Registration Dossier

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Diss Factsheets

Administrative data

Description of key information

Skin irritation / corrosion
- OECD 404
- No sign of dermal irritation was found
- Result: not irritating to the skin
Eye irritation
- OECD 405
- All effects found were fully reversible within 72hrs
- Result: not irritating to the eye

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:
1986-12-17 to Feb 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
not specified
GLP compliance:
yes
Remarks:
GLP declaration included in full study report.
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
- Source: Nottingham University, School of Agriculture, Sutton Bonington, Leicestershire, UK
- Weight at start of study: 2.36 - 2.48 kg
- Age at start of study: 12 - 16 weeks
- Identification: Ear mark and cage label
- Acclimatisation: min 5 days
- Housing: individually in suspended metal cases
- Diet: Rabbit Diet, Preston Farmers Ltd, New Leake, Boston, Lincolnshire, UK, ad libitum
- Water: drinking water, ad libitum
- Room temperature: 17 - 21°C
- Relative humidity: 45 - 50 %
- Air exchange rate: approx. 15 per hour
- Lighting: 12 hours light / 12 hours darkness
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
- 0.5 g of the test material moistend with 0.5 ml of distilled water.
Duration of treatment / exposure:
4 hours
Observation period:
One hour, 24, 48 and 72 hours after removal of the patch.
Number of animals:
3
Details on study design:
- Area of exposure: 2.5 x 2.5 cm
- Type of patch: gauze patch

- Removal of residual test material four hours after application.
- Removal of residual test material by gentle swabbing with cotton wool soaked in distilled water.

SCORING SYSTEM:
According to Draize J.H. (1959) Association of Food and Drug Officials of the United States, Austin, TX, "The Appraisal of the Safety of Chemicals in Food, Drugs and Cosmetics".
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
48 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
48 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
48 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #1
Time point:
48 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #1
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #2
Time point:
48 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #2
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #3
Time point:
48 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritation parameter:
edema score
Basis:
animal #3
Time point:
72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible
Irritant / corrosive response data:
No data
Other effects:
No data
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test material, CA 794, was found to be a non-irritant to rabbit skin according to the EEC labelling regulations and requires no symbol or risk phrase.
Executive summary:

Summary

The potential for skin irritation/corrosion of the test substance was investigated by applying the test substance to the skin of 3 New Zealad White rabbits.

No evidence of skin irritation was noted during the study period.

The test material, CA 794, was found to be a non-irritant to rabbit skin according to the EEC labelling regulations and requires no symbol or risk phrase.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

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:
1986-12-30 to Feb 1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
not specified
GLP compliance:
yes
Remarks:
GLP declaration attached to full study report.
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
- Source: Nottingham University, School of Agriculture, Sutton Bonington, Leichestershire, UK and David Percival, Moston, Sandbach, Cheshire, UK
- Weight at start of study: 2.86 - 3.25 kg
- Age at start of study: 12 - 16 weeks
- Acclimatisation: min 5 days
- Identification: Ear mark and cage label
- Housing: Suspended metal cages
- Diet: Rabbit Diet, Preston Farmers Ltd., New Leake, Boston, Lincolnshire, UK, ad libitum
- Water: drinking water, ad libitum
- Room temperature: 17 - 18°C
- Relative humidity: 45 - 50 %
- Air exchange rate: 15 per hour
- Lighting: 12 hours light, 12 hours darkness
Vehicle:
unchanged (no vehicle)
Controls:
other: yes: Untreated eye was used as control.
Amount / concentration applied:
- A volume of 0.1 ml of the test material which was found to weigh 86.6 mg
Duration of treatment / exposure:
acc. to guideline.
Observation period (in vivo):
1 hour, 24, 48 and 72 hours following treatment.
Number of animals or in vitro replicates:
3
Details on study design:
SCORING SYSTEM:
Scoring according to Draize J.H., 1959 Association of Food and Drug Officials of the United States, Austin, Texas, "The Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics".
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.7
Max. score:
2
Reversibility:
fully reversible within: 72 hrs
Remarks on result:
other: Max. score @ 1hr
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.3
Max. score:
2
Reversibility:
fully reversible within: 72 hrs
Remarks on result:
other: Max. score @ 1hr
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.3
Max. score:
2
Reversibility:
fully reversible within: 72 hrs
Remarks on result:
other: Max. score @ 1hr
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Irritant / corrosive response data:
Iridial inflammation was confined to two treated eyes one hour after treatment. No iridal effects were noted at subsequent observations.
Conjunctival irritation was noted in all treated eyes one hour after treatment and at the 24 hour observation, but was confined to minimal conjunctival redness in one treated eye at the 48-hour observation. All treated eyes were normal at the 72-hour observations.

Individual and mean scores for Cornea, Iris & Conjunctivae

Rabbit number

Time after treatment

[h]

Cornea opacity

Iridial effects

Conjunctival redness

Conjunctival chemosis

124

1

0

0

2

1

24

0

0

1

0

48

0

0

1

0

72

0

0

0

0

TOTAL 24, 48 & 72 hrs

0

0

2

0

Mean *

0.0

0.0

0.7

0

137

1

0

1

2

1

24

0

0

1

0

48

0

0

0

0

72

0

0

0

0

TOTAL 24, 48 & 72 hrs

0

0

1

0

Mean *

0.0

0.0

0.3

0.0

135

1

0

1

2

1

24

0

0

1

0

48

0

0

0

0

72

0

0

0

0

TOTAL 24, 48 & 72 hrs

0

0

1

0

Mean *

0.0

0.0

0.3

0.0

(*) Individual mean of 24, 48 and 72-hour readings

 

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test material was found to be non-irritant to the rabbit eye according to EEC labelling regulations and requires no symbol or risk phrase.
Executive summary:

Summary

The potential for eye irritation/corrosion of the test substance was investigated by applying the test substance to the eyes of 3 New Zealad White rabbits.

No evidence of eye irritation was noted during the study period.

The test material was found to be a non-irritant to the rabbit eye according to the EEC labelling regulations and requires no symbol or risk phrase.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation / corrosion

Two studies on skin irritation were considered for the present registration dossier (see IUCLID 5). One of these studies was conducted according to GLP and to previous OECD guidelines, while the other study was conducted to a standard protocol (similar to OECD 404) before implementation of GLP and development of OECD guidelines. Although the OECD study is regarded as key study it is missing some information on the purity of the test item.Since starting material for a synthesis of phenothiazine is diphenylamine, diphenylamine can be regarded as the most relevant impurity. Following the summary and conclusion drawn from the European Union Risk Assessment Report on diphenylamine (final version approved on 2008 -05 -29), data on skin irritancy indicates no to very slight effects to rabbit skin. The non-irritant results of the present phenothiazine study could theoretically be due to dilution of the test item phenothiazine with its precursor substance diphenylamine as main impurity. However, this is regarded as unlikely, due to the nature of the test material e.g. as a precursor of medicinal substances, where usually high purities are demanded. Potential dilution should therefore not be an issue. In conclusion the results of the present study are regarded as reliable, not indicating irritant effects to skin due to exposure to the test item phenothiazine. In addition, no irritant effects to the skin were found in the pre-OECD study, where the purity of phenothiazine used for testing (99.80 %) is given.

Eye irritation

Two studies on eye irritation were considered for the present registration dossier (see IUCLID 5). One of these studies was conducted according to GLP and to previous OECD guidelines, while the other study was conducted to a standard protocol (similar to OECD 405) before implementation of GLP and development of OECD guidelines. Although the OECD study is regarded as key study it is missing some information on the purity of the test item.Since starting material for a synthesis of phenothiazine is diphenylamine, diphenylamine can be regarded as the most relevant impurity. Following the summary and conclusion drawn from the European Union Risk Assessment Report on diphenylamine (final version approved on 2008 -05 -29), data on eye irritation is conflicting, but indicates severe eye damage due to diphenylamine treatment. However, the present OECD study using phenothiazine as test item clearly resulted in a non-irritant result (i.e. some effects were found, all of them reversible within 72hrs and not leading to classification either according to 67/548/EEC or 1278/2008/EC). Therefore, even if diphenylamine was theoretically present as an impurity it did not exhibit any irritating effect. In addition, no irritant effects to the eye were found in the pre-OECD study, where the purity of phenothiazine used for testing (99.80 %) is given.

Justification for classification or non-classification

Based on the studies on skin irritation and the studies on eye irritation no classification is necessary either according to 67/548/EEC or 1272/2008/EC.