4-fluoroaniline

Endpoint summary

Description of key information

Read-across approach to structural analogue substances were used.
Skin irritation: In the skin irritation test the test substance 3,5-Difluoroaniline (CAS 372-39-4) was determined to be corrosive to the skin of rabbit.
Eye irritation: In the eye irritation test the test substance 3-Chloro-4-fluoroaniline (CAS 367-21-5) was determined to cause severe non reversible damage  to the eye of rabbit.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994-03-14 to 1994-03-27

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

Adopted: 12 May 1981

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Froxfield (U.K.) Ltd., Petersfield, Hampshire, England.
- Age at study initiation: 10--1 weeks
- Weight at study initiation: 2.3- 2.6 kg
- Housing: Individually in metal cages with perforated floors
- Diet: SDS Stanrab (P) Rabbit Diet, ad libitum
- Water: Drinking water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature: 19°C
- Humidity: 30-70 %
- Air changes: 19 air changes per hour
- Photoperiod: 12 hours light in each 24 hours period

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

water

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.5 g

Duration of treatment / exposure:

4 hours

Observation period:

14 days

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: Dorso-lumbar region
-Coverage area: 25 mm x 25 mm
- Type of wrap if used: Gauze pad, each treatment site was covered with "Elastoplast" elastic adhesive dressing

REMOVAL OF TEST SUBSTANCE
- Washing: Yes, warm water (30°C-40°C)
- Time after start of exposure: At the end of the exposure period.

SCORING SYSTEM:
Erythema and eschar formation:
No erythema: 0
Very slight erythema (barely perceptible): 1
Well-defined erythema: 2
Moderate to severe erythema: 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth)preventing erythema reading: 4

Oedema formation:
No oedema: 0
Very slighr oedema (barely perceptible): 1
Slight oedema (edges of area weII-defined by definite raising): 2
Moderate oedema (raised approximately 1 millimetre): 3
Severe oedema (raised more than 1 millimetre and extending beyond the area of exposure): 4

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

3.33

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Remarks on result:

other: Necrosis

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

not fully reversible within: 14 days

Remarks on result:

other: Brown hardening of the skin

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.67

Max. score:

4

Reversibility:

not fully reversible within: 14 days

Remarks on result:

other: Necrosis

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 14 days

Remarks on result:

other: Brown hardening of the skin

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 14 days

Remarks on result:

other: Desquamation of the stratum corneum

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2.33

Max. score:

4

Reversibility:

not fully reversible within: 14 days

Irritant / corrosive response data:

Clinical signs:
There were no signs of toxicity or ill health in any rabbit during the observation period.

Dermal responses
Moderate to severe erythema with slight to moderate oedema was seen following removal of the dressings. On day 3 severe erythema with necrosis was seen. Necrotic reactions, brown hardening of the skin and desquamation of the stratum corneum was seen between day 6 and 14.

Interpretation of results:

Category 1C (corrosive)

Remarks:

Migrated information

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (corrosive)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1979-01-22

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

other: Federal Register 38, No. 187, Para. 1500.42, P.27029 from 27.09.1973

GLP compliance:

not specified

Species:

rabbit

Strain:

Vienna White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Weight at study initiation: M: 3220 g F: 2950 g
- Diet: SSNIFF der Firma Intermast

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied: 81 mg

Observation period (in vivo):

8 days

Number of animals or in vitro replicates:

3 (2 male, 1 female)

Irritation parameter:

cornea opacity score

Remarks:

opacity

Basis:

animal #1

Remarks:

male

Time point:

other: 24, 72 hours

Score:

1.5

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Remarks on result:

other: no information on 48h available

Irritation parameter:

cornea opacity score

Remarks:

opacity

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Irritation parameter:

cornea opacity score

Remarks:

opacity

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Irritation parameter:

iris score

Basis:

animal #1

Remarks:

male

Time point:

other: 24, 72 hours

Score:

1

Max. score:

2

Reversibility:

not fully reversible within: 8 days

Remarks on result:

other: no information on 48h available

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.33

Max. score:

2

Reversibility:

fully reversible within: 8 days

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not fully reversible within: 8 days

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #1

Remarks:

male

Time point:

other: 24, 72 hours

Score:

2

Max. score:

3

Reversibility:

not fully reversible within: 8 days

Remarks on result:

other: no information on 48h available

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

not fully reversible within: 8 days

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #3

Time point:

other: 24,48, 72 hours

Score:

2

Max. score:

3

Reversibility:

not fully reversible within: 8 days

Irritation parameter:

chemosis score

Basis:

animal #1

Remarks:

male

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.33

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 8 days

Irritant / corrosive response data:

For animal no. 1 the scores at 48 hours could not be evaluated.
The mean cornea score opacity was >= 1 at all animals.
The mean iris score was 1 at 2 animals.
The mean conjunctivae score redness was 2 at all animals.
The mean chemosis score was 2 at 2 animals.

Following symptoms after 8 days were observed:
Animal no.1: Norrowed pupil, intergrown vessels, scar
Animal no.2: Scar
Animal no.3: Scar

Interpretation of results:

Category 1 (irreversible effects on the eye)

Remarks:

Migrated information

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation

 

No data for this endpoint with the test substance is available. Thus, data from the similar substance 3,5-difluoroaniline (CAS 372-39-4) and3-Chloro-4-fluoroaniline (CAS 367-21-5) was summarised to cover these endpoints. For further justification see IUCLID section 13.

 

Key study

Sandoz Crop Protection Ltd., study no.: 180/940203/SE, 1994

 

Read-across approach to structural analogue substance 3,5-difluoroaniline (CAS 372-39-4) was used.

A study was performed to assess the skin irritation potential of the test substance to the rabbit. The method followed was that described in OECD Guideline for Testing of Chemicals No. 404 “Acute Dermal Irritation/Corrosion”. Adopted: 12 May 1981.

Three rabbits were each administered a single dermal dose of 0.5 g of the test substance and observed for 14 days.

A single semi-occlusive application of the test substance to intact rabbit skin for four hours elicited severe dermal reactions with necrosis.

 

The mean erythema and edema scores at the time point of 24, 48 and 72 hours were as following for the three animals:

 

Erythema score: 3.33, 3, 1.67

Edema score: 2, 2, 2.33

 

All reactions persisted at day 14. Based on these results the test substance is determined to be corrosive to the skin of rabbits

 

Supporting study

BASF SE, study no. 78/176, 1980 (a)

 

Read-across approach to structural analogue substance 3-Chloro-4-fluoroaniline (CAS 367-21-5) was used.

In the neither guideline nor GLP compliant skin irritation study, an 80 % aqueous test solution was applied to the rabbit to the intact and scarified skin.The rabbits were observed over a period time of 8 days. Observations of erythema and edema scores were recorded after 24 and 72 hours.

The mean erythema and edema scores at the time point of 24 and 72 hours were as following for the three animals:

 

Erythema score: 4, 4, 2

Edema score: 2, 2, 1.5

 

The effects were not reversible after 8 days. Leather like necrosis was observed at two animals.

The results revealed that the test substance is corrosive to the skin.

 

Supporting study

BASF SE, study no. 78/176, 1980 (b)

 

Read-across approach to structural analogue substance 3-Chloro-4-fluoroaniline (CAS 367-21-5) was used.

In the neither guideline nor GLP compliant skin irritation study, an 80 % aqueous test solution was applied to the rabbit. The rabbits were observed over a period time of 8 days. Observations of erythema and edema scores were recorded after 24 and 48 hours. At the exposure time of 1 hour 4 animals were used.

At the exposure time of 4 hours only 2 animals were used.

The mean erythema score at 24 and 48 hours was for animal no. 1 and 2 as following: 3 and 2.

The mean edema score at 24 and 48 hours was for animal no.1 and 2 as following: 2.5 and 2.

At the end of the observation period of 8 days the erythema was fully reversible but necrosis was still observed, the edema was not reversible within 8 days.

Based on these results the test substance is determined to be corrosive to the skin of rabbits

 

 

Eye irritation test

Key study

BASF SE, substance no.78/176, 1980

 

Read-across approach to structural analogue substance 3-Chloro-4-fluoroaniline (CAS 367-21-5) was used.

In the neither guideline nor GLP compliant eye irritation study 82 mg of the test substance was applied to the eye of three rabbits. Effects like cornea opacity, iris, conjunctivae redness and chemosis were reported at 24, 48 and 72 hours. The mean cornea score opacity was >= 1 at all animals.

The mean iris score was 1 at 2 animals. The mean conjunctivae score redness was 2 at all animals. The mean chemosis score was 2 at 2 animals.

Based on these results it can be stated that the test substance causes severe non reversible damage to the eye.

 

 

Literature data with the test substance

 

In Gilleron et a. (1997) a Hen’s Egg Test-Chorioallantoic Membrane Test Substance Applicator (HET-CAM TSA) with the test substance was reported.

Based in the overall irritation score of 15.49, the test substance was determined to be an irritant.

 

In a EpiOcular-EIT PM test cited in Kaluzhny et al. (2011), the mean tissue viability was determined to be 6.28.

Based on this result the test substance was determined to be irritating.

 

In the ECETOC technical report no. 48 (2), (1998), an in vivo test with 6 rabbits was conducted similar to OECD 405.

 

The mean scores of 6 animals at the time point of 24, 48 and 72 hours were as following:

Cornea score (opacity): 1.6

Iris score: 0.6

Conjunctivae score (redness): 2.7

Chemosis score: 2.2

 

As the animals were observed only 3 days and no information about reversibility is given it cannot be clearly defined if the test item is irritating or corrosive.

 

In Verstraelen et al. (2013) in a Bovine Corneal Opacity and Permeability (BCOP) in vitro test, the test item was classified as category 1 irritating based on laser light-based opacitometer (LLBO) measurements.

Justification for selection of skin irritation / corrosion endpoint:
GLP and guideline compliant study. The test substance was a structural analogue substance, please refer to IUCLID section 13 for read across justification.

Justification for selection of eye irritation endpoint:
Neither guideline nor GLP compliant study but nevertheless well documented and scientifically acceptable. The test substance was a structural analogue substance.

Effects on skin irritation/corrosion: corrosive

Effects on eye irritation: corrosive

Justification for classification or non-classification

Skin irritation

Dangerous Substance Directive (67/548/EEC)
The available study is considered reliable and suitable for classification purposes under Directive 67/548/EEC. As a result the substance is considered to be classified for skin corrosive C; R34: Causes burns 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 considered to be classified for skin corr. 1C, H314: Causes severe skin burns and eye damage under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation (EC) No 605/2014.

Eye irritation

Dangerous Substance Directive (67/548/EEC)
The available study is considered reliable and suitable for classification purposes under Directive 67/548/EEC. As a result the substance is considered to be classified for eye damage Xi; R41: Risk of serious damage to eyes 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 considered to be classified for eye damage cat. 1, H318: Causes serious eye damage under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation (EC) No 605/2014.