Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
15 April 2013 -- 03 July 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report Date:
2013

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: colorless viscous liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: breeder: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: approximately 8 weeks old on the day of treatment
- Mean body weight at study initiation: 200 g (range: 190 g to 210 g)
- Fasting period before study: yes, during the night before treatment
- Housing: polycarbonate cages
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: 21 May 2013 to 19 June 2013

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: sesame oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Justification for choice of vehicle: as unsatisfactory solubility of the test item was obtained in drinking water treated by reverse osmosis (i.e. heterogeneous emulsion at the concentration of 200 mg/mL was obtained), another vehicle was chosen from the following organic solvents (in order of preference): 0.5% methylcellulose aqueous solution, corn oil, PEG 400 and sesame oil.
A homogenous emulsion was obtained at the concentration of 200 mg/mL in sesame oil.
- Maximum dose-volume applied: 10 mL/kg

CLASS METHOD:
- Rationale for the selection of the starting dose: since no relevant toxicity data were available for the estimation of a lethal dose-level and any existing data were taken into account by the Sponsor, the starting dose level was 300 mg/kg for ethical reasons.
Doses:
300 and 2000 mg/kg
No. of animals per sex per dose:
300 mg/kg: 3 females
2000 mg/kg : 3 females + 3 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Clinical observations: frequently during the hours following treatment; then, at least once a day.
- Body weight on the day of group allocation, just before treatment on day 1; then on days 8 and 15.
- Necropsy of survivors performed: yes (macroscopic).
Statistics:
no

Results and discussion

Preliminary study:
no
Effect levels
Sex:
female
Dose descriptor:
LD0
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No unscheduled deaths occurred during the study.
Clinical signs:
At 2000 mg/kg, hunched posture was observed in 2/3 females from group 3 (B20327 and B20329) on days 1 and 2. This was associated with piloerection in one of these females (B20329) on day 1 only.
No clinical signs were observed in any other animals.
Body weight:
The mean body weights and mean body weight changes (g) recorded in test item-treated animals during the observation period and in historical control data are summarized in the Table 1.

At 2000 mg/kg and when compared to CiToxLAB France historical control data, a lower body weight gain was noted in 2/3 females from group 3 (+32 and +34 g vs. +58 ± 5.8 g in control data base) over the whole study period. The body weight of the other animals was unaffected by the test item treatment.
Gross pathology:
There were no findings considered to be related to the test item administration.
Dilatation of the uterus with translucent content was noted in 2/3 females from group 1 given the test item at 300 mg/kg. This is a common background change in rats related to the estrous cycle.
Other findings:
no

Any other information on results incl. tables

 Table 1

Sex

Female

Group

historical control data

1

2

3

Dose-level (mg/kg)

0

300

2000

2000

Body weight (mean (± SD))

 

 

 

 

. Day 1

208 (± 11.7)

208 (± 2.5)

193 (± 2.6)

198 (± 6.1)

. Day 8

246 (± 12.7)

252 (± 3.2)

233 (± 11.6)

221 (± 3.1)

. Day 15

266 (± 14.0)

275 (± 13.1)

255 (± 7.4)

236 (± 2.5)

Body weight change (mean (± SD))

 

 

 

 

. Days 1-8

+39 (± 5.1)

+45 (± 2.1)

+40 (± 11.7)

+23 (± 6.0)

. Days 8-15

+20 (± 6.3)

+22 (± 10.8)

+21 (± 5.9)

+15 (± 3.1)

. Days 1-15

+58 (± 5.8)

+67 (± 10.5)

+62 (± 6.5)

+38 (± 8.1)

SD: standard deviations.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Under the experimental conditions of this study, the oral LD50 of the test item, 4,4'-lsopropylidenediphenol, ethoxylated, esters with acrylic acid and isononanoic acid, was higher than 2000 mg/kg in rats.
Executive summary:

The objective of this study was to evaluate the potential acute toxicity of the test item following a single oral administration (gavage) to rats.

This study was conducted in compliance with OECD Guideline No. 423 and the principles of Good Laboratory Practices.

 

Methods

The test item was administered once by oral route (gavage) to three groups of three fasted female Sprague-Dawley rats under a dosage-volume of 10 mL/kg. The test item was prepared in sesame oil.

Since no relevant toxicity data were available for the estimation of a lethal dose-level and any existing data have been taken into account by the Sponsor, the starting dose-level was 300 mg/kg for ethical reasons. After the first assay, the next higher dose-level of 2000 mg/kg was tested. Then, as no toxicity was observed at this higher dose-level, the results were confirmed in other females.

Each animal was observed at least once a day for mortality and clinical signs for 15 days. Body weight was recorded on day 1 and then on days 8 and 15.

On completion of the observation period, the animals were sacrificed and then submitted for a macroscopic post-mortem examination.Macroscopic lesions were preservedin buffered formalinthendestroyed at the finalization of the study reportas no microscopic examination was performed.

Results

No unscheduled deaths occurred during the study.

At 2000 mg/kg, hunched posture was observed in 2/3 females from group 3 on days 1 and 2. This was associated with piloerection in one of these females on day 1 only. No clinical signs were observed in any other animals.

At 2000 mg/kg and when compared to historical control data, a lower body weight gain was noted in 2/3 females from group 3 over the whole study period. The body weight of the other animals was unaffected by the test item treatment.

The test item administration did not induce any macroscopic findings at necropsy.

Conclusion

Under the experimental conditions of this study, the oral LD50 of the test item was higher than 2000 mg/kg in rats.

Therefore, the test item should not be classified as harmful or toxic by oral route according to the criteria of CLP Regulation.