Registration Dossier

Administrative data

Description of key information

A 90 -day rat study is available for the submission substance 2 -oxepanone, polymer with 1,4-butanediol (CAPA 2043).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
29 September 2016 - 02 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 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Version / remarks:
21 September 1998
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
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 number: WAC000478
CAS number: 31831-53-5
EC number: 608-670-1
Expiry date: 10 May 2018
Appearance: Clear, colourless liquid
Storage conditions: Ambient controlled conditions
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Standard species and strain used for this type of study.
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS srl, San Pietro al Natisone (UD), Italy
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at arrival: 27-29 days
- Weight at arrival: 78-95 g
- Fasting period before study: not specified
- Housing: The animals were housed up to 5 of one sex to a cage, in clear polysulfone solid bottomed cages as indicated in the relevant SOP. Nesting material was provided inside suitable bedding bags and changed at least twice a week.
- Diet (e.g. ad libitum): commercially available laboratory rodent diet (4 RF 21); ad libitum
- Water (e.g. ad libitum): drinking water; ad libitum
- Acclimation period: 13 days

DETAILS OF FOOD AND WATER QUALITY: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 °C ± 2 °C
- Humidity (%): 55% ± 15%
- Air changes (per hr): 15 to 20 per hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light
Route of administration:
oral: gavage
Details on route of administration:
The test item was administered orally, by gavage. The oral route was selected as it is a possible route of exposure of the test item in man.
Vehicle:
corn oil
Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: The required amount of CAPA 2043 was suspended in the vehicle. The formulation was prepared weekly at concentrations of 20, 45 and 100 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 5 mL/kg body weight. Control animals received the vehicle alone at the same dose volume. The dose was administered to each animal on the basis of the most recently recorded body weight and the volume administered was recorded for each animal.

- VEHICLE: corn oil
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical method was validated in RTC Study no. A2242 in the range from 10 to 120 mg/mL. Linearity, accuracy and precision were within the limits stated in this study (r > 0.98; accuracy 80-120%; precision CV < 10%). Formulations of the test item were prepared as suspensions in corn oil. Concentration and homogeneity of the low and high dose level were assessed by taking six analytical aliquots in different positions. For the intermediate levels, only concentration was assessed by taking two different analytical aliquots. Each analytical aliquot was analysed separately. Concentration was evaluated as the mean of the single determinations and homogeneity as the coefficient of variation of the sextuplicate set.

In RTC Study no. A2242, a 3- and 8-day stability at room temperature was verified in the range from 10 to 120 mg/mL. According to this study, suspensions are 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).

The proposed formulation procedure for the test item was checked in the range from 10 to 120 mg/mL by chemical analysis (concentration and homogeneity) in RTC Study no. A2242, to confirm that the method was suitable. Final results for all levels were within the acceptability limits stated in this study for concentration (80-120%) and homogeneity (CV <10%).

Samples of the formulations prepared on Weeks 1 and 13 were analysed to check the homogeneity and concentration. Results of the analyses were within the acceptability limits stated in RTC Study no. A2242 (80-120% for concentration and CV < 10% for homogeneity).
Duration of treatment / exposure:
90 days (main groups); 90 days with 28-day recovery (satellite groups)
Frequency of treatment:
Daily for 90 days (main groups); daily for 90 days followed by a 28-day recovery period (satellite groups)
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Vehicle (corn oil) control
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
225 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10/sex (main study groups); 5/sex (for recovery groups in control and high dose group)
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 500 mg/kg bw/day was used, which is expected to induce toxicity but not death or severe suffering in a subchronic study, as required in the OECD guideline 408.
Furthermore, according to OECD guideline 408, 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 (NOAEL) at the lowest dose level. 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 225 mg/kg bw was chosen for the subchronic study and a low dose of 100 mg/kg bw/day was selected based on the recommendation of the intervals of the guideline.

- Rationale for animal assignment: Control and high dose groups included 5 additional animals per sex which were sacrificed after 4 weeks of recovery. The group identification and animal numbers assigned to the treatment (males: even; females: odd) are as follows:

Group 1 (0 mg/kg bw/day) Main phase: Rat numbers: males 2-20, females 1-19; recovery phase: Rat numbers: males 22-30, females 21-29

Group 2 (100 mg/kg bw/day) Main phase: Rat numbers: males 32-50, females 31-49

Group 3 (225 mg/kg bw/day) Main phase: Rat numbers: males 52-70, females 51-69

Group 4 (500 mg/kg bw/day) Main phase: Rat numbers: males 72-90, females 71-89; recovery phase: Rat numbers: males 92-100, females 91-99


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 Pristima® Version 6.4.1.

- Post-exposure recovery period in satellite groups: 4 weeks
Positive control:
Not required for this study type
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily (early and afternoon)

DETAILED CLINICAL OBSERVATIONS/ NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule: Once before commencement of treatment and at least once per week from the start of treatment each animal was given a detailed clinical examination. Each animal was observed in an open arena
- Observations: changes in gait and posture, reactivity to handling, presence of clonic or tonic movements, stereotypies or bizarre behaviour and effects on the autonomic nervous system (e.g. lachrymation, piloerection, unusual respiratory pattern); Changes in fur, skin, eyes, mucous membranes, occurrences of secretions and excretions. Once during Week 12 of treatment and once during Week 4 of recovery, an evaluation of sensory reactivity to stimuli of different modalities (e.g. auditory, visual and proprioceptive stimuli) and an assessment of grip strength were also performed. The motor activity (MA) of all animals was measured once during Week 13 of treatment and once during Week 4 of recovery by an automated activity recording. Measurements were performed using a computer generated random order.

BODY WEIGHT: Yes
- Time schedule for examinations: on the day of allocation to treatment group, on the day before treatment commenced, weekly thereafter and just prior to necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Time schedule: weekly
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No (no feeding study)

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

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

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to the commencement and during Week 13 of treatment
- Dose groups that were examined: all animals in each dose group

HAEMATOLOGY: Yes
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: Yes (isoflurane anaesthesia)
- Animals fasted: Yes, overnight food deprivation (16-17 hours)
- How many animals: 10 males and 10 females from each group
- Parameters checked in table No.1 in box “Any other information on materials & methods” were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to necropsy
- Animals fasted: Yes, overnight food deprivation (16-17 hours)
- How many animals: 10 males and 10 females from each group
- Parameters checked in table No.2 in box “Any other information on materials & methods” were examined.

URINALYSIS: No

IMMUNOLOGY: No

OTHER: Organ weights: From all animals completing the scheduled test period, the organs indicated in table 3 in box "Any other information on materials & methods incl. tables" were dissected free of fat and weighed. The ratios of organ weight to body weight were calculated for each animal.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 3 in box in “Any other information on materials & methods incl. tables” under column “Fixation Preservation”)

HISTOPATHOLOGY: Yes (see table 3 in box “Any other information on materials & methods incl. tables” under column “Microscopic examination”)
Other examinations:
None
Statistics:
Standard deviations were calculated as considered appropriate. For continuous variables the significance of the differences amongst groups was assessed by analysis of variance. Differences between each treated group and the control group were assessed by Dunnett’s test using a pooled error variance. The homogeneity of the data was verified by Bartlett’s test before Dunnett’s test. If the data were found to be inhomogeneous a Modified t test (Cochran and Cox) was applied. The mean values, standard deviations and statistical analysis were calculated from the actual values in the computer without rounding off. Statistical analysis of histopathological finding was carried out by means of a nonparametric Kolmogorov-Smirnov test.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
One male animal of the mid-dose group showed occasional signs of lethargy. This clinical sign was also observed in 6 males and 3 females of the high-dose group. Salivation was sporadically observed in 4 males of the high-dose group; slight ataxia was observed on Day 49 in one male of the mid-dose group. No clinical signs which could be considered treatment-related were observed during the recovery period.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One male animal from the low dose group was found dead on Day 12 (Week 2) of the treatment period. Dyspnoea and piloerection were observed in this animal prior to death. At post mortem examination, this animal showed abnormal clear fluid content in the thoracic cavity and dark colour of the thymus. Chronic inflammation localized mainly in the adjacent adipose tissue and /or in the visceral serosa of the heart, lungs and thymus, considered related to uncorrect dosing, were described at histopathological examination. No treatment-induced changes were seen. All other reported microscopic observations were considered to be an expression of spontaneous and/or incidental pathology. In particular, the mild lymphocytolysis reported in the thymus can be considered stress-related.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No significant body weight and absolute body weight changes were noted between treated animals and controls during the treatment and recovery periods.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No toxicologically significant changes were observed in food consumption during treatment and recovery periods.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
Animals with no ocular abnormality were selected for the study by an ophthalmoscopic examination performed before the start of treatment. No findings were detected in both eyes of all surviving animals, from high dose and control groups, when they were re-examined during Week 13 of treatment.
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Statistically significant differences between control and treated animals were recorded, such as increased neutrophils in mid-dose males dosed and increased haemoglobin in high dose females. Due to the slight severity or the absence of dose-relation, these findings were not considered to be of toxicological relevance.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Fluctuations of some biochemical parameters were recorded in treated animals. In particular, glucose was increased in males dosed at 500 mg/kg/day and in all treated females (22% to 31%); calcium and inorganic phosphorus were increased in males of all treated groups (2% to 3% for calcium and 13% to 20% for phosphorus) while alkaline phosphatase was decreased in all treated females (20% to 31%). None of the above findings was dose-related. Due to the slight severity, the absence of dose-relation and/or the direction, these changes were considered of no toxicological relevance.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No changes of toxicological significance were found at the weekly clinical examination, which included an evaluation of neurotoxicity. No differences between treated animals and controls, which could be considered treatment-related, were observed at functional tests (sensory reactivity, landing footsplay, grip strength) performed at the end of treatment and recovery periods. Motor activity measurements performed at the end of the treatment and recovery periods did not show any toxicologically significant differences between treated animals and controls.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Very slight reductions of terminal body weight, statistically significant in Group 3 male animals, were observed in the mid- and high dose males when compared to controls, at the end of the treatment period (-6% and -5%, respectively). Dose-related and statistically significant increases in relative weight of adrenal glands were noted in the mid- and high dose male animals (+16% and +26%, respectively), considered to be due to the slightly reduced terminal body weight in these groups in absence of other correlated changes. This change was no longer present at the end of recovery. No toxicological significance was attributed to the statistically significant increases observed in the females at the end of recovery (adrenal glands +15%, heart +15% and liver +19%), since they were not present at the end of treatment and were not supported by other relevant data.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related changes were noted following gross pathology examination, both in the main and recovery phases. All observed changes were considered incidental, having a comparable incidence in control and treated groups, and/or are characteristically seen in untreated Sprague Dawley SD rats of the same age.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No treatment-related changes were noted, following histopathological evaluation. All findings were considered incidental, having a comparable incidence in control and treated groups, and/or are characteristically seen in untreated Sprague Dawley SD rats of the same age.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Details on results:
The oral toxicity of CAPA 2043 in Sprague Dawley rats, following daily oral administration at dose levels of 100, 225 and 500 mg/kg/day for 13 consecutive weeks, and recovery from any treatment-related effect during a period of 4 weeks, were investigated in this study.
One male animal, belonging to the low dose group, was found dead on Day 12 of the treatment period. Dyspnoea and piloerection were observed in this animal prior to death. The histopathological examination established that the factors contributory to the death of the animal was not related to the toxicity of the test item. Lethargy and salivation were the major signs observed (mainly in male animals) of the mid- and high dose groups, with occasional frequency, during the treatment period. These signs were reversible at the end of the recovery period. Body weight and food consumption were not affected by treatment. No other significant signs of toxic or neurotoxic effects were seen during the in vivo phase of the study. No lesions were recorded at ophthalmological examination. No changes of toxicological relevance were observed in haematological, clinical chemistry parameters and coagulation.
The relative weight of the adrenal glands was slightly increased in males treated at 225 and 500 mg/kg/day. This change was no longer observed at the end of recovery. This change was not considered to be of toxicological relevance in absence of other correlated changes (may be due to the slight reductions of terminal body weight). No other changes of toxicological relevance were observed.
No treatment-related findings were reported at post mortem macroscopic observations and at histopathological examination of animals.

In conclusion, signs of effects related to treatment with CAPA 2043 were limited to few clinical signs (lethargy, salivation and occasional ataxia) observed in animals treated at 500 mg/kg/day, when administered by oral gavage for 13 consecutive weeks at the dosages of 100, 225 and 500 mg/kg/day. Due to the transitorial nature of these signs and to their mild severity, these signs were not considered to be adverse.
No other changes which could be considered to be adverse were observed at any of the dose levels investigated.
No treatment-related effects were observed in animals dosed at 100 mg/kg/day.

For the summary of relevant findings see table 4 in box "Any other information on results incl. tables".
Key result
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed
Key result
Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
organ weights and organ / body weight ratios
Key result
Critical effects observed:
no

Table 4: Summary of relevant findings in the 90 -day study with CAPA 2043

 

Males

Females

mg/kg bw/d

0

100

225

500

0R

500R

0

100

225

500

0R

500R

n

10

10

10

10

5

5

10

10

10

10

5

5

Mortality

-

1

-

-

-

-

-

-

-

-

-

-

Clinical signs

-

Piloerection, slight (1/10 animals/1.0 days per animal)

Dispnoea (1/10 animals/1.0 days per animal)

Lethargy (1/10 animals/4.0 days per animal)

Tooth/teeth cut (1/10 animals/5.0 days per animal)

Tooth/teeth missing (1/10 animals/5.0 days per animal)

Ataxia, slight (1/15 animals/1.0 days per animal)

Lethargy (6/15 animals/2.5 days per animal)

Salivation (4/15 animals/1.8 days per animal

-

-

-

-

Staining, Eye, Right, Slight, Brown (1/10 animals/12.0 days per animal)

Lethargy (3/15 animals/1.0 days per animal)

Tooth/teeth cut (1/15 animals/4.0 days per animal)

-

-

Weight gain (g) (1)

277.62

271.32

248.37

267.89

23.94

20.18

121.67

129.37

116.55

129.63

7.22

7.06

Haematology

Hb (g/dL)

14.86

14.94

15.27

15.10

 

 

13.68

13.60

14.04

14.18**

 

 

Neutrophils (%)

10.09

12.93*

17.11*

10.90

 

 

7.28

9.81*

8.98

7.10

 

 

Lymphocytes (%)

84.46

80.86*

77.47*

82.93

 

 

87.67

84.29*

85.73

87.38

 

 

Clinical chemistry

AP (U/L)

233.18

248.91

213.69

212.53

 

 

184.77

147.62*

127.78**

139.73**

 

 

Glucose (mg/dL)

154.79

150.34

152.66

202.39*

 

 

96.83

123.76**

123.06**

118.22*

 

 

Ca (mM)

2.638

2.719**

2.729**

2.702*

 

 

2.589

2.589

2.590

2.628

 

 

P (mg/dL)

4.894

5.522**

5.858**

5.655**

 

 

4.618

4.984

5136

5.214

 

 

Organ weights

Terminal body weight (g)

462.71

464.16

436.95**

441.63

501.74

502.32

261.70

266.60

252.66

268.64

283.66

278.74

Adrenals (g)

0.0470

0.0523

0.0515

0.0566

0.0460

0.0486

0.0565

0.0555

0.0578

0.0563

0.0558

0.0634

Adrenals (%)

0.0120

0.0113

0.0118*

0.0129*

0.0092

0.0097

0.0216

0.0209

0.0230

0.0210

0.0197

0.0227*

Heart (g)

1.4196

1.549

1.432

1.496

1.557

1.536

0.975

0.980

0.961

0.971

0.953

1.076*

Heart (%)

0.3235

0.3338

0.3276

0.3393

0.3108

0.3067

0.3279

0.3679

0.3808

0.3613

0.3371

0.3861**

Liver (g)

12.537

12.771

11.512*

12.128

17.123

16.294

6.632

7.010

6.684

6.826

7.725

9.006

Liver (%)

2.7086

2.7516

2.6336

2.7462

3.4095

3.2440

2.5330

2.6263

2.6398

2.5408

2.7159

3.2220**

R: recovery groups

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

(1) for treatment group measured on Day 91; for recovery group measured on Day 28 post-dose

Conclusions:
Based on the results of this study, it can be concluded that the NOAEL is 500 mg/kg/day in the absence of any adverse findings of toxicological significance at any dose level. The NOEL for this study is 100 mg/kg bw/day.
Executive summary:

In a subchronic toxicity study conducted according to OECD guideline 408, the test item CAPA 2043 (2-oxepanone, polymer with 1,4-butanediol) in corn oil was administered to Sprague-Dawley rats (10/sex/dose) by gavage at dose levels of 0, 100, 225 and 500 mg/kg bw/day for 90 days. Five rats/sex were included in the high-dose and control groups for recovery assessment. The dose selection was based on a preliminary 2-week dose range finding study.

One male animal from the low dose group was found dead on Day 12, due to uncorrect dosing. Lethargy was observed in 1/10 and 6/15 male animals of the mid- and high-dose groups, respectively, and in 3/15 high-dose females. Salivation was also noted in 4/15 high-dose males of Group 4 (500 mg/kg bw/day). These signs were not observed during the recovery period. No changes of note were found at the weekly clinical examination which included an evaluation of neurotoxicity during treatment and recovery periods. No differences between treated and control groups were evident during the functional tests and at the motor activity measurements at the end of the treatment and recovery periods. Body weights and food consumption were not affected by treatment. No significant findings were detected at the ophthalmoscopic examinations at the end of the study. No changes of toxicological relevance were observed in haematological parameters. Fluctuations in some biochemical parameters were recorded in treated animals; however due to the slight severity and/or absence of a dose-response relationship, they were not considered to be of toxicological significance. Very slight reductions in terminal male body weight (significant in mid-dose males) were observed when compared to controls. No changes of toxicological relevance were observed on organ weights. Gross and microscopic pathology did not reveal any effects of treatment.

The effects of CAPA 2043 in this study were therefore limited to clinical signs (lethargy, salivation and occasional ataxia) in rats at the highest dose levels of 500 mg/kg bw/day. Due to the transient nature and mild severity, these signs were not considered to be adverse. A NOAEL of 500 mg/kg bw/day is therefore determined for this study; a NOEL of 100 mg/kg bw/day is determined.

 

This subchronic toxicity study in the rat is acceptable and satisfies the guideline requirement for a subchronic oral study (OECD 408) in rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
A modern, GLP-and guideline-compliant study is available for the submission substance.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The toxicity of CAPA 2043 was investigated in a study conducted according to OECD guideline 408. In this study the test item CAPA 2043 (2-oxepanone, polymer with 1,4-butanediol) in corn oil was administered to Sprague-Dawley rats (10/sex/dose) by gavage at dose levels of 0, 100, 225 and 500 mg/kg bw/day for 90 days. Five rats/sex were included in the high-dose and control groups for recovery assessment.The dose selection was based on a preliminary 2-week dose range finding study.

One male animal from the low dose group was found dead on Day 12, due to uncorrect dosing. Lethargy was observed in 1/10 and 6/15 male animals of the mid- and high-dose groups, respectively, and in 3/15 high-dose females. Salivation was also noted in 4/15 high-dose males of Group 4 (500 mg/kg bw/day). These signs were not observed during the recovery period. No changes of note were found at the weekly clinical examination which included an evaluation of neurotoxicity during treatment and recovery periods. No differences between treated and control groups were evident during the functional tests and at the motor activity measurements at the end of the treatment and recovery periods. Body weights and food consumption were not affected by treatment. No significant findings were detected at the ophthalmoscopic examinations at the end of the study. No changes of toxicological relevance were observed in haematological parameters. Fluctuations in some biochemical parameters were recorded in treated animals; however due to the slight severity and/or absence of a dose-response relationship, they were not considered to be of toxicological significance. Very slight reductions in terminal male body weight (significant in mid-dose males) were observed when compared to controls. No changes of toxicological relevance were observed on organ weights. Gross and microscopic pathology did not reveal any effects of treatment.

The effects of CAPA 2043 in this study were therefore limited to clinical signs (lethargy, salivation and occasional ataxia) in rats at the highest dose levels of 500 mg/kg bw/day. Due to the transient nature and mild severity, these signs were not considered to be adverse. A NOAEL of 500 mg/kg bw/day is therefore determined for this study; a NOEL of 100 mg/kg bw/day is determined.

 

Justification for classification or non-classification

Classification for repeated dose toxicity (STOT-RE) for CAPA 2043 is not proposed based on the absence of toxicologically significant effects at relevant dose levels in the 90 -day study.