Registration Dossier

Diss Factsheets

Administrative data

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 - 07 April 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. 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 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:
PREPARATION OF DOSING SOLUTIONS: The required amount of CAPA 2047A was suspended in the vehicle and maintained under magnetic stirring up to dosing. The formulation was 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 test item was administered orally by gavage at a dose volume of 4mL/kg body weight. Control animals received the vehicle alone at the same dose volume.

VEHICLE: corn oil
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.
- 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
- 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.
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.
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.
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.
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.
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.
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.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Litter size was not affected by treatment.
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 mid-dose group and 1 out of 324 in the high dose group.
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.
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.
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 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.
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*
Corpora lutea (#) 12.21 15.13 14.68 14.70
Implantations (#) 15.04 145.96 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 (%) 2.56 4.42 5.29 3.94
Mean viable foetuses (#) 14.83 14.48 13.91 14.09
Mean foetal weight (g) (sexes combined) 3.81 3.78 3.65 3.76
Mean foetal weight (g) (by sex) not reported
Small foetuses (#) 1 1 4 1
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

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 days6 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.

Additional information