Registration Dossier

Administrative data

Description of key information

Skin irritation:

The dermal irritation potential of target chemical was assessed in various in-vivo experimental studies.Based on the available studies,it can be concluded that the test chemical is unable to cause skin irritation and considered as not irritating. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified''.

Eye irritation:

The ocular irritation potential of target chemical was assessed in various in-vivo experimental studies.Based on the available studies,it can be concluded that the test chemical is unable to cause eye irritation and considered as not irritating. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified''.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
calculation (if not (Q)SAR)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Justification for type of information:
data is from Danish QSAR
Qualifier:
according to
Guideline:
other: Estimated data
Principles of method if other than guideline:
To estimate the dermal irritation potential of the test chemical in rabbits
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Details on test animals and environmental conditions:
not specified
Type of coverage:
not specified
Preparation of test site:
not specified
Vehicle:
not specified
Controls:
not specified
Amount / concentration applied:
not specified
Duration of treatment / exposure:
not specified
Observation period:
not specified
Number of animals:
not specified
Details on study design:
not specified
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: not specified
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
not specified
Other effects:
not specified

Table showing skin irritation estimation by four different models i.e, Battery,SciQSAR and Leadscope.The average skin irritation results was given by the first model i.e, Battery model.

DK

Battery

SciQSAR

CASE Ultra

Leadscope

Skin irritation in rabbit

NEG

NEG

NEG

NEG

Domain

IN

IN

OUT

IN

 

Where,

IN = inside applicability domain

OUT = outside applicability domain

Interpretation of results:
other: not irritating
Conclusions:
No severe skin irritation effects of the test chemical were estimated in rabbit skin by three different models i.e, Battery, SciQSAR and Leadscope used within Danish QSAR database.
Executive summary:

Skin irritation effects were estimated by three different models i.e, Battery, SciQSAR and Leadscope used within Danish QSAR database for the test chemical. Based on estimation, No severe skin irritation effects were known when the test chemical was exposed to rabbit skin.

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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
experimental data of read across substances
Justification for type of information:
Data for the target chemical is summarized based on the structurally similar read across chemicals
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
other: as mentioned below
Principles of method if other than guideline:
The data is based on weight of evidence approach based on various test chemicals
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Vehicle:
other: 1.unchanged (no vehicle) 2.not specified 3.30% PEG-6 solution
Controls:
other: 1.yes 2.Not specified 3.yes,The untreated eye served as control.
Amount / concentration applied:
1.TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 gm

2.0.1 ml

3.5% in 30% PEG-6 solution (0.1mL)
Duration of treatment / exposure:
1.21 days
2.72 hours
Observation period (in vivo):
1.1, 24, 48 and 72 hours.
To determine the reversibility of the effect the animal was observed normally for 21 days.
3.1, 24, 48 and 72 hours

2.Not specified
Number of animals or in vitro replicates:
1.Three female rabbits
2.2 male, 1 female
3.1, 24, 48 and 72 hours
Details on study design:
The data is based on weight of evidence approach based on various test chemicals
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
21 d
Score:
0
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
No signs of irritation observed
Interpretation of results:
other: Not irritating
Conclusions:
The Test chemical was considered to be not irritating to the eyes of treated rabbits.
Executive summary:

Various studies were performed on rabbits to assess the ocular irritation potential of test chemical which have been summarized as follows:

 

The acute eye irritation study of test chemical was conducted in New Zealand White Rabbits as per the Guideline OECD- 405. Initial study of test chemical was conducted on one healthy rabbits of body weight 2.0kg. Both eyes of rabbits were examined for any abnormal disch arge such as eye irritation, ocular defects or pre-existing corneal injury from eye 24 hours prior to application of test compound. The test compound when applied to conjunctival sac of rabbit in the amount of 0.1gm did not produce any eye irritation during the observation period. Furthermore, no other clinical signs were recorded after application of test compound such as cage side activity, pain etc. The result obtained from the initial test was confirmed in additional two animals of same sex and same dose level (OECD-405). Test compound was applied in the amount of 0.1 gm in the conjunctival sac of each rabbit after gently pulling the lower lid away from the eyeball. The other eye which remain untreated, served as a control. The acute irritation to eye conjunctiva, cornea and iris was evaluated at 1, 24, 48 and 72 hours after the treatment. The grades of ocular reaction (conjunctiva, cornea and iris) were recorded at each observation. To determine the reversibility of the effect the animals were observed normally for 21 days. Any other lesions in the eye viz pannus, staining were observed and scored accordingly. Examination of reactions was facilitated by use of biomicroscope and hand slit lamp. Test compound applied to the conjunctival sac of the rabbits at the dose level of 0.1 gm did not produce any eye irritation as well as eye discharge. Furthermore, there was no other clinical sign recorded in both of the animals during the whole observation period for 21 days. Based on above findings, it can be concluded that the test compound was practically non-irritant when applied in the amount of 0.1 gm in the conjunctival sac of the rabbits

 

The above result was supported by an eye irritation study in 2 male and 1 female New Zealand white rabbits which was conducted to assess the irritation potential of test chemical.The study was performed according to OECD 405.0.1ml of 30% aqueous solution instilled into conjunctival sac of left eye and right eye was untreated as control.Slight reddening of the conjunctiva was observed in 1 animal on day 1 of the study only. No other effects were observed during the 8-day observation period. Hence, test chemical can be considered to be not irritating to rabbit eyes.

The above results were further supported by an ocular irritation study which was conducted on three female New Zealand White Rabbits to assess the ocular irritation potential of test chemical. 0.1ml of 5% 6-Hydroxy-1H-indole in 30% PEG-6 solution was instilled into the right eye of each rabbit whereas the other untreated eye served as control.Both the eyes were observed for ocular lesions at 1, 24, 48 and 72 hours post-treatment. Since none of the rabbits developed any ocular lesion, the test chemical was considered to be not irritating to the eyes of three female New Zealand White Rabbits.

 

Based on the above summarized studies for target chemical and its structurally and functionally similar read across substances,it can be concluded that the test chemical is not able to cause eye irritation and considered as not irritating. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin Irritation:

In different studies, the test chemical has been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in-vivo experiment conducted in human and rabbits. The predicted data using the Danish QSAR database has also been compared with the experimental data and summarized as below :

According to Danish QSAR database, Skin irritation effects were estimated by three different models i.e, Battery, SciQSAR and Leadscope used within Danish QSAR database for the test chemical. Based on estimation, No severe skin irritation effects were known when the test chemical was exposed to rabbit skin.

The above study was supported by acute Dermal Irritation/corrosion Study of test chemical was performed as per OECD guideline No. 404.Three healthy young adult male rabbits were used for the study. The hairs of all the rabbits were clipped at contralateral sites, approximately 24 hours prior to treatment.A dose of 500 mgof test item (moistened with 0.5 ml distilled water) was applied to the skin,over an area of approximately 6 x 6 cm clippedof hair on one side of rabbits.The other untreated side was kept as control area and 0.5 ml of distilled water was applied at this site. At the end of 4 hours, the gauze patch was removed and test item application site was wiped with water. Initially, the test item was applied to the clipped area of skin of one rabbit. The test site was covered with gauze patch.After 4 hours of exposure in animal no. 1,very slight erythema (barely perceptible) and no oedema observed at 1 hour of observation. At 24, 48 and 72 hours observation no erythema and oedema was observed in animal no 1.Hence the confirmatory test was conducted on additional two rabbits (No. 2 and 3)to confirm the non irritant nature of the test item. The patch was removed after 4 hours and rabbits wereobservedfor erythema and oedemaat 1, 24, 48 and 72 hours after patch removal, evaluatedand graded as per draize method. In animal no. 2 and 3 at 1 hour observation post patch removal, revealed very slight erythema (barely perceptible) and no oedema. At 24 hour animal no. 2 showed no erythema and oedema whereas animal no. 3 revealed very slight erythema (barely perceptible) and no oedema, At 48 and 72 hour post patch removal, both the animals recovered to normal. The individual mean score at 24, 48 and 72 hours for animal nos. 1, 2 and 3 were 0.00, 0.00, 0.33 and 0.00, 0.00, 0.00, for erythema and oedema formation, respectively. Hence, test chemical was considered to be Non-Irritating to the skin of male New Zealand White rabbits under the experimental conditions tested.

Both the above studies were further supported by the test chemical was tested for its dermal irritation potential in New Zealand White Rabbits at the Institute for Industrial Research & Toxicology. The study was conducted according to guideline OECD-404 as follows-

Initial test (using one animal):

In the initial test one healthy rabbit of body weight 2.24 kg selected for study after acclimatization. The test compound in the amount of 0.5 gm was applied at the different sites on the shaven back skin of animal. The hairs of back sides were removed (approximately 6 cm2) with the help of electric clipper one day earlier before the treatment. Animal was also observed for any dermal irritation or skin related infection at the site of application one day earlier.

The site of application was covered with impervious dressing secured in position with adhesive tape. The first patch was applied on the shaven back skin of rabbit and removed after three minutes. No serious reaction was observed at the site of application. The second patch was applied on the different shaven back side and removed after one hour. There were no signs of skin reaction observed at this site of application. Finally, a third patch was applied at a different site and was removed after four hour. No skin reaction was observed at the site of application of test compound. Finally, the animal was observed for 14 days, for any irritation and corrosion.

Confirmatory test (with addition animals):

Because no corrosive effect was observed in the initial test, a confirmatory test was done using two additional animals.

In the confirmatory test the test compound in the amount of 0.5 gm was applied on the shaven back skin of two animals (body weight ranges 2.14 and 2.09 kg), each with one patch, for an exposure period of four hours.

After four hours the patch was removed and the skin reactions were graded according to Draize’s method. The test chemical in the amount of 0.5 gm did not produce any dermal irritation in terms of erythema or edema in any of the animals after the four hours application. Both the animals were also free from any clinical signs of toxicity throughout the observation period of 14 days. The dermal irritation index of New Zealand white rabbits is calculated as 0.00 and test compound can be classified under non irritant categories. Thus based on result obtained from present experimentation, it can be concluded that the test chemical is non irritant to skin of the New Zealand white under test condition.

Furthermore, Skin irritation study was conducted to evaluate skin irritation potency of test chemical. 16 females aged 32 to 55 yrs old participated in the study. The test chemical concentration of 0.2 ml was applied in duplicate to the left and right sides of the back approximately 3 cm away from and parallel to the midline. The humans were exposed for 2 days and observed up to 3 days. The skin sites were evaluated for erythema and edema scores and also checked for redness of the skin. The mean erythema  and edema scores after 24 hours were 0.62, 0.0 respectively. Based on the scores, test chemical can be considered as not irritating to skin.

All these studies lead to a conclusion that Test chemical is indeed not irritating to skin. Hence, comparing the above annotations with the criteria of CLP regulation, Test chemical can be classified under the category “Not Classified”.

 

Eye Irritation:

Various studies were performed on rabbits to assess the ocular irritation potential of test chemical which have been summarized as follows:

The acute eye irritation study of test chemical was conducted in New Zealand White Rabbits as per the Guideline OECD- 405. Initial study of test chemical was conducted on one healthy rabbits of body weight 2.0kg. Both eyes of rabbits were examined for any abnormal disch arge such as eye irritation, ocular defects or pre-existing corneal injury from eye 24 hours prior to application of test compound. The test compound when applied to conjunctival sac of rabbit in the amount of 0.1gm did not produce any eye irritation during the observation period. Furthermore, no other clinical signs were recorded after application of test compound such as cage side activity, pain etc. The result obtained from the initial test was confirmed in additional two animals of same sex and same dose level (OECD-405). Test compound was applied in the amount of 0.1 gm in the conjunctival sac of each rabbit after gently pulling the lower lid away from the eyeball. The other eye which remain untreated, served as a control. The acute irritation to eye conjunctiva, cornea and iris was evaluated at 1, 24, 48 and 72 hours after the treatment. The grades of ocular reaction (conjunctiva, cornea and iris) were recorded at each observation. To determine the reversibility of the effect the animals were observed normally for 21 days. Any other lesions in the eye viz pannus, staining were observed and scored accordingly. Examination of reactions was facilitated by use of biomicroscope and hand slit lamp. Test compound applied to the conjunctival sac of the rabbits at the dose level of 0.1 gm did not produce any eye irritation as well as eye discharge. Furthermore, there was no other clinical sign recorded in both of the animals during the whole observation period for 21 days. Based on above findings, it can be concluded that the test compound was practically non-irritant when applied in the amount of 0.1 gm in the conjunctival sac of the rabbits.

The above result was supported by an eye irritation study in 2 male and 1 female New Zealand white rabbits which was conducted to assess the irritation potential of test chemical.The study was performed according to OECD 405.0.1ml of 30% aqueous solution instilled into conjunctival sac of left eye and right eye was untreated as control.Slight reddening of the conjunctiva was observed in 1 animal on day 1 of the study only. No other effects were observed during the 8-day observation period. Hence, test chemical can be considered to be not irritating to rabbit eyes.

The above results were further supported by an ocular irritation study which was conducted on three female New Zealand White Rabbits to assess the ocular irritation potential of test chemical. The 0.1ml of 5% 6-Hydroxy-1H-indole in 30% PEG-6 solution was instilled into the right eye of each rabbit whereas the other untreated eye served as control.Both the eyes were observed for ocular lesions at 1, 24, 48 and 72 hours post-treatment. Since none of the rabbits developed any ocular lesion, the test chemical was considered to be not irritating to the eyes of three female New Zealand White Rabbits.

Based on the above summarized studies for target chemical and its structurally and functionally similar read across substances,it can be concluded that the test chemical is not able to cause eye irritation and considered as not irritating. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Justification for classification or non-classification

The skin and eye irritation potential of test chemical was observed in various studies. The results obtained from these studies indicate that the test chemical is not likely to cause skin and eye irritation. Hence the test chemical can be classified under the category “Not Classified” for skin and eye as per CLP.