Registration Dossier

Administrative data

Description of key information

Skin irritation

The dermal irritation potential of target chemical Nicotine sulphate (CAS No: 65-30-5) andits structurally similar read across substanceswas assessedin various experimental studies which were conducted on humans and guinea pigs.Based on the available key data and supporting studies,it can be concluded thatchemical Nicotine sulphate (CAS No: 65-30-5) is unable to cause skin irritation and considered as 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 Nicotine sulphate (CAS No: 65-30-5) andits structurally similar read across substanceswere assessedin various experimental studies which were conducted on rabbits.Based on the available data for the target and read across substances and applying the weight of evidence approach, it can be concluded that chemical Nicotine sulphate (CAS No: 65-30-5) is unable to cause eye damage and thus can be 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:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from peer reviewed journal
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: as mentioned below
Principles of method if other than guideline:
The skin irritation study was conducted on 14 patients to determine the degree of contact irritation caused by the test chemical Nicotine sulphate (CAS No: 65-30-5).
GLP compliance:
not specified
Test material information:
Composition 1
Specific details on test material used for the study:
- IUPAC Name: 3-[(2S)-1-methylpyrrolidin-2-yl]pyridine; sulfuric acid
- Common Name: Nicotine sulphate
- InChI: 1S/2C10H14N2.H2O4S/c2*1-12-7-3-5-10(12)9-4-2-6-11-8-9;1-5(2,3)4/h2*2,4,6,8,10H,3,5,7H2,1H3;
(H2,1,2,3,4)/t2*10-;/m00./s1
- Smiles: CN1CCC[C@H]1c2cccnc2.CN3CCC [C@H]3c4cccnc4.OS(=O)(=O)O
- Molecular formula:C10H16N2O4S
- Molecular weight :422.547 g/mol
- Substance type:Organic
- Physical state:Solid, white brown crystalline
Species:
other: Human
Strain:
other: Not applicable
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Department of Dermatology, University of Basel, Switzerland
- Age at study initiation: mean age – 38.6 years (range 23 – 65 years)
Type of coverage:
open
Preparation of test site:
not specified
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
5%
Duration of treatment / exposure:
20 minutes
Observation period:
20 minutes
Number of animals:
14 patients (10 male and 4 female)
Details on study design:
TEST SITE
- Area of exposure: ventral forearm
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 20 minutes
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
Equivocal reaction was observed in 1 out of 14 treated patients.
Interpretation of results:
other: Not irritating
Conclusions:
The test chemical Nicotine sulphate (CAS No: 65-30-5) was considered to be not irritating to the skin of treated patients.
Executive summary:

The skin irritation study was conducted on 14 patients to determine the degree of contact irritation caused by the test chemical Nicotine sulphate (CAS No: 65-30-5).

The test chemical was applied on the skin of ventral forearm of each subject at concentration of 5%.

 

The skin reactions were assessed 20min after application from 0 to +++.

 

Rating of equal or greater than + were quantified as contact urticarial reaction. In addition, subjective symptoms such as burning or itching were recorded.

 

Equivocal reaction was observed in 1 out of 14 treated patients.

 

Since the skin lesions were not observed in most of the treated patients the test chemical Nicotine sulphate (CAS No: 65-30-5) was considered to be not irritating to the skin of each subjects.

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
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: as mentioned below
Principles of method if other than guideline:
WoE report is based on 2 eye irritation studies as- WoE-2 and WoE-3.
An eye irritation study of test chemical was conducted rabbits to assess its eye irritating effects.

GLP compliance:
not specified
Test material information:
Composition 1
Specific details on test material used for the study:
- IUPAC Name: 3-[(2S)-1-methylpyrrolidin-2-yl]pyridine; sulfuric acid
- Common Name: Nicotine sulphate
- InChI: 1S/2C10H14N2.H2O4S/c2*1-12-7-3-5-10(12)9-4-2-6-11-8-9;1-5(2,3)4/h2*2,4,6,8,10H,3,5,7H2,1H3;
(H2,1,2,3,4)/t2*10-;/m00./s1
- Smiles: CN1CCC[C@H]1c2cccnc2.CN3CCC [C@H]3c4cccnc4.OS(=O)(=O)O
- Molecular formula:C10H16N2O4S
- Molecular weight :422.547 g/mol
- Substance type:Organic
- Physical state:Solid, white brown crystalline
Species:
rabbit
Strain:
other: 1.New Zealand White 2.Not specified
Details on test animals or tissues and environmental conditions:
No data available
Vehicle:
other: 1.water 2.not specified
Controls:
not specified
Amount / concentration applied:
1.15% and 25%
2.not specified
Duration of treatment / exposure:
1.10 days
2.14 days
Observation period (in vivo):
1.10 days
2.1 hr, then at 1, 2, 3, 4, 7 and 14 days.
Number of animals or in vitro replicates:
1.No data available
2. 3 rabbits
Details on study design:
1.No data available

2.REMOVAL OF TEST SUBSTANCE
Washing (if done): Yes , for 3 rabbits
Time after start of exposure: No data

SCORING SYSTEM: Only ocular lesions (cornea, iris and conjunctiva) were scored (Draize et al., 1944) at 1 hr, then at 1, 2, 3, 4, 7 and 14 days. In the case of positive score, eyes were also examined at 21 days.
Raw data were also used to classify chemicals according to the rating system described by Kay and Calandra (1962), and the EC criteria.
Irritation parameter:
other: 1.overall irritation score
Basis:
mean
Time point:
other: 10 d
Score:
0.67
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritation parameter:
other: 2.overall irritation score
Basis:
mean
Time point:
other: 1 hour
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
1.No eye irritating effects were observed.
2.No eye irritation was observed .
Interpretation of results:
other: Not irritating
Conclusions:
The test material Nicotine sulphate (CAS No: 65-30-5) was considered to be non-irritating to the eye of New Zealand White Rabbits in Low volume eye test.
Executive summary:

Data available for the structurally and functionally similar read across chemicals has been reviewed to determine the ocular irritation potential of the test chemical Nicotine sulphate (CAS No: 65-30-5). The studies are as mentioned below:

 

The Low volume eye test of read across chemical was performed by peer reviewed journal in New Zealand White Rabbits to determine the degree of eye irritancy caused by the chemical. During the test, 16% and 25% of test substance dissolved in water was placed into the eye of each rabbits. The maximum average score (MAS) observed was 0.67 and the effects observed were cleared within 10 days. Since the chemical did not produce any acute ocular hazards, the chemical was considered to be non-irritating to the eye of New Zealand White Rabbits.

 

 

The above result was further supported by another ocular irritation test conducted by peer reviewed journal in rabbits. The tests were performed according to EEC (1984 and 1991) and French (1984 and 1991) directives with few modifications: ocular lesions (cornea, iris and conjunctiva) were scored. Three rabbits were used per test compound, and maximal average score (MAS) as well as score at day 1 were calculated. At the request of the participants, any mass of material present in the conjunctival sac was removed after the 1-hr observation. Also, a fluorescein solution was used for observation of corneal lesions. Only ocular lesions (cornea, iris and conjunctiva) were scored (Draizeet al.,1944) at 1 hr, then at 1, 2, 3, 4, 7 and 14 days. In the case of positive score, eyes were also examined at 21 days. Raw data were also used to classify chemicals according to the rating system described by Kay and Calandra (1962), and the EC criteria (1984). The MAS score for the test chemical was obtained to be 8.7 and score measured at day 1 was observed to be 7.7. As all the observed effects were not persisted, the test chemical was considered as Non-irritant.

 

Based on the above summarized studies for target chemical Nicotine sulphate (CAS No: 65-30-5) and its structurally similar read across substances,it can be concluded that the testchemical 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:

Various studieshas been investigated for the test chemicalNicotine sulphate (CAS No: 65-30-5) andits structurally similar read across substance to observe the potential for skin irritation to a greater or lesser extent. The studies are based on in vivo experiments in human and guinea pigs for target chemicalNicotine sulphate (CAS No: 65-30-5) which have beensummarized as below;

 

 

The skin irritation study was conducted on 14 patients to determine the degree of contact irritation caused by the test chemical Nicotine sulphate (CAS No: 65-30-5). The test chemical was applied on the skin of ventral forearm of each subject at concentration of 5%. The skin reactions were assessed 20min after application from 0 to +++. Rating of equal or greater than + were quantified as contact urticarial reaction. In addition, subjective symptoms such as burning or itching were recorded. Equivocal reaction was observed in 1 out of 14 treated patients. Since the skin lesions were not observed in most of the treated patients the test chemical Nicotine sulphate (CAS No: 65-30-5) was considered to be not irritating to the skin of each subjects.

 

The same skin irritation study was conducted for another read across chemical by the same peer reviewed journal as mentioned in above study that supported the above mentioned result. The test chemical was applied on the skin of ventral forearm of each subject at concentration of 1%. The skin reactions were assessed 20min after application from 0 to +++. Only 1 treated patient showed slight erythema. Since the skin lesions were not observed in most of the treated patients the test chemical was considered to be not irritating to the skin of each subjects.

 

The above results were further supported by the preliminary irritation test conducted by peer reviewed journal for another similar read across chemical in guinea pigs to determine the concentration suitableforthe sensitization study[injection challenge concentration (ICC) and application challenge concentration(ACC)].In the preliminary test, the guinea pigs were treated intradermally and dermally.8 previously untreated guinea pigs were (4/SEX) were injected intradermally in the clipped and shaved flanks with 0.1ml aliquots of a range of concentration of test substance in physiological saline. 24 hours later, the skin was examined for erythema and edema.The concentration giving slight but perceptible irritation with no oedema was selected as the injection challenge concentration (ICC). Aliquots of 0.1ml using a range of concentration of the test substance in distilled water were applied in small circular areas to the shaved flanks of 4 previously untreated guinea pigs.24 hours later, the skin was examined for erythema and the highest concentration which caused no irritation was selected as the application challenge concentration (ACC). As a result of preliminary studies, the concentration of test chemical at which no irritation was observed were 5% for the ICC and 20% for ACC. Since the test chemical did not induce any cutaneous effects at these concentrations, the test chemical was considered to be not irritating to the skin of guinea pigs.

 

Based on the available key data and supporting studies,it can be concluded thatchemical Nicotine sulphate (CAS No: 65-30-5) is unable to cause skin irritation and considered as irritating. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

 

 

Eye irritation

Data available for the structurally and functionally similar read across chemicals has been reviewed to determine the ocular irritation potential of the test chemical Nicotine sulphate (CAS No: 65-30-5). The studies are as mentioned below:

 

The Low volume eye test of read across chemical was performed by peer reviewed journal in New Zealand White Rabbits to determine the degree of eye irritancy caused by the chemical. During the test, 16% and 25% of test substance dissolved in water was placed into the eye of each rabbits. The maximum average score (MAS) observed was 0.67 and the effects observed were cleared within 10 days. Since the chemical did not produce any acute ocular hazards, the chemical was considered to be non-irritating to the eye of New Zealand White Rabbits.

 

 

The above result was further supported by another ocular irritation test conducted by peer reviewed journal in rabbits. The tests were performed according to EEC (1984 and 1991) and French (1984 and 1991) directives with few modifications: ocular lesions (cornea, iris and conjunctiva) were scored. Three rabbits were used per test compound, and maximal average score (MAS) as well as score at day 1 were calculated. At the request of the participants, any mass of material present in the conjunctival sac was removed after the 1-hr observation. Also, a fluorescein solution was used for observation of corneal lesions. Only ocular lesions (cornea, iris and conjunctiva) were scored (Draizeet al.,1944) at 1 hr, then at 1, 2, 3, 4, 7 and 14 days. In the case of positive score, eyes were also examined at 21 days. Raw data were also used to classify chemicals according to the rating system described by Kay and Calandra (1962), and the EC criteria (1984). The MAS score for the test chemical was obtained to be 8.7 and score measured at day 1 was observed to be 7.7. As all the observed effects were not persisted, the test chemical was considered as Non-irritant.

 

Based on the above summarized studies for target chemical Nicotine sulphate (CAS No: 65-30-5) and its structurally similar read across substances,it can be concluded that the testchemical 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 Nicotine sulphate (CAS No: 65-30-5)  and its structurally and functionally similar read across substanceswere observed in various studies. The results obtained from these studies indicate that the chemical is unlikely to cause skin and eye irritation. Hence Nicotine sulphate (CAS No: 65-30-5)  can be classified under the category “Not Classified” for skin and eye as per CLP.