Registration Dossier

Administrative data

Description of key information

Two skin irritation studies are available.  Slight irritation was noted in both studies.  However, the degree of irritation was just border line in one leading to classification in accordance with  Guidance to Regulation (EC) No 1272/2008 on classifica tion, labelling and packaging (CLP) of substances and mixtures Version 3.0 November 2012.
The substance was only very slightly irritating to the eyes in two apparently well conducted studies. However the degree of irritation did not meet the criteria for classification.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
April-May 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well conducted study acording to GLP
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
GLP compliance:
yes (incl. certificate)
Species:
guinea pig
Strain:
New Zealand White
Details on test animals and environmental conditions:
Three New Zealand White rabbits supplied by David Percival Ltd, Moston,
Sandbach, Cheshire, UK were used. At the start of the study the animals
weighed 2.61 to 2.71 kg and were twelve to sixteen weeks old. After a
minimum acclimatisation period of five days each animal was given a number
unique within the study which was written with a black indelible marker-pen
on the inner surface of the ear and on the cage label.

The animals were individually housed in suspended metal cages. Free access
to mains drinking water and food (STANRAB SQC Rabbit Diet, Special Diets
Services Ltd, Witham, Essex, UK) was allowed throughout the study.

The animal room was maintained at a temperature of 17 to 21 . C and relative
humidity of 46 to 65%. The rate of air exchange was approximately fifteen
changes per hour and the lighting was controlled by a time switch to give
twelve hours continuous light and twelve hours darkness.
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
other: None
Controls:
no
Amount / concentration applied:
0.5 mL
Duration of treatment / exposure:
4 h
Observation period:
1, 24, 48, 72 h up to 14 days
Number of animals:
3
Details on study design:
On the day before the test each rabbit was clipped free of fur from the dorsal
flank area using veterinary clippers. Only animals with a healthy intact
epidermis by gross observation were selected for the study.

On the day of the test a suitable test site was selected on the back of each
rabbit. A quantity of 0.5 ml of the test material was introduced under a 2.5 cm
x 2.5 cm cotton gauze patch and placed in position on the shorn skin. The
patch was secured in position with a strip of surgical adhesive tape
(BLENDERM: approximate size 2.5 cm x 4.0 cm). To prevent the animals
interfering with the patches, the trunk of each rabbit was wrapped in an
eJasticated corset (TUBIGRJP) and the animals were returned to their cages for
the duration of the exposure period.

Four hours after application the corset and patches were removed from each
animal and any residual test material removed by gentle swabbing with cotton
wool soaked in 74% Industrial Methylated Spirits.

Approximately one hour following the removal of the patches, and 24, 48 and
72 hours later, the test sites were examined for evidence of primary irritation
and scored according to the following scale from Draize J H, (1977) "Dermal
and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the
Toxicity of Household Substances, National Academy of Sciences, Washington
DC p.31.
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal: 115
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 14 d
Remarks on result:
other: Score 2 after 1 hr
Irritation parameter:
erythema score
Basis:
animal: 59
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 14 d
Remarks on result:
other: Score 1 after 1 hr
Irritation parameter:
erythema score
Basis:
animal: 142
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 14 d
Remarks on result:
other: Score 2 after 1 hr
Irritation parameter:
edema score
Basis:
animal: 115
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 d
Remarks on result:
other: Score 1 after 1 hr
Irritation parameter:
edema score
Basis:
animal: 59
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 d
Remarks on result:
other: Score 0 after 1 hr
Irritation parameter:
edema score
Basis:
animal: 142
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 d
Remarks on result:
other: Score 1 after 1 hr
Irritant / corrosive response data:
Reversibility of any observed effect: Changes fully reversible within 14 days
Other effects:
None

Summary of dermal lesions (following 4-h application)

 

Animal no.

Effect

Hour

Days after application

Mean score erythema

(24/48/72 h)

Mean score oedema

(24/48/72 h)

1

1

2

3

7

14

115

Erythema

Oedema

2

1

2

1

2

1

2LeLf

1

0D

0

0

0

2

 

1

59

Erythema

Oedema

1

0

2

1

2

1

2

1

1D*

0

0

0

2

 

1

142

Erythema

Oedema

2

1

2

1

2

1

2

1

0D

0

0

0

2

 

1

Mean all animals

 

 

 

 

 

 

 

 

2

 

1

 

Le= loss of skin elasticity, Lf= loss of skin flexibility, D=slight desquamation, D*= moderate desquamation

Interpretation of results:
not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Based on a mean erythema score of 2 and a mean oedema score of 1 and full reversibility of the effects within 14 days, the test substance does not meet the criteria for classification in accordance with Guidance to Regulation (EC) No 1272/2008 on classifica tion, labelling and packaging (CLP) of
substances and mixtures Version 3.0 November 2012. However, the test material would be classified as R 38 in accordance with Annex VI of CounciDirective 67/548/EEC, Relating to the Classification, Packaging and Labelling of Dangerous Substances
Executive summary:

The study was performed to assess the irritancy potential of the test material following a single, 4-hour, semi-occluded application to the intact rabbit skin (Safepharm Standard Method Number 540.01). The method used followed the recommendations of the OECD Guidelines for Testing of Chemicals No. 404 "Acute Dermal Irritation/Corrosion" (adopted 17 July 1992) and Method B4 of Commission Directive 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

Three New Zealand White rabbits supplied by David Percival Ltd, Moston, Sandbach, Cheshire, UK were used. On the day before the test each rabbit was clipped free of fur from the dorsal flank area using veterinary clippers. Only animals with a healthy intact epidermis by gross observation were selected for the study. On the day of the test a suitable test site was selected on the back of each rabbit. A quantity of 0.5 ml of the test material was introduced under a 2.5 cm x 2.5 cm cotton gauze patch and placed in position on the shorn skin. The patch was secured in position with a strip of surgical adhesive tape (BLENDERM: approximate size 2.5 cm x 4.0 cm). To prevent the animals interfering with the patches, the trunk of each rabbit was wrapped in an eJasticated corset (TUBIGRJP) and the animals were returned to their cages for the duration of the exposure period. Four hours after application the corset and patches were removed from each animal and any residual test material removed by gentle swabbing with cotton wool soaked in 74% Industrial Methylated Spirits.

Approximately one hour following the removal of the patches, and 24, 48 and 72 hours later, the test sites were examined for evidence of primary irritation and scored according to the following scale from Draize J H, (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC p.31.

The test material produced positive criteria in 3/3 rabbits according to the EU labelling regulations, Annex VI of CounciDirective 67/548/EEC, Relating to the Classification, Packaging and Labelling of Dangerous Substances, and was classified as IRRITANT to rabbit skin (R 38 "IRRITATING TO SKIN").

However, based on a mean erythema score of 2 and a mean oedema score of 1 and full reversibility of the effects within 14 days, the test substance does not meet the criteria for classification in accordance with Guidance to Regulation (EC) No 1272/2008 on classifica tion, labelling and packaging (CLP) of substances and mixtures Version 3.0 November 2012.

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
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
May 1997
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well conducted study according to GLP
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Qualifier:
equivalent or similar to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Three New Zealand White rabbits, supplied by David Percival Ltd, Moston,
Sandbach, Cheshire, UK, were used. At the start of the study the animals
weighed 2.64 to 2.97 kg and were twelve to sixteen weeks old. After a
minimum acclimatisation period of five days each animal was given a number
unique within the study which was written with a black indelible marker-pen
on the inner surface of the ear and on the cage label.

The animals were individually housed in suspended metal cages. Free access
to mains drinking water and food (STANRAB SQC Rabbit Diet, Special Diets
Services Ltd, Witham, Essex, UK) was allowed throughout the study.

The animal room was maintained at a temperature of 17 to 20' C and relative
humidity of 46 to 65%. The rate of air exchange was approximately fifteen
changes per hour and the lighting was controlled by a time switch to give
twelve hours continuous light and twelve hours darkness.
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.1 mL
Duration of treatment / exposure:
single application into the conjunctival sac of one eye
Observation period (in vivo):
1, 24, 48 and 72 h
Number of animals or in vitro replicates:
3
Details on study design:
Immediately before the start of the test, both eyes of the provisionally selected
test rabbits were examined for evidence of ocular irritation or defect with the
aid of a light source from a standard ophthalmoscope. Animals shOWing
evidence of ocular lesions were rejected and replaced.
One rabbit was initially treated. A volume of 0.1 ml of the test material was
instilled into the conjunctival sac of the right eye, formed by gently pulling the
lower lid away from the eyeball. The upper and lower eyelids were held
together for about one second immediately after instillation, to prevent loss of
the test material, and then released. The left eye remained untreated and was
used for control purposes. Immediately after administration of the test material,
an assessment of the initial pain reaction was made.
After consideration of the ocular responses produced in the first treated animal,
two additional animals were treated. In order to minimise pain on instillation
of the test material, one drop of local anaesthetic ("Ophthaine", 0.5%
proxymetacaine hydrochloride, E R Squibb & Sons Limited, Hounslow,
Middlesex, UK) was instilled into both eyes of these animals 1 to 2 minutes
before treatment.

Assessment of ocular damage/irritation was made approximately 1 hour and 24,
48 and 72 hours following treatment, according to the numerical evaluation
given in Appendix I, (from Draize J H (1977) "Dermal and Eye Toxicity Tests"
In: Principles and Procedures for Evaluating the Toxicity of Household
Substances, National Academy of Sciences, Washington DC p.48 to 49).
Any other ocular effects were also noted. Examination of the eye was
facilitated by the use of the light source from a standard ophthalmoscope.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable as no corneal effects were seen
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
2
Reversibility:
other: see above
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
0.22
Max. score:
3
Reversibility:
fully reversible within: 2 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable as no chemosis was seen
Irritation parameter:
cornea opacity score
Basis:
animal: 129
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable as score is 0
Remarks on result:
other: Score 0 after 1 hr
Irritation parameter:
cornea opacity score
Basis:
animal: 14
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable as score is 0
Remarks on result:
other: Score - after 1 hr
Irritation parameter:
cornea opacity score
Basis:
animal: 20
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable as score is 0
Remarks on result:
other: Score 0 after 1 hr
Irritation parameter:
iris score
Basis:
animal: 129
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable as score is 0
Remarks on result:
other: Score 0 after 1 hr
Irritation parameter:
iris score
Basis:
animal: 14
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable as score is 0
Remarks on result:
other: Score 0 after 1 hr
Irritation parameter:
conjunctivae score
Basis:
animal: 129
Time point:
24/48/72 h
Score:
0
Max. score:
3
Reversibility:
fully reversible within: 24 h
Remarks on result:
other: Score 1 after 1 hr
Irritation parameter:
conjunctivae score
Basis:
animal: 14
Time point:
24 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 48 h
Remarks on result:
other: Score 2 after 1 hr
Irritation parameter:
conjunctivae score
Basis:
animal: 14
Time point:
48 h
Score:
0
Max. score:
3
Reversibility:
fully reversible within: 48 h
Irritation parameter:
conjunctivae score
Basis:
animal: 14
Time point:
72 h
Score:
0
Max. score:
3
Reversibility:
fully reversible within: 48 h
Irritation parameter:
chemosis score
Basis:
animal: 129
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable as score is 0
Remarks on result:
other: Score 0 after 1 hr
Irritation parameter:
chemosis score
Basis:
animal: 14
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 24 h
Remarks on result:
other: Score 1 after 1 hr
Irritation parameter:
chemosis score
Basis:
animal: 20
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 24 hr
Remarks on result:
other: Score 1 after 1 hr
Irritant / corrosive response data:
Reversibility of any observed effect: Changes fully reversible within 2 days
Other effects:
None

Summary of ocular lesions

 

Anim.

No.

Effect

Hours

Days after application

Mean

score cornea

Days

1/2/3

Mean score iritis

Days 1/2/3

 

Mean score redness Days 1/2/3

Mean score chemosis Days 1/2/3

1

1

2

3

7

21

129

Cornea*

Iris

Redness

Chemosis

0

0

1

0

0

0

0

0

0

0

0

0

0

0

0

0

-

-

-

-

-

-

-

-

0

 

0

 

 

0

 

 

 

0

14

Cornea*

Iris

Redness

Chemosis

0

0

2

1

0

0

1

0

0

0

0

0

0

0

0

0

-

-

-

-

-

-

-

-

0

 

0

 

 

0.33

 

 

 

0

20

Cornea*

Iris

Redness

Chemosis

0

0

2

1

0

0

1

0

0

0

0

0

0

0

0

0

-

-

-

-

-

-

-

-

0

 

0

 

 

0.33

 

 

 

0

Mean all anim.

 

 

 

 

 

 

 

 

0

 

0

 

0.22

 

0

Interpretation of results:
not irritating
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Because very slight eye irritation was seen which fully disappeared within 2 days, no classification is needed.

The test substance would not be classified as an eye irritant in accordance with the criteria for classification in accordance with Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures Version 3.0 November 2012.

Executive summary:

The study was performed to assess the irritancy potential of the test material following a single instillation to the rabbit eye (Safepharm Standard Method Number 560.01). The method used followed the recommendations of the OECD Guidelines for Testing of Chemicals No. 405 "Acute Eye Irritation/Corrosion" (adopted 24 February 1987) and Method 85 of Commission Directive 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC). The results may be used as a basis for classification and labelling under Annex VI of Council Directive 67/548/EEC (as adapted to technical progress by Commission Directive 93/21/EEC) relating to the classification, packaging and labelling of dangerous substances.

No corneal or iridial effects were noted during the study. Moderate conjunctival irritation was noted in one treated eye with minimal conjunctival irritation in two treated eyes one hour after treatment. Minimal conjunctival redness was noted in two treated eyes at the 24-hour observation. Treated eyes appeared normal at the 24 or 48-hour observations.

The test substance would not be classified as an eye irritant in accordance with the criteria for classification in accordance with Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures Version 3.0 November 2012.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In one skin irritation study, the test material produced positive criteria in 3/3 rabbits according to the EU labelling regulations, Annex VI of CounciDirective 67/548/EEC, Relating to the Classification, Packaging and Labelling of Dangerous Substances, and was classified as IRRITANT to rabbit skin (R 38 "IRRITATING TO SKIN"). However, based on a mean erythema score of 2 and a mean oedema score of 1 and full reversibility of the effects within 14 days, the test substance does not meet the criteria for classification in accordance with Guidance to Regulation (EC) No 1272/2008 on classifica tion, labelling and packaging (CLP) of substances and mixtures Version 3.0 November 2012.

In the second study, exposure to the test substance resulted in well defined or moderate to severe erythema and slight oedema in the treated skin-areas of the three rabbits. Scaliness was observed in all animals 7 days after exposure. The skin irritation had resolved within 14 days after exposure in all animals. Sticky remnants of the test substance, which became dry remnants after day 1, were present in the treated skin-areas of all animals up to 72 hours after exposure. Based on these results and according to the EEC criteria For classification and labelling requirements For dangerous substances and preparations (Guidelines in Commission Directive 93/21/EEC, 27th April 1993), the test substance should be labelled as: irritating to the skin (R 38). The test substance would be classified as a category 2 irritant in accordance with the criteria for classification in accordance with Guidance to Regulation (EC) No 1272/2008 on classifica tion, labelling and packaging (CLP) of substances and mixtures Version 3.0 November 2012.

In one eye irritation study, no corneal or iridial effects were noted during the study. Moderate conjunctival irritation was noted in one treated eye with minimal conjunctival irritation in two treated eyes one hour after treatment. Minimal conjunctival redness was noted in two treated eyes at the 24-hour observation. Treated eyes appeared normal at the 24 or 48-hour observations. The test substance would not be classified as an eye irritant in accordance with the criteria for classification in accordance with Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures Version 3.0 November 2012.

In the second eye irritation study, instillation of 0.1 ml of the test substance into one eye of each of three rabbits resulted in irritation of the conjunctivae, which consisted of redness and chemosis. The irritation had completely resolved within 24 hours in two animals and within 48 hours in the third animal. Based on these results and according to the EEC criteria for classification and labelling requirements for dangerous substances and preparations (Guidelines in Commission Directive 93/21/EEC, 27th April 1993), the test substance does not have to be classified and has no obligatory labelling requirement. The test substance would not be classified as an eye irritant in accordance with the criteria for classification in accordance with Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures Version 3.0 November 2012.


Justification for selection of skin irritation / corrosion endpoint:
Apparently well conducted GLP study.

Justification for selection of eye irritation endpoint:
Apparently well conducted GLP study.

Effects on skin irritation/corrosion: irritating

Justification for classification or non-classification

The test substance met the criteria for classification as a category 2 skin irritant but did not meet the criteria for classification as an eye irritant as noted above.