Registration Dossier

Administrative data

Description of key information

The test substance was assessed for skin irritation in albino rabbits.  There were some signs of erythema and edema but  the test susbtance is not classified for skin irritation.
The test substance was assessed for eye irritation in New Zealand White albino rabbits. There were some signs of irritation but the test substance is not classified for eye irritation.

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:
The study was conducted in 1980.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards with acceptable restrictions.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
not specified
Principles of method if other than guideline:
Primary irritation to the skin is measured by a patch-test technique on the abraded and intact skin of albino rabbits.
GLP compliance:
no
Remarks:
The study pre-dates GLP.
Species:
rabbit
Strain:
New Zealand White
Type of coverage:
occlusive
Preparation of test site:
other: Intact and abraded skin
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.5 mL
Duration of treatment / exposure:
24 hours
Observation period:
72 hours
Number of animals:
12 rabbits
Details on study design:
Protocol for Primary skin irritation test
Primary irritation to the skin is measured by a patch-test technique on the abraded and intact skin of albino rabbits.
Twelve healthy adult New Zealand White albino rabbits are used for 1 - 4 test substances. Twenty four hours prior to applying the materials, the hair is removed from the backs of the animals with an electric clipper in such a way as to avoid abrasions.
An amount of 0.5 ml (in case of liquids) or 0.5 g (in case of solids or semi-solids) of the test substance is brought on the intact or abraded skin under a surgical patch measuring l inch x 1 inch. The patches are fixed to the application site by means of adhesive tape and the entire trunk of the rabbits is wrapped with an impervious material to maintain the test patches in position and to retard evaporation of volatile substances.
Six rabbits are treated on the intact skin, the other six on the abraded skin. The abrasions are minor incisions through the stratum corneum, but not sufficiently deep to disturb the derma or to produce bleeding. After an exposure period of 24 hours the patches and the material applied are removed and the resulting skin reactions are evaluated by the method of Draize (J. Pharmacol. 82 (1944) 377 - 390). A second reading is made 48 hours later (72 hours after application).
In the case of surface active test substances the skin reactions after 72 hours usually consist of scaliness and or necrosis. Since the Draize grading system does not comprise these abnormalities the second reading is carried out on the basis of the CIVO grading system.

Evaluation of skin reactions (Draize) Value
A. 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
B. Edema formation
No edema 0
Very slight edema (barely perceptible) 1
Slight edema (edges of area well defined by definite raising) 2

Moderate edema (raised approximately 1 millimeter) 3
Severe edema (raised more than 1 millimeter and extending beyond the area of exposure) 4
Total possible score for primary irritation: 8 (4 + 4)

Evaluation of skin reactions (CIVO) Value
No reaction at all 0
Very slight scaliness 1
Distinct scaliness or very slight incrustation 2
Distinct incrustation 3
Severe incrustation 4
Irritation parameter:
erythema score
Basis:
mean
Time point:
24 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: Intact skin
Irritation parameter:
erythema score
Basis:
animal: 8416
Time point:
24 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: Intact skin
Irritation parameter:
erythema score
Basis:
animal: 8417
Time point:
24 h
Score:
0
Max. score:
4
Remarks on result:
other: Intact skin
Irritation parameter:
erythema score
Basis:
animal: 8418
Time point:
24 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: Intact skin
Irritation parameter:
erythema score
Basis:
animal: 8419
Time point:
24 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: Intact skin
Irritation parameter:
erythema score
Basis:
animal: 8420
Time point:
24 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: Intact skin
Irritation parameter:
erythema score
Basis:
animal: 8421
Time point:
24 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: Intact skin
Irritation parameter:
edema score
Basis:
mean
Time point:
24 h
Score:
0.16
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: Intact skin
Irritation parameter:
edema score
Basis:
animal: 8416
Time point:
24 h
Score:
0
Max. score:
4
Remarks on result:
other: Intact skin
Irritation parameter:
edema score
Basis:
animal: 8417
Time point:
24 h
Score:
0
Max. score:
4
Remarks on result:
other: Intact skin
Irritation parameter:
edema score
Basis:
animal: 8418
Time point:
24 h
Score:
0
Max. score:
4
Remarks on result:
other: Intact skin
Irritation parameter:
edema score
Basis:
animal: 8419
Time point:
24 h
Score:
0
Max. score:
4
Remarks on result:
other: Intact skin
Irritation parameter:
edema score
Basis:
animal: 8420
Time point:
24 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: Intact skin
Irritation parameter:
edema score
Basis:
animal: 8421
Time point:
24 h
Score:
0
Max. score:
4
Remarks on result:
other: Intact skin
Irritation parameter:
other: Evaluation of Skin Reaction - CIVO
Basis:
mean
Time point:
72 h
Score:
1.33
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: Intact skin
Irritation parameter:
erythema score
Basis:
mean
Time point:
24 h
Score:
1.6
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: Abraded skin. One animal died during the test.
Irritation parameter:
edema score
Basis:
mean
Time point:
24 h
Score:
0.2
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: Abraded skin. One animal died during the test.
Irritation parameter:
other: Evaluation of Skin Reaction - CIVO
Basis:
mean
Time point:
72 h
Score:
1.4
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: Abraded skin. One animal died during the test.
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
1.25
Max. score:
4
Reversibility:
not specified
Remarks on result:
other: score based on 24h and 72h skin observation (not measured at 48h)
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
1.25
Max. score:
4
Reversibility:
not specified
Remarks on result:
other: Score based on skin observation at 24h and 72h (not measured at 48h)
Irritant / corrosive response data:
The skin reactions observed after 24 hours consisted of very slight erythema or well—defined erythema together with very slight edema.
The skin reactions observed after 72 hours consisted of slight to distinct scaliness.
There were no distinct differences between the skin reactions of the intact skin and those of the abraded skin.
From the results of the primary skin irritation test it is concluded that Herboxane is a slight primary skin irritant.

One rabbit died during the exposure period probably because of amechanical trauma.

The individual and average skin irritation scores are presented inthe table below:

Rabbit

Number

Intact Skin

Rabbit

Number

Abraded Skin

24 hr

72 hr

24 hr

72 hr

a

b

a

b

8416

1

0

2

8410

1

0

2

8417

0

0

0

8411

*

*

*

8418

1

0

1

8412

4

1

1

8419

1

0

2

8413

1

0

2

8420

2

1

2

8414

1

0

0

8421

1

0

1

8415

1

0

2

average

1.2

1.3

1.4

1.4

 

Where: A=erythema, B=edema, *=dead

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
It was concluded that Herboxane is a slight primary skin irritant
Executive summary:

The product Herboxane was examined for primary skin irritating properties and acute dermal toxicity in experiments with albino rabbits.

It was concluded that Herboxane is a slight primary skin irritant.

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:
The study was conducted in July 1981.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards with acceptable restrictions.
Qualifier:
equivalent or similar to guideline
Guideline:
other: FDA of the United. States (Fed. Reg. 28 (119), 5582, 1963)
Deviations:
not specified
Qualifier:
equivalent or similar to guideline
Guideline:
other: Draize and Kelley (Drug Cosmet. Industr. 71 (1952) 36)
Deviations:
not specified
GLP compliance:
no
Remarks:
Study pre-dates GLP.
Species:
rabbit
Strain:
New Zealand White
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
100%
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
6 animals
Details on study design:
Protocol for eye irritation test
In general the techniques of tests as published by the FDA of the United. States (Fed. Reg. 28 (119), 5582, 1963) and. Draize and Kelley (Drug Cosmet. Industr. 71 (1952) 36) are followed.
Six New Zealand White albino rabbits are used for each test substance.
The animals are caged individually and receive no hay or other extraneous material that might enter the eyes.
The eyes of the animals are examined before testing and only those animals without observable eye defects are used. One tenth of a millilitre of the test substance, or in the case of solids or semisolids, 100 milligrams of the test substance, is allowed to tell everted lower lid. of one eye of each rabbit; the War and lower eye lid are then carefully closed and subsequently held together for at least one second before releasing, to prevent loss of material. The other eye, remaining untreated, serves as a control.
The eyes are not washed following instillation and the animals are released immediately.
The eyes are examined at 2%, 1&8, 72 hours and 7 days after instillation of the test material.
An animal is considered as giving a positive reaction if there is, at any of the readings, discernible opacity of the cornea (other than a slight dulling of the normal lustre), or ulceration of the cornea, or inflammation of the iris (other than a. slight deepening of the folds (rugse) or a. slight circumcorneal injection), or if such substance produces in the conjunctivae (palpebrel and bulbar, excluding the cornea and iris) an obvious swelling with partial eversion of the lids, or a diffuse deep-crimson red with individual vessels not easily discernible. The FDA-scoring scale was used.
The test is considered positive it four or more of the animals in the test group of six rabbits exhibit a positive reaction. If one animal exhibits a positive reaction, the test is regarded as negative.
If two or three animals exhibit 9, positive reaction, the test is re- pea-ted, using a different group of six animals. The second test is considered as positive if three or more of the animals exhibit a positive reaction. If only one or two animals in the second test exhibit a positive reaction, the test is again repeated with a different group of six animals. Should a third test he needed, the substance will be regarded as an irritant if two or more animals exhibit a positive response.
A substance which has elicited corneal and/or iris lesions which have not cleared by the seventh day reading, is considered a severe eye irritant.

Grades for ocular lesions:
Cornea.
No ulceration or opacity = 0
Scattered or diffuse areas of opacity (other than slight dulling of normal luster), details of iris clearly visible = (1)'
Easily discernible translucent areas, details of iris slightly obscured = 2
Nacreous areas, no details of iris visible, size of pupil barely discernible = 3
Complete corneal opacity, iris not discernible = 4

Iris
Normal = 0
Markedly deepened folds, congestion, swelling, moderate circumcorneal 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)
Vessels normal = 0
Some vessels definitely injected = 1
Diffuse, crimson red, individual vessels not easily discernible = (2)*
Diffuse beefy red = 3
-Chemosis
No swelling = 0
Any swelling above normal (includes nictitating membrane) 1
Obvious swelling with partial eversion of lids (2)*
Swelling with lids about half closed = 3
Swelling with lids more than half closed = 4
(*Bracket figures indicate lowest grades considered positive.)
Irritation parameter:
conjunctivae score
Remarks:
Animal 1
Basis:
mean
Time point:
24/48/72 h
Score:
1.33
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Based on conjunctival redness
Irritation parameter:
conjunctivae score
Remarks:
Animal 2
Basis:
mean
Time point:
24/48/72 h
Score:
1.33
Max. score:
3
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Based on conjunctival redness
Irritation parameter:
conjunctivae score
Remarks:
Animal 3
Basis:
mean
Time point:
24/48/72 h
Score:
1.33
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Based on conjunctival redness
Irritation parameter:
conjunctivae score
Remarks:
Animal 4
Basis:
mean
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Based on conjunctival redness
Irritation parameter:
conjunctivae score
Remarks:
Animal 5
Basis:
mean
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Remarks on result:
other: Based on conjunctival redness
Irritation parameter:
conjunctivae score
Remarks:
Animal 6
Basis:
mean
Time point:
24/48/72 h
Score:
1.66
Max. score:
3
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Based on conjunctival redness
Irritation parameter:
chemosis score
Remarks:
Animal 1
Basis:
mean
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Remarks:
Animal 2
Basis:
mean
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Remarks:
Animal 3
Basis:
mean
Time point:
24/48/72 h
Score:
0.66
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Remarks:
Animal 4
Basis:
mean
Time point:
24/48/72 h
Score:
1.66
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Remarks:
Animal 5
Basis:
mean
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #5
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #6
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #5
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #6
Time point:
24/48/72 h
Score:
0
Max. score:
2

Herboxane caused slight conjunctivitis in 2/6 rabbits and moderate conjunctivitis in 4/6 rabbits. Two animals (no. 3 and 4) showed slight discharge of eye fluid. At the end of the seven—day observation period four animals still showed slight redness of the conjunctivae.

Table Of Individual Scores Awarded To The Ocular Lesions Elicited By Herboxane

Rabbit Number

Score

Cornea

Iris

Conjunctivae

Redness

Chemosis

after 24 hours

1

0

0

2

1

2

0

0

1

0

3

0

0

2

1

4

0

0

2

2

5

0

0

1

1

6

0

0

2

1

after 48 hours

1

0

0

1

0

2

0

0

2

1

3

0

0

1

1

4

0

0

2

2

5

0

0

1

0

6

0

0

2

0

after 72 hours

1

0

0

1

0

2

0

0

1

0

3

0

0

1

0

4

0

0

2

1

5

0

0

1

0

6

0

0

1

0

after 7 days

1

0

0

1

0

2

0

0

0

0

3

0

0

1

0

4

0

0

1

0

5

0

0

1

0

6

0

0

0

0

 

On the basis of the present results it is concluded that according to the FDA-standards undiluted Herboxane is considered to be an eye irritant.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
On the basis of the present results it is concluded that according to the FDA-standards undiluted Herboxane is considered to be an eye irritant.
Executive summary:

The product Herboxane was examined an in-eye irritation test. New Zealand White albino rabbits were used as the experimental animals. According to the FDA-standards, undiluted Herboxane is considered to be an eye irritant.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The test substance was examined for primary skin irritatingproperties and acute dermal toxicity in experiments with albinorabbits. The skin reactions observed after 24 hours consisted of very slight erythema or well-defined erythema together with very slight edema. The skin reactions observed after 72 hours consisted of slight to distinct scaliness. There were no distinct differences between the skin reactions of the intact skin and those of the abraded skin.

 

Thetest substancewas examined for eye irritation in New Zealand White albino rabbits. There was slight conjunctivitis in 2/6 rabbits and moderate conjunctivitis in 4/6 rabbits. Two animals showed slight discharge of eye fluid. At the end of the seven-day observation period, four animals still showed slight redness of the conjunctivae.


Justification for selection of skin irritation / corrosion endpoint:
The study was conducted on the target substance in vivo and in an appropriate test species.

Justification for selection of eye irritation endpoint:
The study was conducted on the target substance in vivo and in an appropriate test species.

Justification for classification or non-classification

Skin irritation

Skin corrosion is defined as the production of irreversible damage to the skin following application of the test substance. Skin irritation is the production of reversible damage to the skin following application of the test substance. Substances can be allocated to one of two categories based on corrosive effects on the skin (Category 1) and irritation to the skin (Category 2) according to the Globally Harmonized Classification System and Regulation (EC) No. 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures.

A substance is classified in category 2 when a substance produces at least in 2 of 3 animals tested a positive response of:

  • a mean value of ≥ 2.4 ≤4.0 for erythema / eschar or for oedema in at least 2 of 3 animals tested, based on gradings at 24, 48 and 72 hours after patch removal, or if reactions are delayed, from grades on three consecutive days after the onset of skin reactions.
  • Inflammation that persists to the end of the observation period (usually 14 days) in at least two animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia and scaling, or
  • In some cases where there is profound variability of responses among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above.

In this study the test reactions were not graded in a manner which allows mean values for erythema or oedema to be calculated at 24, 48 and 72 hours. Similarly, the observation period was insufficient to determine whether the scaling that was noted during the study was fully reversed. However, the mean values at 24 hours were ≤ 2, and at 72 hours the scaling that was noted was only slightly encrusted. Furthermore the results were consistent between all six of the animals tested and a parallel test on abraded skin did not induce significantly more irritation than the intact skin. The test substance is therefore not classified for irritation.

 

Eye irritation

Serious eye damage is defined as the production of tissue damage in the eye, or serious physical decay if vision following application of a test substance to the anterior surface of the eye, which is not fully reversible within 21 days of application.

Eye irritation is defined as the production of changes in the eye following application of the test substance to the anterior surface of the eye, which are fully reversible within 21 days.

Substances that have the potential to seriously damage the eyes are classified as Category 1 (irreversible effects on the eye).

Substances that have the potential to induce reversible eye irritation are classified in Category2 (irritating to eyes). 

A substance is classified in category 2 when in the eye of an animal a substance produces at least in 2 of 3 animals tested a positive response of:

  • Corneal opacity ≥ 1 and / or
  • Iritis ≥1 and /or
  • Conjunctival redness ≥ 2 and /or
  • Conjunctival oedema (chemosis) ≥ 2

when calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the test material and which fully reverses within 21 days.

 

Although some conjunctival redness and chemosis were noted during the study this was ≤ 2 and therefore insufficient to trigger classification. Furthermore, there was no corneal opacity and no iritis. The test substance is therefore not classified for eye irritation.