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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
from 2007-10-02 to 2007-11-27
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study is regarded as reliable without restrctions because it was conducted in accordance with GLP regulation and guideline. For read across justification please refer to IUCLID section 13.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report Date:
2007

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
2001
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
2004/73/EC
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
NA

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (Europe) Laboratories Inc. TOXI COOP Ltd. 1103 Budapest, Cserkesz u. 90.
- Age at study initiation: Young adult rats, 9-10 weeks old
- Weight at study initiation: 205 – 221 g
- Housing: Group caging (3 animals/cage)
- Diet (e.g. ad libitum): Animals received ssniff® R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany and tap water from the municipal supply, ad libitum.
- Water: ad libitum
- Acclimation period: 22 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 24°C
- Humidity (%): 38 - 58 %
- Air changes (per hr): 8-12 air exchanges/hour by central air-condition system.
- Photoperiod (hrs dark / hrs light): light 12 hours daily, from 6.00 a.m. to 6.00 p.m.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: PEG 400
Details on oral exposure:
A single oral administration - followed by a fourteen days observation period - was performed by gavage. Animals were treated with the test item prepared freshly in the morning hours. A constant treatment volume of 10 mL/kg body weight was applied. The concentration was adjusted to ensure constant volumes at all dose levels.
Doses:
The acute toxic class method was carried out involving a stepwise procedure with the use of 2000 mg/kg bw as the starting dose in three female rats. As all the three animals were found dead in the first treatment group (2000 mg/kg bw), a second group of three animals was dosed at
300 mg/kg bw. A single mortality occurred in the second treatment group. A third treatment group of three animals was then dosed at 300 mg/kg body weight. No animals were found dead. Further testing was not required according to the test guidelines (OECD 423, Directive 2004/73/EC B.1. tris).
No. of animals per sex per dose:
2000 mg/kg bw: 3 females
300 mg/kg bw: 2 test groups 3 females each
Control animals:
no
Details on study design:
Observation
Animals were observed daily for 14 days after dosing.

Clinical Examination
Animals were observed individually 30 minutes, 1 h, 2 h, 3 h, 4 h, 6 h after the treatment and once each day for 14 days thereafter. Individual observations were performed on the skin and fur, eyes and mucous membranes and also respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. The time of onset and cessation of symptoms and death were recorded as precisely as possible.

Weight Assessment
The body weights were measured and recorded on day 0 (beginning of the experiment), on days 7 and 14 with a precision of 1 g.

Pathology
All animals including those that died during the test were subjected to gross pathology. All surviving animals were exsanguinated under pentobarbital (100 mg/kg bw Euthasol® 40 %; Lot No.: 07E29 8, Expiry Date: April 2009, Product of AST Beheer B.V. Oudewater, Netherlands) anaesthesia. After examination of the external appearance the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed. All gross pathological changes were recorded for each animal on the post mortem record sheets.
Statistics:
Evaluation of Results
The method used is not intended to allow calculation of a precise LD50 value, but an LD50 value is assigned, according to the OECD Guideline No. 423 and Directive 2004/73/EC B.1 tris. Individual animal data are provided and all data are summarised in tabular form, showing for each dose group the number of animals used, the number of animals displaying signs of toxicity, the number of animals found dead during the test and the time of death of each individual animal. Toxic response data and reversibility were recorded for each dose level. Nature, severity and duration of clinical observations were described.

Results and discussion

Preliminary study:
no preliminary study
Effect levelsopen allclose all
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 300 - <= 2 000 mg/kg bw
Sex:
female
Dose descriptor:
LD50
Effect level:
500 mg/kg bw
Remarks on result:
other: cut off value
Mortality:
Reaction Product of Bisphenol A (BADGE) with IPDA caused mortality at 2000 mg/kg bw and 300 mg/kg bw dose levels in female CRL:(WI) BR rats as follows:
3/3 animals at 2000 mg/kg bw
1/3 animals at 300 mg/kg bw (group 1)
0/3 animals at 300 mg/kg bw (group 2)
Clinical signs:
2000 mg/kg bw – Treatment group 1
Activity decrease (3/3), prone position (1/3), squatting position (2/3), hunched back (3/3), cyanotic skin (3/3), piloerection (2/3) and dyspnoea (1/3) were noted for this group on the day of the treatment. White mucous faeces were found in the bedding material at the first hour observation, but no animal showed signs of disturbed defecation. The first symptoms (slight activity decrease, hunched back, dyspnoea and piloerection) appeared 2 hours after administration in animals No. 7847 and 7886. Animal No.: 7842 showed signs from 6th hour. All animals were found dead at the daily observation next day.

300 mg/kg bw – Treatment group 2
Activity decrease (2/3), squatting position (2/3), hunched back (2/3), diarrhoea (3/3), and piloerection (2/3) were observed in this group. One animal (No.: 7862), which was found dead next day, showed signs from the second hour. Surviving animals had signs from the 6th hour up to day 1 (No.: 7875) or to day 3 (No.: 7866). These animals were symptom-free during the remaining days of observation period.

300 mg/kg bw – Treatment group 3
Activity decrease (1/3), hunched back (3/3), diarrhoea (1/3), and piloerection (3/3) were observed in this group. Onset of the first signs was 30 minutes for each animal and no clinical signs were noted for these animals from day 2. The behaviour and general state of animals were considered to be normal during the remaining days of the study.
Body weight:
300 mg/kg bw – Treatment groups 2 and 3
The body weight development of each animal treated with 300 mg/kg bw was normal throughout the two weeks observation period, similar to untreated female animals of the same age and strain.
Gross pathology:
2000 mg/kg bw – Treatment group 1
All animals (No.: 7842, 7847, 7886) were found dead. Dark red lungs (2/3), congestive liver (3/3) and distended, liquid filled small intestines (3/3) were noted at the gross necropsy.

300 mg/kg bw – Treatment group 2
In dead animal (No.: 7862), reddish mottled lungs and congestive liver were observed. In one of the two surviving animals, pinprick-sized haemorrhages were found in the lungs (No.: 7875).

300 mg/kg bw – Treatment group 3
Pale raised areas (No.: 7831) and point like haemorrhages (No.: 7837) were recorded in the lungs of these animals.

In the dead animals, distended, liquid filled intestines were related to the local effect of the test item at 2000 mg/kg bw. The pulmonary alterations and congestive liver were signs of circulatory disturbance developed during the death.
No macroscopic alterations related to any toxic effect of the test item were found in surviving animals. The haemorrhages and pale raised areas in the lungs were due to the method of anaesthesia and exsanguinations, which are also observable in untreated animals after anaesthesia.
Other findings:
no other findings.

Applicant's summary and conclusion

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the present study, a single oral administration of the test item Reaction Product of Bisphenol A (BADGE) with IPDA caused mortality at 2000 mg/kg bw (3/3) and at 300 mg/kg bw (1/6). The acute oral LD50 value of Reaction Product of Bisphenol A (BADGE) with IPDA was between 300 mg/kg bw and 2000 mg/kg bw in female CRL:(WI) BR rats and it was ranked into Category 4 with a cut off value of 500 mg/kg bw. Reaction product of Bisphenol A (BADGE) with IPDA is classified as toxic category 4 (H302) according to Regulation 1272/2008/EC (CLP) and harmful if swallowed, Xn, R22, according to Directive 67/548/EC (DSD).
Executive summary:

The acute toxic class method according to OECD 423 and Directive 2004/73/EC B.1. tris was performed with Reaction Product of Bisphenol A (BADGE) with IPDA.

Three groups of three female CRL:(WI) BR Wistar rats were treated with Reaction Product of Bisphenol A (BADGE) with IPDA by single oral gavage at dose levels of 2000 mg/kg bw (Treatment group 1) and 300 mg/kg bw (Treatment groups 2 and 3) Polyethylene glycol 400 (PEG 400) in three independent experiments. The concentrations of the formulations were adjusted to ensure the constant treatment volume of 10 ml/kg bw (200 mg/mL and 30 mg/mL, respectively).

Results

Mortality

Reaction Product of Bisphenol A (BADGE) with IPDA caused mortality at 2000 mg/kg bw and 300 mg/kg bw/day dose levels in female CRL:(WI) BR rats as follows:

Treatment group:

1

2

3

Dose level (mg/kg bw):

2000

300

300

Number of animals treated:

3

3

3

Mortality:

3/3

1/3

0/3

Clinical signs

Treatment group 1 – 2000 mg/kg bw

All animals of the first treatment group were found dead one day after the treatment. Activity decrease, prone position, squatting position, hunched back, cyanotic skin, piloerection and dyspnoea were observed. Onset of signs was 2 hours and 6 hours.

Treatment group 2 – 300 mg/kg bw

Activity decrease, squatting position, hunched back, diarrhoea and piloerection were observed in this group. Onset of the first signs was 2 hours for animal, which was found dead next day and 6 hours for surviving animals.

Treatment group 3 – 300 mg/kg bw

No animal of the third treatment group died but activity decrease, hunched back, diarrhoea and piloerection were observed with an onset of 30 minutes of the first signs. All animals became symptom-free from day 2.

Body weight

The body weight development of each animal treated with 300 mg/kg bw was normal throughout the two weeks observation period, similar to untreated female animals of the same age and strain.

Necropsy

Distended, liquid filled small intestines were signs of the local effect of the test item at 2000 mg/kg bw. There were no test item related necropsy findings in dead animal or in surviving animals at 300 mg/kg bw.