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

Endpoint summary

Description of key information

In vivo skin irritation: not irritating; OECD 404; Daikin 2001e

In vivo Eye irritation: Severely irritating to the eye (Eye Damage Category 1); OECD 405; Daikin 2001f

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12 April 2001 to 15 April 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 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature, 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 was moistened with water (Milli-U) immediately before application.
- Preliminary purification step (if any): n/a
- Final dilution of a dissolved solid, stock liquid or gel: n/a
- Final preparation of a solid: n/a

FORM AS APPLIED IN THE TEST (if different from that of starting material) n/a

OTHER SPECIFICS: Test item was moistened with water (Mill-U) immediately before application.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Kisslegg, Germany
- Age at study initiation: ca. 6 weeks
- Weight at study initiation: 1.0 - 3.5 kg
- Housing: Individually housed in cages with perforated floors (Scanbur, Denmark - 53.5 x 63 x 38.5 cm)
- Diet (e.g. ad libitum): Standard laboratory diet (Charles River Breeding and Maintenance Diet for Rabbits, Altorim, Germany) supplied at 100 g / day.
- Water (e.g. ad libitum): Free access to tap water.
- 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

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

water

Remarks:

test item moistened just prior to application with 1 mL Milli-U water to ensure contact with the skin

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g (applied with 1 mL of Milli-U water)
- Concentration (if solution): n/a

VEHICLE
- Amount(s) applied (volume or weight with unit): 1 mL
- Concentration (if solution): n/a
- Lot/batch no. (if required): n/a
- Purity: n/a

NEGATIVE CONTROL
- Amount(s) applied (volume or weight): n/a
- Concentration (if solution): n/a

POSITIVE CONTROL
- Amount(s) applied (volume or weight): n/a
- Concentration (if solution): n/a

Duration of treatment / exposure:

4 h

Observation period:

72 h

Number of animals:

3 (males)

Details on study design:

TEST SITE
- Area of exposure: 2 x 3 cm
- % coverage: not reported
- Type of wrap if used: test item applied using metalline patch, which was subsequently held in place using micropore tape and a Coban elastic bandage. (Semi-occlusive).

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes, water used.
- Time after start of exposure: 4 h

OBSERVATION TIME POINTS
(indicate if minutes, hours or days) 1, 24, 48 and 72 h observations for irritation

SCORING SYSTEM:
- Method of calculation: erythema and oedema severity scored numerically on a scale of 0-4 (0: no erythema/ oedema, 1: very slight erythema/ oedema, 2: well defined erythema / slight oedema, 3: moderate erythema/ oedema, 4: severe erythema (beet redness, necrosis, deep injury)/ oedema)

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No skin irritation was observed in any of the treated individuals. There was also no sign of skin corrosion, skin staining/ colouration, systemic toxicity or mortality.

Other effects:

- Other adverse local effects: none
- Other adverse systemic effects: none

Table 1:         Irritant/corrosive response data for each animal at each observation time up to removal of each animal from the test

Score at time point / Reversibility	Erythema	Edema
	Max. score: 4	Max. score: 4
60 min	0 / 0 / 0	0 / 0 / 0
24 h	0 / 0 / 0	0 / 0 / 0
48 h	0 / 0 / 0	0 / 0 / 0
72 h	0 / 0 / 0	0 / 0 / 0
Average 24h, 48h, 72h	0	0
Reversibility	n/a	n/a
Average time (unit) for reversion	n/a	n/a

n/a: not applicable

Interpretation of results:

GHS criteria not met

Conclusions:

The test item was considered to be non-irritant and therefore cannot be classified as irritating to skin.

Executive summary:

In a primary dermal irritation study (OECD 404), young adult New Zealand white rabbits (3 males) were dermally exposed to 0.5 g of test item in 1 mL of water for 4 hours to a 2 x 3 cm area.  The test item was applied on to the clipped skin under semi-occlusive dressing. Animals then were observed for 3 days.  Irritation, including erythema and oedema formation, was scored numerically on a scale of 0-4 based on severity.

 

No erythema or oedema were observed in any of the treated individuals. In addition there were also no local or systemic effects observed and no mortality occured.

 

In this study, test item is not a dermal irritant.

Reference 2

Endpoint:

skin irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
In accordance with REACH Regulation (EC) 1907/2006 as amended: Annex VII, section 8.1: the skin corrosion: in vitro / ex vivo study does not need to be conducted based on existing data sufficient for classification and labelling being already available. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.2.2, July 2017) the study does not need to be conducted.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

23 - 26 April 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 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature and 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: No
- Preliminary purification step (if any): No
- Final dilution of a dissolved solid, stock liquid or gel: N/A
- Final preparation of a solid: N/A

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

OTHER SPECIFICS: Test item instilled into test system as delivered by Sponsor.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Kisslegg, Germany
- Age at study initiation: minimum of 6 weeks old
- Weight at study initiation: between 1.0 - 3.5 kg
- Housing: Animals individually housed in cages with perforated floors (Scanbur, Denmark - 53.5 x 63 x 38.5 cm)
- Diet (e.g. ad libitum): Stadard laboratory diet (Charles River breeding and maintenance diet for rabbits, Altromin, Germany). 100 g/ day supplied to each individual. Hay was also provided wice weekly.
- Water (e.g. ad libitum): Tap water supplied 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

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): ca. 33 mg of unchanged test item
- Concentration (if solution): n/a

VEHICLE
- Amount(s) applied (volume or weight with unit): n/a
- Concentration (if solution): n/a
- Lot/batch no. (if required): n/a
- Purity: n/a

Duration of treatment / exposure:

24 h

Observation period (in vivo):

72 h

Number of animals or in vitro replicates:

3 (males)

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No
- Time after start of exposure: n/a

SCORING SYSTEM:

Immediately after the 24 h observation, a solution of 2 % fluoroscein in water (pH 7) was instilled into both eyes of each animal to quantitatively determine corneal epithelial damage. Any stained areas (indicating epitheleal damage) was estimated as a percentage of the total corneal area.

Irritation was assessed once daily for 3 days. The key parameters measured were; corneal irritation (including % of cornea involved), changes to the iris, conjunctival irritation, chemosis and discharge. Each parameter was measured on a numerical scale as described in OECD 405 TG.

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2.33

Max. score:

4

Reversibility:

not reversible

Remarks:

within 72 hrs

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.33

Max. score:

4

Reversibility:

not reversible

Remarks:

within 72 hrs

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2.33

Max. score:

4

Reversibility:

not reversible

Remarks:

within 72 hrs

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Remarks:

within 72 hrs

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.67

Max. score:

2

Reversibility:

not reversible

Remarks:

within 72 hrs

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Remarks:

within 72 hrs

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2.67

Max. score:

3

Reversibility:

not reversible

Remarks:

within 72 hrs

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2.67

Max. score:

3

Reversibility:

not reversible

Remarks:

within 72 hrs

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

not reversible

Remarks:

within 72 hrs

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not reversible

Remarks:

within 72 hrs

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2.67

Max. score:

4

Reversibility:

not reversible

Remarks:

within 72 hrs

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not reversible

Remarks:

within 72 hrs

Other effects:

OTHER EFFECTS:
- Visible damage on test system:

Corneal injury was seen as opacity (max. grade 3) and epitheleal damage (max. 90 % of corneal area). The corneal injury persisted until termination (72 h).

Iridial irritation (grade 1) was observed and persisted until termination.

Irritation of the conjunctivae was seen as redness, chemosis and discharge and persisted until termination.

Grey/ white discolouration (sign of necrosis) of the nicititating membrane was noted in two animals at 48 and 72 h. Reduced elasticity of the eyelids was noted in one animal at 48 hours in all animals at 72 h after instillation.

Based on the severity of the ocular lesions observed, no reversibility was expected- the animals were humanely sacrificed at 72 h.

DEMONSTRATION OF TECHNICAL PROFICIENCY: Yes

ACCEPTANCE OF RESULTS:
- Acceptance criteria met for negative control: Not indicated
- Acceptance criteria met for positive control: N/A
- Range of historical values if different from the ones specified in the test guideline: N/A

Table 1:       Irritant/ corrosive response data for each animal at each observation time up to the removal of each animal from the test

Score at time point / Reversibility	Cornea	Iris	Conjunctivae	Chemosis	Discharge
	Max. score: 4	Max. score: 2	Max. score: 3	Max. score: 4	Max. score: 3
60 min	1 / 1 / 1	0 / 1 / 0	1 / 1 / 1	2 / 2 / 2	1 / 1 / 2
24 h	2 / 1 / 2	1 / 0 / 1	2 / 2 / 3	2 / 3 / 2	1 / 2 / 2
48 h	2 / 1 / 2	1 / 1 / 1	3 / 3 / 3	2 / 3 / 2	1 / 2 / 2
72 h	3 / 2 / 3	1 / 1 / 1	3 / 3 / 3	2 / 2 / 2	1 / 2 / 2
Max. area effected (% of total cornea)	80 / 80 / 90	n/a	n/a	n/a	n/a
Reversibility*	nr	n/a	n/a	n/a	n/a
Average time (unit) for reversion	n/a	n/a	n/a	n/a	n/a

nr: not reversible

n/a: not applicable

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

The test item can be classified as a Category 1 eye irritant based on GHS criteria.

Executive summary:

In a primary eye irritation study (OECD 405), ca. 33 mg (equivalent to ca. 0.1 mL) of test item was instilled into the conjunctival sac of young adult, New Zealand White rabbits (3 males). Animals then were observed for 3 days.  Irritation was scored by the numerical scoring system described in OECD 405 TG.

Severe and non-reversible corneal injury occurred in all three individuals. Irritation of the conjunctivae, chemosis, discharge and necrosis of the nictitating membrane was also observed and persisted until study termination.

In this study, test item was found to be extremely irritant to the eye based on the ocular corrosion that occurred.

Reference 2

Endpoint:

eye irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
In accordance with REACH Regulation (EC) 1907/2006 as amended: Annex VII, section 8.2: the eye irritation: in vitro / ex vivo study does not need to be conducted based on existing data sufficient for classification and labelling being already available. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.2.2, July 2017) the study does not need to be conducted.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation/corrosion:

The skin corrosion/irritation potential of the test item was determined in a primary dermal irritation study (OECD 404). Young adult white male New Zealand rabbits were dermally exposed to 0.5 g of Bisphenol AF in 1 mL of water for 4 hours to clipped skin  (2 x 3 cm area) under semi-occlusion.  Animals then were observed for 3 days with irritation scores recorded hour post exposure, 24, 48 and 72 hours later .  Irritation, including erythema and oedema formation, was scored numerically on a scale of 0 - 4 based on severity. No erythema or oedema were observed in any of the treated individuals. In addition there were also no local or systemic effects observed and no mortality occurred. Under the condition of this study, Bisphenol AF is not considered a skin irritant and cannot be classified according to GHS criteria.

 

Eye irritation:

In a primary eye irritation study (OECD 405), ca. 33 mg (equivalent to ca. 0.1 mL) of Bisphenol AF was instilled into the conjunctival sac of young adult, New Zealand White rabbits (3 males). Animals then were observed for 3 days.  Irritation was scored by the numerical scoring system described in OECD 405 TG. Severe and non-reversible corneal injury occurred in all three individuals. Irritation of the conjunctivae, chemosis, discharge and necrosis of the nictitating membrane was also observed and persisted until study termination. Under the condition of this study, Bisphenol AF was found to be extremely irritating to the eye based on the ocular corrosion that occurred.  

Justification for classification or non-classification

The substance does not meet the classification for skin corrosion/irritation. With regards to eye irritation, the substance meets the criteria for Category 1 Serious Eye Damage in accordance with Regulation (EC) No 1272/2008 (CLP).