4,4'-[2,2,2-trifluoro-1-(trifluoromethyl)ethylidene]diphenol; bisphenol AF

Endpoint summary

Description of key information

Acute Oral Toxicity: LD50 (rats, combined) ≥ 2000 mg/kg bw; OECD 420; Anon. (2001a)

Acute Inhalation Toxicity: Waiver

Acute Dermal Toxicity: LD50 (rats, combined) ≥ 2000 mg/kg bw; OECD 402; Anon. (2001b)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

13 February - 02 March 2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Study was conducted in accordance with International guidelines and in accordance with GLP. All guideline validity criteria were met.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature in the dark
- Stability under test conditions: Not reported
- Solubility and stability of the test substance in the solvent/vehicle: Not reported
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: Not reported

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Test item formulated in propylene glycol within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level.
- Preliminary purification step (if any): N/A
- Final dilution of a dissolved solid, stock liquid or gel: Not reported
- Final preparation of a solid: N/A

FORM AS APPLIED IN THE TEST (if different from that of starting material): Liquid

OTHER SPECIFICS: Homogeneity of formulation confirmed by visual inspection.

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: ca. 9 weeks
- Weight at study initiation: Did not exceed ± 20 % of the sex mean
- Fasting period before study: Yes - 20 h prior to dosing (max.) and for 3-4 h after dosing.
- Housing: 3 animals housed per Macrolon cage (Type IV, height 15 cm) containing purified sawdust as bedding material (SAWI, Jelu Werk, Rosenburg, Germany).
- Diet (e.g. ad libitum): Standard pelleted laboratory animal diet (from Altromin (Code VRF 1)) provided ad libitum.
- Water (e.g. ad libitum): Tap water provided ad-libitum.
- Acclimation period: Minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 3 ºC
- Humidity (%): 30 - 70 %
- Air changes (per hr): ca. 15.
- Photoperiod (hrs dark / hrs light): 12:12 light:dark

IN-LIFE DATES: From: To: Not reported

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

VEHICLE
- Concentration in vehicle: Not reported
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: Guideline recommended
- Lot/batch no. (if required): Not reported
- Purity: Not reported

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg bw

DOSAGE PREPARATION (if unusual): Test item formulated in propylne glycol within 4 hours prior to dosing. Homogeneity of formulation confirmed by visual inspection.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Not reported

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3 males and 3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for mortality were made twice daily. Bdy weights were recorded on Day 1 (pre-dose) and Day 8 and 15. Clinical signs were recorded once daily.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weights and necropsy.

Statistics:

Not performed

Preliminary study:

N/A

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed

Clinical signs:

lethargy (hypoactivity)

Body weight:

lower than 10% body weight loss

Remarks:

Slight body weight loss in individuals animals was noted between day 1 and 8 (1 male -12% and 1 female -8%).

Gross pathology:

No abnormalities were observed.

Table 2:       Number of animals dead (and with evident toxicity) (and time range within which mortality occured)

Nominal dose (mg/kg bw)	Mortality (No. dead / total)			Time range of deaths (hours)	Clinical signs (No. / total)
	Male	Female	Combined		Male	Female	Combined
2000	0 /3	0 / 3	0 / 6	N/A	3 / 3	2 / 3	5 / 6

N/A not applicable

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 value of the test item in Wistar rats exceeded 2000 mg/kg bw.

Executive summary:

In an acute oral toxicity study (OECD 423) groups of fasted, 9 week old, Wistar rats (3 male, 3 female) were given a single oral dose of  test item in propylene glycol at a single dose of 2000 mg/kg bw and observed for 14 days.

No mortality was observed in the limit test.

Clinical signs of toxicity were observed in 2 /3 females, namely hunched posture between Days 1 - 3 and 7 - 9.  Clinical signs of toxicity were also observed in all of the males rats including lethargy, hunched posture, chromodacryorrhoea, rales and/or piloerection between Days 1 - 7. Salivation was also observed in all male rats however this is commonly seen after treatment by oral gavage and was therefore not considered to be of toxicologial relevance. No macroscopic abnormalities were observed in the post mortem examination.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

>= 2 000 mg/kg bw

Quality of whole database:

The endpoint is concluded based on a single key study with a Klimisch rating of 1. No effects were observed up to the limit dose of 2000 mg/kg bw.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
The substance meets the Annex VIII, Section 8.5.2, Column 2 criteria as the vapour pressure is 5E-06 Pa. The use pattern for the substance will not present situations where exposure to aerosols, particles or droplets of an inhalable size is relevant.

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

The acute inhalation toxicity study was waived in accordance with Annex VIII, Section 8.5.2, Column 2.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

28 February - 14 March 2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Study was conducted in accordance with International guidelines and in accordance with GLP. All guideline validity criteria were met.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature in the dark
- Stability under test conditions: Not reported
- Solubility and stability of the test substance in the solvent/vehicle: Not reported
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: N/A

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Test item formulated using proylene glycol within 4 h of dosing.
- Preliminary purification step (if any): N/A
- Final dilution of a dissolved solid, stock liquid or gel: Not reported
- Final preparation of a solid: N/A

FORM AS APPLIED IN THE TEST (if different from that of starting material): Liquid

OTHER SPECIFICS: Homogeneity of the formulation was confirmed by visual inspection.

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: ca. 8-9 weeks old
- Weight at study initiation: ± 20 % of the sex mean
- Fasting period before study: No
- Housing: Individually housed in polycarbonate cages (Type III, height 15 cm) containing purifed sawdust as bedding (SAWI, Jelu Werk, Rosenburgh, Germany).
- Diet (e.g. ad libitum): Standard pelleted laboratory animal feed (from Altorim (code VRF 1)) provided ad libitum.
- Water (e.g. ad libitum): Tap water provided ad libitum.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 3 ºC
- Humidity (%): 30 - 70 % relative humidity (RH)
- Air changes (per hr): ca. 15
- Photoperiod (hrs dark / hrs light): 12:12 light:dark

IN-LIFE DATES: From: To: Not reported

Type of coverage:

occlusive

Vehicle:

propylene glycol

Details on dermal exposure:

TEST SITE
- Area of exposure: Back
- % coverage: 10
- Type of wrap if used: Surgical gauze (Surgy 1D) covered with aluminium foil and Coban flexible bandage. Dressings on females were further fixed with Micropore tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes- water.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mL/kg bodyweight
- Concentration (if solution): Not reported
- Constant volume or concentration used: Not reported
- For solids, paste formed: N/A

VEHICLE
- Amount(s) applied (volume or weight with unit): Not reported
- Concentration (if solution): Not reported
- Lot/batch no. (if required): Not reported
- Purity: Not reported

Duration of exposure:

24 h

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 males and 5 females per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for mortality and clinical signs were made twice daily. Body weights were recorded on Day 1 (pre-exposure), Day 8 and 15.
- Necropsy of survivors performed: Yes
- Other examinations performed: Clinical signs and body weight.

Statistics:

Not performed

Preliminary study:

Not conducted

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occured

Clinical signs:

lethargy (hypoactivity)

Body weight:

lower than 10% body weight loss

Remarks:

Slightly body weigh loss was noted in 2 females between day 1 and 8.

Gross pathology:

No abnormalities were noted.

Table 2:       Number of animals dead (and with evident toxicity) (and time range within which mortality occured)

Nominal dose (mg/kg bw)	Mortality (No. dead / total)			Time range of deaths (hours)	Clinical signs (No. / total)
	Male	Female	Combined		Male	Female	Combined
2000	0 /5	0 / 5	0 / 10	N/A	5 / 5	5 / 5	10 / 10

N/A not applicable

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD50 value of the test item in Wistar rats exceeded 2000 mg/kg bw.

Executive summary:

In an acute dermal toxicity study (OECD 402) groups of young adult Wistar rats (male and female) were dermally exposed to test item in ethylene glycol for 24 hours to 10 % of the total skin area at a single dose 2000 mg/kg bw.  Animals then were observed for 14 days.

No mortality was observed in the limit test.

Clinical signs of toxicity were observed in all individuals including lethargy, tremor, hunched posture, chromodacryorrhoea, ptosis, quick breathing and/or piloerection were noted among the animals between Day 1 - 9.  In one female hunched posture was noted until Day 13.  In a second female chromodacryorrhoea was noted between Day 9 - 12.  In another female chromodacryorrhoea was noted from Day 9 on wards.  General erythema, scales, scabs and/or swelling were seen in the treated skin-area of the animals during the observation period.  Reduced body weight gain was observed in the males between Day 1 - 8 and among females through the whole study period.  Slight body weight loss was observed in some females between Day 1 – 8.  No macroscopic abnormalities were observed in the post mortem examination.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

>= 2 000 mg/kg bw

Quality of whole database:

The endpoint is concluded based on a single key study with a Klimisch rating of 1. No effects were observed up to the limit dose of 2000 mg/kg bw.

Additional information

Acute toxicity: oral

OECD 423 (2001a) - In an acute oral toxicity study, a group of fasted, 9 week old Wistar rats (3 male, 3 female) were given a single oral dose of Bisphenol AF in propylene glycol at a single dose of 2000 mg/kg bw and observed for 14 days.

 

In the absence of mortality during the observation period, the oral LD50 was estimated to be greater than 2000 mg/kg bw. Clinical signs of toxicity observed were lethargy, hunched posture, chromodacryorrhoea, rales and/or piloerection between Days 1 – 7 in all male animals. In female rats, hunched posture was observed between day 1-3 and 7-9. Salivation was also observed in all male rats however this is commonly seen after treatment by oral gavage and was therefore not considered to be of toxicologial relevance. No macroscopic abnormalities were observed in the post mortem examination.

 

Acute toxicity: dermal

OECD 402 (2001b) - In an acute dermal toxicity study, groups of young adult Wistar rats (5 males and 5 females) were dermally exposed to Bisphenol AF in ethylene glycol for 24 hours to 10 % of the total skin area at a single dose 2000 mg/kg bw.  Animals then were observed for 14 days.

 

Clinical signs of toxicity were observed in all individuals included; lethargy, tremor, hunched posture, chromodacryorrhoea, ptosis, quick breathing and/or piloerection noted among the animals between Day 1 – 9. Hunched posture was noted in one female until day 13 and chromodacryorrhoea in 2 females between Day 9 – 12.  General erythema, scales, scabs and/or swelling were seen in the treated skin-area as well as reduced weight gain in all treated animals. No macroscopic abnormalities were observed in the post mortem examination.

Justification for classification or non-classification

Bisphenol AF does not meet the criteria for classification under GHS or Regulation (EC) No 1272/2008 (CLP).