Registration Dossier

Administrative data

Description of key information

The available information indicate that the main constituent of Basic Orange 064 is expected to not possess any skin/eye irritating potential. However, the main substance's impurity can, in the worst case, determine a classification as Skin Irrit. 2 (H315) and Eye Dam 1 (H318).

Based on the content and/or their characteristics, the remaining impurities have no impact  to the classification of the Basic Orange 064.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
From 25th to 28th February, 1988
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Justification for type of information:
The test substance is the acid form of the substance under registration; justification for Read Across is detailed in the IUCLID section 13.
Reason / purpose:
read-across source
Related information:
Composition 1
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
1981
GLP compliance:
yes
Test material information:
Composition 1
Specific details on test material used for the study:
For the purpose of the study the test material was ground to a fine powder using a mortar and pestle.
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: David Percival Ltd., Moston, Sandbach, Cheshire, U.K.
- Age at study initiation: at the start of the study the animals were approximately twelve to sixteen weeks old.
- Weight at study initiation: at the start of the study the animals weighed 2.64 - 2.78 kg.
- Housing: individually housed in suspended metal cages.
- Diet: Rabbit Diet, Preston Farmers Limited, New Leake, Boston, Lincolnshire, U.K., ad libitum.
- Water: drinking water, ad libitum.
- Acclimation period: minimum acclimatisation period of five days.

ENVIRONMENTAL CONDITIONS
- Temperature: 15 - 19 °C
- Humidity: 40 - 60 %
- Air changes: approximately 15 changes per hour.
- Photoperiod: the lighting was controlled by a time switch to give 12 hours light and 12 hours darkness.
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
water
Controls:
yes, concurrent no treatment
Amount / concentration applied:
A quantity of 0.5 g of the test material moistened with 0.5 ml of distilled water.
Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
Three rabbits
Details on study design:
TEST SITE
- Area of exposure: approximately twenty-four hours prior to the commencement of the test, each rabbit was prepared by closely clipping the fur from the dorsal/flank areas using veterinary clippers. Only animals with a healthy intact epidermis by gross observation were selected for the study. Test material was introduced under a 2.5 cm x 2.5 cm gauze patch and placed in position on the shorn skin.
- Type of wrap if used: the patch was secured in position over the test material with a strip of surgical adhesive tape (BLENDERM: approximate size 2.5 cm x 4.0 cm). To prevent the animals from interfering with the patches the trunk of each rabbit was wrapped in an elasticated corset (TUBIGRIP).

REMOVAL OF TEST SUBSTANCE
- Washing: any residual test material was removed by gentle swabbing with cotton wool soaked in distilled water followed by diethyl ether.
- Time after start of exposure: 4 hours.

OBSERVATION TIME POINTS
Approximately one hour following removal of the patches, and 24, 48 and 72 hours later, the test sites were examined.

SCORING SYSTEM:
For evidence of primary irritation and scored according to the following scale i.e. 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".

Evaluation of skin reactions
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) 4

Oedema Formation
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-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: 3/3
Time point:
24/48/72 h
Score:
< 2.3
Irritation parameter:
edema score
Basis:
animal: 3/3
Time point:
24/48/72 h
Score:
< 2.3
Irritant / corrosive response data:
No erythema or oedema was noted at the 72-hour observation and the study was terminated.
No adverse dermal reactions were noted one hour after removal of the patches.
Very silght erythema was confined to one treatment site at the 24 and 48-hour observations. No adverse skin reactions were noted at the other two treatment sites during the study period.
Desquamation was noted at one treatment site at the 72-hour observation.

Individual daily and individual mean scores

Skin reaction Reading (hour) Individual scores - rabbit N.
18 21 26
Ertythem/eschar 1 0 0 0
Ertythem/eschar 24 0 1 0
Ertythem/eschar 48 0 1 0
Ertythem/eschar 72 0 0D 0
Mean 24, 48 and 72 hrs 0.0 0.7 0.0
Oedema 1 0 0 0
Oedema 24 0 0 0
Oedema 48 0 0 0
Oedema 72 0 0 0
Mean 24, 48 and 72 hrs 0.0 0.0 0.0

D: desquamation

Interpretation of results:
other: not classified, according to the CLP Ragulation (EC) No 1272/2008
Conclusions:
Not classified, according to the CLP Regulation (EC) No 1272/2008.
Executive summary:

A study was performed to assess the irritation of the test material to the skin of the New Zealand White rabbit. The method followed OECD Guidelines 404. A single 4 -hour semi-occluded application (0.5 g of the test material moistened with 0.5 ml of distilled water) was administered to the intact skin of three rabbits. Skin reactions were recorded 1, 24, 48 and 72 hours after administration.

No erythema or oedema was noted at the 72-hour observation and the study was terminated. No adverse dermal reactions were noted one hour after removal of the patches. Very silght erythema was confined to one treatment site at the 24 and 48-hour observations. No adverse skin reactions were noted at the other two treatment sites during the study period. Desquamation was noted at one treatment site at the 72-hour observation.

Conclusion

Mean values from gradings at 24, 48 and 72 hours after patch removal were lower than 2.3 in all animals for both erythema/eschar and oedema reactions, thus the test item does not meet the criteria to be classified as irritating, according to the CLP Regulation (EC) No 1272/2008.

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:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
From 29th February to 4th March, 1988
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Justification for type of information:
The test substance is the acid form of the substance under registration; justification for Read Across is detailed in the IUCLID section 13.
Reason / purpose:
read-across source
Related information:
Composition 1
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
1981
GLP compliance:
yes
Test material information:
Composition 1
Specific details on test material used for the study:
For the purpose of the study the test material was ground to a fine powder using a mortar and pestle before use.
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: David Percival Ltd., Moston, Sandbach, Cheshire, U.K.
- Age at study initiation: at the start of the study the animals were approximately twelve to sixteen weeks old.
- Weight at study initiation: at the start of the study the animals weighed 2.72 - 2.96 kg.
- Housing: individually housed in suspended metal cages.
- Diet: Rabbit Diet, Preston Farmers Limited, New Leake, Boston, Lincolnshire, U.K., ad libitum.
- Water: drinking water, ad libitum.
- Acclimation period: minimum acclimatisation period of five days.

ENVIRONMENTAL CONDITIONS
- Temperature: 17 - 19 °C
- Humidity: 40 - 48 %
- Air changes: approximately 15 changes per hour.
- Photoperiod: the lighting was controlled by a time switch to give 12 hours light and 12 hours darkness.
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
A volume of 0.1 ml of the test material (as measured by gently compacting the required volume into an adapted syringe) which was found to weigh approximately 64 mg was placed into the right eye of each rabbit by gently pulling the lower lid away from the eyeball to form a cup into which the test material was dropped. The upper and lower eyelids were held together for about one second immediately after application, to prevent loss of the test material from the eye, and then released.
Observation period (in vivo):
72-hour
Number of animals or in vitro replicates:
Three rabbits
Details on study design:
Immediately before commencement of the test, both eyes of each rabbit provisionally selected, were examined for evidence of ocular irritation or defect using the light source from an ophthalmoscope. Animals showing evidence of ocular lesions were rejected and replaced.

TOOL USED TO ASSESS SCORE: examination of the eye was facilitated by use of the light source from standard ophthalmoscope (Keeler).

SCORING SYSTEM
Assessment of damage/irritation was made 1, 24, 48 and 72 hours following treatment, according to the numerical evaluation given (i.e. 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").

Grades of ocular lesions
CORNEA
Opacity: Degree of density (area most dense taken for reading).
No ulceration or opacity 0
Scattered or diffuse areas of opacity (other than slight dulling of normal lustre) details of iris clearly visible 1
Easily discernible translucent area, details of iris slightly obscured 2
Opalescent area, no details of iris visible, size of pupil barely discernible 3
Opaque cornea, iris not discernible through the opacity 4

IRIS
Normal 0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia, or injection, any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive) 1
No reaction to light, haemorrhage, gross destruction (any or all of these) 2

CONJUNCTIVAE
Redness: (refers to palpebral and bulbar conjunctivae excluding cornea and iris)
Blood vessels normal 0
Some blood vessels definitely hyperaemic (injected) 1
Diffuse, crimson colour, individual vessels not easily discernible 2
Diffuse beefy red 3

CHEMOSIS Value
Chemosis: Lids and/or nictitating membranes.
No swelling 0
Any swelling above normal (includes nictitating membranes) 1
Obvious swelling with partial eversion of lids 2
Swelling with lids about half closed 3
Swelling with lids more than half closed 4
Irritation parameter:
cornea opacity score
Basis:
animal: 3/3
Time point:
24/48/72 h
Score:
< 1
Irritation parameter:
iris score
Basis:
animal: 3/3
Time point:
24/48/72 h
Score:
< 1
Reversibility:
fully reversible within: 24 hours
Irritation parameter:
conjunctivae score
Basis:
animal: 3/3
Time point:
24/48/72 h
Score:
< 2
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
animal: 3/3
Time point:
24/48/72 h
Score:
< 2
Reversibility:
fully reversible within: 48 hours
Irritant / corrosive response data:
No ocular irritation was noted at the 72-hour observation and the study was terminated.

A dulling of the normal lustre of the corneal surface and iridial inflammation were noted in all treated eyes one hour after treatment. No adverse corneal or
iridial effects were noted at subsequent observations.
Moderate conjunctival irritation was also noted in all treated eyes one hour after instillation. The conjunctival irritation regressed and all treated eyes appeared normal at the 48-hour observation.

Individual and mean scores for cornea, iris and conjuncivae.

Rabbit Time after treatment (h) Corneal opacity Iridial inflammation Conjunctival redness Conjunctival chemosis
80 1 D 1 2 2
24 0 0 1 0
48 0 0 0 0
72 0 0 0 0

Mean 24, 48 and 72 hrs

0.0 0.0 0.3 0.0
41 1 D 1 2 2
24 0 0 1 1
48 0 0 0 0
72 0 0 0 0

Mean 24, 48 and 72 hrs

0.0 0.0 0.3 0.3
34 1 D 1 2 2
24 0 0 1 1
48 0 0 0 0
72 0 0 0 0

Mean 24, 48 and 72 hrs

0.0 0.0 0.3 0.3

D: dulling of corneal surface

Interpretation of results:
other: not classified, according to the CLP Ragulation (EC) No 1272/2008
Conclusions:
Not classified, according to the CLP Ragulation (EC) No 1272/2008
Executive summary:

A study was performed to assess the irritation of the test material to the eye of the New Zealand White rabbit. The method followed OECD Guidelines No. 405. A volume of 0.1 ml of the test material was placed into the right eye of each rabbit. The upper and lower eyelids were held together for about one second immediately after application, to prevent loss of the test material from the eye, and then released. Assessment of damage/irritation was made 1, 24, 48 and 72 hours following treatment. No ocular irritation was noted at the 72-hour observation and the study was terminated. A dulling of the normal lustre of the corneal surface and iridial inflammation were noted in all treated eyes one hour after treatment. No adverse corneal or iridial effects were noted at subsequent observations. Moderate conjunctival irritation was also noted in all treated eyes one hour after instillation. The conjunctival irritation regressed and all treated eyes appeared normal at the 48-hour observation.

Conclusion

The mean values from gradings at 24, 48 and 72 hours were lower than 1 for corneal opacity, lower than 1 for iritis, lower than 2 for both conjunctival redness and oedema, in all the three tested animals.

Therefore, the substance does not meet the criteria to be classified as eye irritating, according to the CLP Regulation (EC) No 1272/2008.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

SKIN IRRITATION

There are no information about the skin irritation potentialof Basic Orange 064, thus the available information on the structural analogues Similar Substance 01 and Similar Substance 02 have been taken into consideration. Similar Substance 01 is the acid form of Basic Orange 064; the read across approach can be considered as appropriate and suitable to assess the property under investigation (details about the approach are reported into the IUCLID section 13).

A study was performed to assess the irritation of Similar Substance 01 to the skin of the New Zealand White rabbit. The method followed OECD Guidelines 404. No erythema or oedema was noted at the 72-hour observation and the study was terminated. No adverse dermal reactions were noted one hour after removal of the patches. Very silght erythema was confined to one treatment site at the 24 and 48-hour observations. No adverse skin reactions were noted at the other two treatment sites during the study period. Desquamation was noted at one treatment site at the 72-hour observation.

The mean values from gradings at 24, 48 and 72 hours after patch removal were lower than 2.3 in all animals for both erythema/eschar and oedema reactions, thus the test item does not meet the criteria to be classified as irritating, according to the CLP Regulation (EC) No 1272/2008.

In addition, a study on the irritancy potential of the Similar Substance 02 to the skin of rabbits is also available. The method used followed that described in the OECD Guidelines No. 404. Under the conditions of the experiment, the substance was found to cause a primary irritation score of 0, when applied to intact skin. In the area of application, a clearly visible brown-orange discolouration of the skin was observed which could be related to effects proper to the test article. No corrosive effect had occurred on the skin at any measuring interval.

EYE IRRITATION

There are no information about the eye irritation potentialof Basic Orange 064, thus the available information on the structural analogues Similar Substance 01 and Similar Substance 02 have been taken into consideration. Similar Substance 01 is the acid form of Basic Orange 064; the read across approach can be considered as appropriate and suitable to assess the property under investigation (details about the approach are reported into the IUCLID section 13).

A study was performed to assess the irritation of the Similar Substance 01 to the eye of the New Zealand White rabbit. The method followed OECD Guidelines No. 405. No ocular irritation was noted at the 72-hour observation and the study was terminated. A dulling of the normal lustre of the corneal surface and iridial inflammation were noted in all treated eyes one hour after treatment. No adverse corneal or iridial effects were noted at subsequent observations. Moderate conjunctival irritation was also noted in all treated eyes one hour after instillation. The conjunctival irritation regressed and all treated eyes appeared normal at the 48-hour observation.

The mean values from gradings at 24, 48 and 72 hours were lower than 1 for corneal opacity, lower than 1 for iritis, lower than 2 for both conjunctival redness and oedema, in all the three tested animals. Therefore, the substance does not meet the criteria to be classified as eye irritating, according to the CLP Regulation (EC) No 1272/2008.

In addition, a study was performed to assess the irritancy potential of Similar Substance 02 to rabbit’s eyes. The method used followed that described in the OECD Guidelines N.405. Test item showed a primary irritation score of 0.3 when applied to the rabbit eye mucosa. In the area of application a slight yellow discolouration of the cornea and conjunctivae was observed which could be related to the color proper to the test article. No corrosion of the cornea was observed at any of the measuring intervals.

DISCUSSION AND CONCLUSION

The available information indicate that the main constituent of Basic Orange 064 is expected to not possess any skin/eye irritating potential; this conclusion is supported by data on both the acid form and data on the analogous Similar Substance 02, which is salificated with lactic acid, as well as Basic Orange 064.

However, the composition of the Basic Orange 064 lots currently manufactured have more lactic acid, in addition to that involved into the salification of the base, since the substance is produced directly in a highly concentrated lactic acid solution. The final free lactic acid content can range from 0 to 25 % (w/w).

The lactic acid has been already registered under REACH Regulation and the classification proposed in the following: Skin irrit 2 (H315); Eye Dam 1 (H318). Specific concentration limits are: Skin Irrit. 2 conc. ≥ 10 %; Eye Dam 1 conc ≥ 3 %; Eye Irrit 2 conc. ≥ 1 - 3 %.

Therefore, the contribute of lactic acid to the classification of the substance should be taken into consideration. On the basis of the worst-case approach (i.e. maximum lactic acid content of 25 %), the Basic Orange 064 should be classified as skin irritating (Skin Irrit. 2, H315) and as able to cause serious eye damage (Eye Dam 1, H318).

Based on the content and/or their characteristics, the remaining impurities have no impact  to the classification of the Basic Orange 064.

Justification for classification or non-classification

According to the CLP Regulation (EC) No 1272/2008, 3.2 Skin corrosion/irritation section, skin irritation means the production of reversible damage to the skin following the application of a test substance for up to 4 hours.

On the basis of the available information, the main constituent is expected to not possess any skin irritating potential. However, the possible main substance's impurity lactic acid can, in the worst case, determine a classification as Skin Irrit. 2 (H315). Based on the content and/or their characteristics, the remaining impurities have no impact  to the classification of the Basic Orange 064.

According to the CLP Regulation (EC) No 1272/2008, serious eye damage means the production of tissue damage in the eye, or serious physical decay of vision, following application of a test substance, which is not fully reversible within 21 days of application.

On the basis of the available information, the main constituent is expected to not possess any eye irritating potential. However, the possible main substance's impurity lactic acid can, in the worst case, determine a classification as Eye Dam 1 (H318). Based on the content and/or their characteristics, the remaining impurities have no impact  to the classification of the Basic Orange 064.

In conclusion, on the basis of the worst-case approach, a classification as skin irritating (i.e. Skin Irrit. 2, H315) and as able to cause serious eye damage (i.e. Eye Dam 1, H318) is proposed, according to the CLP Regulation (EC) No 1272 /2008.