Registration Dossier

Administrative data

Description of key information

The acute toxicological properties of asymmetrical epoxy amine adduct Reaction Product of Bisphenol A diglycidylether (BADGE) with IPDA and MXDA was assessed using a read across approach from data on symmetrical epoxy amine adducts Reaction Product of Bisphenol A (BADGE) with IPDA and Reaction Product of Bisphenol A (BADGE) with MXDA. 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. The acute oral LD50 value of Reaction Product of Bisphenol A (BADGE) with MXDA was between 300 mg/kg bw and 2000 mg/kg bw in female CRL:(WI) BR rats.
The acute dermal LD50 value of Reaction Product of Bisphenol A (BADGE) with IPDA and MXDA is greater than 2000 mg/kg bw .

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
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.
Reason / purpose:
reference to other study
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
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.
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.
Preliminary study:
no preliminary study
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.
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.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
500 mg/kg bw
Quality of whole database:
The study is regarded as reliable without restrictions because it was conducted in accordance with GLP regulation and guideline.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
from 2007-10-03 to 2007-12-17
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study is regarded as reliable without restrictions because it was conducted in accordance with GLP regulation and guideline. For read across justification please refer to IUCLID section 13.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
92/69/EEC
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
fixed dose procedure
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/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
- Weight at study initiation: Male: 252 - 283 g; Female: 216 - 239 g
- Fasting period before study: None
- Housing: Individual caging (1 animal/cage); Type II polypropylene/polycarbonate
- Diet: Animals received ssniff® SM 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.
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 -24 °C
- Humidity (%): 38 - 58 %
- Air changes (per hr): 8-12 air exchanges/hour by central air-condition system
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.

Type of coverage:
semiocclusive
Vehicle:
other: Test item was pulverized and moistened with water
Details on dermal exposure:
TEST SITE
- Area of exposure: approximately 10 per cent of the total body surface
- % coverage: appr. 10
- Type of wrap if used: semi occlusive plastic wrap


REMOVAL OF TEST SUBSTANCE
- Washing: water at body temperature
- Time after start of exposure: 24 hrs

TEST MATERIAL
- Amount applied: single dose of 2000 mg/kg bw
- For solids, paste formed: yes, with water
Duration of exposure:
24 hrs
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
Males: 5; 2000 mg/kg bw;
Females: 5; 2000 mg/kg bw;
Control animals:
no
Details on study design:
Observations: Animals were observed for a 14-day post-treatment period. Clinical examinations, body weight assessment and gross necropsy were conducted.

Clinical Examination: A careful individual clinical examination was made on the day of treatment 1 h and 5 h after the administration of the test item, 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.

Weight Assessment: The body weight of each animal was recorded on day 0 (beginning of the experiment), on day 7 and on day 14 with a precision of 1 g.

Pathology: On day of the last clinical observation, all animals were exsanguinated under carbon dioxide anaesthesia and gross necropsy was performed. 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 post mortem record sheets.

Evaluation of Results: The method used allows assigning an LD50 value, according to the OECD Guidelines for Testing of Chemicals, No. 402, and B.3. 92/69/EEC.
Individual animal data were provided and summarised in tabular form, showing for each dose group the number of animals used.
Clinical observations were noted individually and in summary tables.
Body weight changes were summarised in tabular form.
Necropsy findings were described and summarised in tabular form.
Statistics:
No statistics performed
Preliminary study:
No preliminary study was performed
Sex:
male
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
Male Female
Dose level (mg/kg bw): 2000 2000
Number of animals treated: 5 5
Number of dead animals: 0 0
Clinical signs:
There were no clinical signs. The behaviour and physical condition of animals were considered to be normal.

2000 mg/kg bw of Reaction Product of Bisphenol A (BADGE) with IPDA caused slight to marked erythema (5/5 male, 5/5 female), erosion (1/5 female) and sloughing (3/5 male, 5/5 female) on the skin after 24-hour exposure. Skin became normal between days 2 and 10 in male animals and between days 8 and 13 in female animals
Body weight:
The mean body weight and the body weight gain of the male and female animals were considered to be normal during the two-week observation period., similar to the expected values in untreated animals of the same age and strain.

The following table contains the body weight and body weight gain values of control animals of same age and strain.
Gross pathology:
No macroscopic alterations due to the effects of the test item were found.
Gross necropsy revealed pinprick-sized haemorrhages (5/5 male, 2/5 female) and reddish mottled colour (1/5 female) in the lungs due to the method of anaesthesia and exsanguinations, which are also observable in untreated animals after anaesthesia.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
Under the conditions of the present study, a single 24-hour dermal administration of 2000 mg/kg bw of the test item, Reaction Product of Bisphenol A (BADGE) with IPDA caused erosion, erythema and sloughing on the treated skin, which recovered within 2-13 days.

Mortalities were not observed, neither in male nor in female CRL:(WI)BR rats.

The acute dermal LD50 value of Reaction Product of Bisphenol A (BADGE) with IPDA is greater than 2000 mg/kg bw in male and female CRL: (WI) BR rats.

Reaction Product of Bisphenol A (BADGE) with IPDA does not meet the criteria for classification according to Regulation 1272/2008/EC (CLP) and Directive 67/548/EC (DSD).
Executive summary:

The acute dermal toxicity study (Limit Test) with Reaction Product of Bisphenol A (BADGE) with IPDA was performed in compliance with OECD guideline No.: 402 and method B.3. 92/69/EEC. A limit test was carried out at 2000 mg/kg bw dose level. Five male and five female CRL:(WI)BR rats were treated with a dose of 2000 mg/kg bw. The test item was applied once in its original form by dermal route and held in contact with the skin for a 24-hour period. The observation period after patch removal continued for 14 days. Clinical observations were made one and five hours after the treatment, then once a day. Body weight was measured weekly. Gross necropsy was performed in all animals at the termination of the experiment

Mortality:

No mortality was observed in male and female animals up to the limit dose of 2000 mg/kg bw.

 

Clinical Observations:

There were no clinical signs. The behaviour and physical condition of animals were considered to be normal.

2000 mg/kg bw of Reaction Product of Bisphenol A (BADGE) with IPDA caused slight to marked erythema (5/5 male, 5/5 female), erosion (1/5 female) and sloughing (3/5 male, 5/5 female) on the skin after 24-hour exposure. Skin became normal between days 2 and 10 in male animals and between days 8 and 13 in female animals.

Body Weight

The mean body weight and the body weight gain of the male and female animals were considered to be normal during the two-week observation period., similar to the expected values in untreated animals of the same age and strain.

The following table contains the body weight and body weight gain values of control animals of same age and strain.

Male animals:

 

 

Body weight (g)

Body weight gain (g)

 

Day 0

Day 7

Day 14

Day 0 - 7

Day 7 - 14

Day 0 - 14

Mean

264.5

316.6

366.4

52.0

49.8

101.9

Sd

15.0

14.1

15.1

4.9

7.6

8.7

n

21

21

21

21

21

21

 

Female animals:

 

 

Body weight (g)

Body weight gain (g)

 

Day 0

Day 7

Day 14

Day 0 - 7

Day 7 - 14

Day 0 - 14

Mean

226.7

242.7

251.3

16.0

8.7

24.7

Sd

6.8

7.3

10.2

7.8

5.8

11.1

n

23

23

23

23

23

23

Necropsy:

No macroscopic alterations due to the effects of the test item were found.

Gross necropsy revealed pinprick-sized haemorrhages (5/5 male, 2/5 female) and reddish mottled colour (1/5 female) in the lungs due to the method of anaesthesia and exsanguinations, which are also observable in untreated animals after anaesthesia.

Conclusions:

Under the conditions of the present study, a single 24 -hour dermal administration of 2000 mg/kg bw of test item, Reaction Product of Bisphenol A (BADGE) with IPDA caused erosion, erythema and sloughing on the treated skin, which recovered within 2 - 13 days.

Mortalities were not observed, neither in male nor in female CRL:(WI)BR rats.

The acute dermal LD50 value of Reaction Product of Bisphenol A (Badge) with IPDA is greater than 2000 mg/kg bw in male and female CRL:(WI) BR rats.

Reaction Product of Bisphenol A (BADGE) with IPDA does not meet the criteria for classification according to EU labelling regulations Commission Directive 2001/59 EC for classification and labelling of dangerous substances.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Quality of whole database:
The study is regarded as reliable without restrictions because it was conducted in accordance with GLP regulation and guideline.

Additional information

The acute toxicological properties of asymmetrical epoxy amine adduct Reaction Product of Bisphenol A diglycidylether (BADGE) with IPDA and MXDA was assessed using a read across approach from data on symmetrical epoxy amine adducts Reaction Product of Bisphenol A (BADGE) with IPDA and Reaction Product of Bisphenol A (BADGE) with MXDA, as these substances were considered to show similar toxicological properties. Inhalation toxicity was extrapolated from worst-case scenario oral toxicity results.

 

Acute oral toxicity

IPDA

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.

MXDA

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 MXDA. Three groups of three female CRL:(WI) BR Wistar rats were treated with Reaction Product of Bisphenol A (BADGE) with MXDA 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) in Polyethylene glycol 400 (PEG 400) in three independent experiments. Based on the results of the study and according to the criteria of the relevant test guidelines no further testing was performed. 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 :

The following mortality was found after a single oral administration of Reaction Product of Bisphenol A (BADGE) with MXDA at 2000 mg/kg bw and 300 mg/kg bw/day dose levels in female CRL:(WI) BR rats:

Treatment group:

1

2

3

Dose level (mg/kg bw):

2000

300

300

Number of animals treated:

3

3

3

Mortality:

2/3

0/3

1/3

Clinical signs :

Treatment group 1 – 2000 mg/kg bw

Two animals of the first treatment group were found dead on day 1 shortly after the daily observation. Severe activity decrease, squatting position, hunched back, cyanosis, diarrhoea, piloerection, convulsions, dyspnoea, decreased righting reflex, decreased grip-and limb tone and decreased body tone were noted for these animals. Surviving animal became symptom-free ten days after the treatment.

Treatment group 2 – 300 mg/kg bw

Decreased activity, squatting position, hunched back, diarrhoea and piloerection were noted two hours after the treatment. All animals were symptom-free on day five, and no clinical symptoms were noted subsequently.

Treatment group 3 – 300 mg/kg bw

One animal of the third treatment group was found dead one day after the treatment. Severe activity decrease, squatting position, hunched back, diarrhoea and piloerection were observed. The surviving animals became symptom free three days after the treatment.

Body weight :

A transiently reduced body weight gain was noted in surviving animals dosed with 2000 mg/kg bw or 300 mg/kg bw on week 1 or on week 2, respectively. The summarised body weight gain was considered to be normal.

Necropsy :

Necropsy revealed distended, liquid filled intestines and stomach at 2000 mg/kg bw or 300 mg/kg bw due to the local effect of the test item resulting in death of these animals. There were no test item related necropsy findings in surviving animals. 

Conclusions :

Under the conditions of the present study, a single oral administration of the test item Reaction Product of Bisphenol A (BADGE) with MXDA caused death of female CRL:(WI)BR rats at 2000 mg/kg bw (2/3) and 300 mg/kg bw (1/6).

According to the Globally Harmonised Classification System, the acute oral LD50 value of Reaction Product of Bisphenol A (BADGE) with MXDA 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 1000 mg/kg bw.

Reaction Product of Bisphenol A (BADGE) with MXDA has to be classified as harmful if swallowed according to Regulation 1272/2008/EC (CLP) and Directive 67/548/EC (DSD) criteria.

Acute inhalation

The performance of a test for toxicity by inhalation route is scientifically unjustified. REACH Regulation No. 1907/2006, Annex VIII, Sect. 8.5.2, Col. 2, states as follows: “testing by inhalation route is appropriate if exposure on humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure of aerosols, particles or droplets of inhalable size.”

Exposure to Reaction product of Bisphenol A diglycidylether (BADGE) with IPDA and MXDA by inhalation is unlikely, as physico-chemical properties suggest no evidence of a significant absorption by inhalation. The substance is practically non-volatile, with vapour pressure estimated in the range of 2.07E-21 Pa to 5.35E-21 Pa at 25 °C (mean ca. 3.33E-21 Pa) using the Modified Grain method. Further, from experience in use formation of inhalable particles is not very likely Thus, acute inhalation toxicity testing of Reaction Product of Bisphenol A diglycidylether (BADGE) with IPDA and MXDA is not scientifically justified.

Acute dermal

IPDA

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.

MXDA

The acute dermal toxicity study (Limit Test) with Reaction Product of Bisphenol A (BADGE) with MXDA was performed in compliance with OECD guideline No.: 402 and method B.3. 92/69/EEC. A limit test was carried out at 2000 mg/kg bw dose level. Five male and five female CRL:(WI)BR rats were treated with a dose of 2000 mg/kg bw. The test item was applied once in its original form by dermal route and held in contact with the skin for a 24-hour period. The observation period after patch removal continued for 14 days. Clinical observations were made one and five hours after the treatment, then once a day. Body weight was measured weekly. Gross necropsy was performed in all animals at the termination of the experiment.

Mortality :

Male Female

Dose level (mg/kg bw): 2000 2000

Number of animals treated: 5 5

Mortality: 0/5 0/5

Clinical Observations :

There were no clinical signs. The behaviour and physical condition of animals were considered to be normal. 2000 mg/kg bw of Reaction Product of Bisphenol A (BADGE) with MXDA caused slight to marked erythema (5/5 male, 5/5 female), and sloughing (1/5 male, 4/5 female) on the skin after 24-hour exposure. Skin recovered within 4 (male) or 7 (female) days after the patch removal.

Body Weight :

The mean body weight and the body weight gain of the male animals were considered to be normal during the two-week observation period. The body weight gain of female animals was slightly less than expected of untreated animals of the same age and strain during the first week.

Necropsy :

No macroscopic alterations due to the effects of the test item were found. Gross necropsy revealed pinprick-sized haemorrhages in the lungs (5/5 male, 4/5 female) due to the method of anaesthesia and exsanguinations, which are also observable in untreated animals after anaesthesia.

Conclusions :

Under the conditions of the present study, a single 24-hour dermal administration of 2000 mg/kg bw of the test item, Reaction Product of Bisphenol A (BADGE) with MXDA caused erythema and sloughing on the treated skin, which recovered within 2-7 days. Mortalities were not observed, neither in male nor in female CRL:(WI)BR rats.

The acute dermal LD50 value of Reaction Product of Bisphenol A (BADGE) with MXDA is greater than 2000 mg/kg bw in male and female CRL: (WI) BR rats.

Reaction Product of Bisphenol A (BADGE) with MXDA does not meet the criteria for classification and labelling according to the criteria of Regulation 1272/2008/EC (CLP) and Directive 67/548/EC (DSD).


Justification for selection of acute toxicity – oral endpoint
The study is regarded as reliable without restrictions because it was conducted in accordance with GLP regulation and guideline.

Justification for selection of acute toxicity – dermal endpoint
The study is regarded as reliable without restrictions because it was conducted in accordance with GLP regulation and guideline.

Justification for classification or non-classification

Acute oral toxicity

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance is considered for acute oral toxicity to be classified as Xn, R22: Harmful if swallowed under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EG.

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data is reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance is considered to be classified as acute oral toxicity cat. 4, H302: Harmful if swallowed for acute oral toxicity under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation No 1297/2014.

Acute dermal toxicity

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under Directive 67/548/EEC. As a result the substance is not considered to be classified for acute dermal toxicity under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EG.

 

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance is not considered to be classified for acute dermal toxicity under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation (EC) No 1297/2014.