centrum asymmetrical dumb-bell shaped	0	184	1	0.54	24	1	4.17
			100	172	2	1.16	23	1	4.35
			300	159	4	2.52	22	4	18.18
			1000	169	5	2.96	23	4	17.39
	VA	Centrum dumb-bell shaped	0	184	1	0.54	24	1	4.17
			100	172	4	2.33	23	4	17.39
			300	159	4	2.52	22	4	18.18
			1000	169	0	0	23	0	0

 

Categories: AN = Anomaly, VA = Variation

 

Table 3: Summary of fixed visceral examination of foetuses (group incidences) in the prenatal developmental toxicity study with CAPA 2047A

Group	Organ	Cat	Observation(s)	Observed	Affected	%	Observed	Affected	%
1	Abdomen	VA	Haemorrhagic	172	1	0.58	24	1	4.17
	Heart	AN	Atrium enlarged slight	172	2	1.16	24	2	8.33
	Kidneys	AN	Haemorrhagic	172	1	0.58	24	1	4.17
	Kidneys	VA	Pelvic dilatation slight	172	1	0.58	24	1	4.17
	Testis	AN	Displaced	172	2	1.16	24	2	8.33
	Thoracic cavity	AN	Haemorrhage	172	2	1.16	24	2	8.33
	Ureter	VA	Enlarged slight	172	2	1.16	24	2	8.33
	Ureter	VA	Kinked slight	172	1	0.58	24	1	4.17
	Whole foetus	AN	Generalised oedema moderate	172	3	1.74	24	2	8.33
	Whole foetus	MA	Generalised oedema extreme	172	5	2.91	24	3	12.50
2	Abdomen	VA	Haemorrhagic	161	2	1.24	23	2	8.70
	Tail	AN	Bent	161	1	0.62	23	1	4.35
	Testis	AN	Displaced	161	3	1.86	23	3	13.04
	Thoracic cavity	AN	Haemorrhage	161	1	0.62	23	1	4.35
	Ureter	VA	Enlarged slight	161	3	1.86	23	3	13.04
	Whole foetus	AN	Generalised oedema moderate	161	1	0.62	23	1	4.35
	Whole foetus	AN	Generalised oedema slight	161	2	1.24	23	2	8.70
3	Abdomen	VA	Umbelical vein left	147	2	1.36	22	2	9.09
	Heart	MA	Persistent truncus arterious	147	1	0.68	22	1	4.55
	Kidneys	VA	Pelvic dilatation slight	147	1	0.68	22	1	4.55
	Testis	AN	Displaced	147	4	2.72	22	4	18.18
	Ureter	AN	Enlarged moderate	147	2	1.36	22	2	9.09
	Ureter	VA	Enlarged slight	147	3	2.04	22	3	13.64
	Whole foetus	MA	Generalised oedema extreme	147	1	0.68	22	1	4.55
4	Abdomen	VA	Haemorrhagic	155	2	1.29	23	2	8.70
	Abdomen	VA	Umbelical vein	155	1	0.65	23	1	4.35
	Kidneys	AN	Haemorrhagic	155	1	0.65	23	1	4.35
	Ureter	AN	Enlarged moderate	155	2	1.29	23	1	4.35
	Whole foetus	MA	Generalised oedema extreme	155	1	0.65	23	1	4.35

 

Categories: AN = Anomaly, VA = Variation, MA = Malformation

Table 4: Litter data and sex ratios (group mean data) in the prenatal developmental toxicity study with CAPA 2047A

 

Group		Corpora Lutea	Implan­tations	Uterine Deaths			Viable young			%	Implantation loss (%)			Litter	Mean Foetal Weight (g)
				Early	Late	Total	Total	M	F	males	Pre	Post	Total	Weight (g)	M	F	combined
1	Mean	15.21	15.04	0.21	0.00	0.21	14.83	7.92	6.92	54.05	1.21	1.36	2.56	56.59	3.89	3.70	3.81
	SD	2.30	2.44	0.51	0.00	0.51	2.46	1.98	2.30	13.52	3.59	3.34	4.54	11.64	0.36	0.35	0.35
	(n)	24	24	24	24	24	24	24	24	24	24	24	24	24	24	24	24
2	Mean	15.13	14.96	0.48	0.00	0.48	14.48	7.57	6.91	52.72	1.17	3.27	4.42	54.70	3.86	3.66	3.78
	SD	1.77	1.82	0.67	0.00	0.67	1.97	2.29	2.63	15.06	2.63	4.74	4.94	8.04	0.17	0.16	0.15
	(n)	23	23	23	23	23	23	23	23	23	23	23	23	23	23	23	23
3	Mean	14.68	14.55	0.64	0.00	0.64	13.91	6.55	7.36	47.39	0.97	4.40	5.29	50.78	3.76	3.55	3.65
	SD	2.15	2.18	1.22	0.00	1.22	2.43	1.84	2.40	12.42	2.55	8.16	8.65	9.06	0.20	0.19	0.18
	(n)	22	22	22	22	22	22	22	22	22	22	22	22	22	22	22	22
4	Mean	14.70	14.61	0.52	0.00	0.52	14.09	6.91	7.17	48.65	0.54	3.41	3.94	52.67	3.91	3.63	3.76
	SD	2.80	2.76	0.99	0.00	0.99	2.75	2.56	2.44	15.21	1.81	6.74	6.69	9.17	0.23	0.23	0.22
	(n)	23	23	23	23	23	23	23	23	23	23	23	23	23	23	23	23

* = Statistically significantly different from control group value at p<0.05

Conclusions:

In this study, based on the results, maternal and developmental NOAELs of 1000 mg/kg bw/day can be determined. There was no evidence of teratogenicity or developmental toxicity under the conditions of this study.

Executive summary:

In a developmental toxicity study conducted according to OECD guideline 414, CAPA 2047A (2-Oxepanone polymer with 1,6-hexanediol diluted in corn oil) was administered to 24 pregnant female Sprague-Dawley rats/dose by gavage at dose levels of 0, 100, 300 or 1000 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 in females (hunched posture, emaciated aspect) observed were considered to be not treatment-related, since no dose-response relationship has been observed. The statistical significant decrease in weight gain observed in the high-dose group were occasionally, in magnitude and associated with a trend of recovery. Thus, these effects were without toxicological significance. Also a significant decrease in weight gain at the high dose at GD15-18 was observed, which is not considered to be treatment-related, since this effect was also occasionally. A total of 4 females were found not pregnant at necropsy: one receiving 100 mg/kg/day, two receiving 300 mg/kg/day and one receiving 1000 mg/kg/day. The number of females with live foetuses on gestation Day 20 was: 24 in the control, 23 in the low, 22 in the mid- and 23 in the high dose groups. These effects were considered to be not-treatment related, since no dose-response relationship was observed. A total of 7 small foetuses (< 2.7 g) were detected, 1 out of 356 in the control group, 1 out of 333 in the low dose group, 4 out of 306 in the mid-dose group and 1 out of 324 in the high dose group. Furthermore, some alterations were noted only in treated groups, but the incidence, in terms of foetuses affected, were similar or observed without a dose-response relationship. A total of 8 foetuses showed malformations: generalized oedema, extreme in five control foetuses, in one foetus at 300 mg/kg bw/day and in one foetus at 1000 mg/kg bw/day. Persistent truncus arteriousus was observed for one foetus at 300 mg/kg bw/day. The findings on skeletal, visceral and external malformation in fetuses are observed without a dose-response relationship.

In the absence of any toxicologically significant maternal effects and in the absence of any developmental toxicity, maternal and developmental NOAELs of 1000 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

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

A modern, GLP- and guideline-compliant developmental toxicity study in the rat is available for the submission substance CAPA 2047A (2-oxepanone polymer with 1,6-hexanediol).

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

In a developmental toxicity study conducted according to OECD guideline 414, CAPA 2047A (2-Oxepanone polymer with 1,6-hexanediol diluted in corn oil) was administered to 24 pregnant female Sprague-Dawley rats/dose by gavage at dose levels of 0, 100, 300 or 1000 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 in females (hunched posture, emaciated aspect) observed were considered to be not treatment-related, since no dose-response relationship has been observed. The statistical significant decrease in weight gain observed in the high-dose group were occasionally, in magnitude and associated with a trend of recovery. Thus, these effects were without toxicological significance. Also, a significant decrease in weight gain at the high dose at GD15-18 was observed, which is not considered to be treatment-related, since this effect was also occasionally. A total of 4 females were found not pregnant at necropsy: one receiving 100 mg/kg/day, two receiving 300 mg/kg/day and one receiving 1000 mg/kg/day. The number of females with live foetuses on gestation Day 20 was: 24 in the control, 23 in the low, 22 in the mid- and 23 in the high dose groups. These effects were considered to be not-treatment related, since no dose-response relationship was observed. A total of 7 small foetuses (< 2.7 g) were detected, 1 out of 356 in the control group, 1 out of 333 in the low dose group, 4 out of 306 in the mid-dose group and 1 out of 324 in the high dose group. Furthermore, some alterations were noted only in treated groups, but the incidence, in terms of foetuses affected, were similar or observed without a dose-response relationship. A total of 8 foetuses showed malformations: generalized oedema, extreme in five control foetuses, in one foetus at 300 mg/kg bw/day and in one foetus at 1000 mg/kg bw/day. Persistent truncus arteriousus was observed for one foetus at 300 mg/kg bw/day. The findings on skeletal, visceral and external malformation in fetuses are observed without a dose-response relationship.

 

In the absence of any toxicologically significant maternal effects and in the absence of any developmental toxicity, maternal and developmental NOAELs of 1000 mg/kg bw/day can be determined for this study.

Justification for classification or non-classification

No classification for reproductive toxicity is proposed, based on the absence of effects on tissues/organs of the male and female reproductive tract seen in the 90 -day oral rat toxicity study performed with CAPA 2047A at dose levels of up to 1000 mg/kg bw/d, and based on the absence of any effects in the rat PNDT study performed with CAPA 2047A at dose levels of up to 1000 mg/kg bw/d.