Registration Dossier

Administrative data

Description of key information

Skin irritation

Based on the available data for the various test chemicals and applying the weight of evidence approach, it can be concluded that the test chemical will also tend to behave in a similar manner. Therefore, the test chemical was considered to be not irritating to skin. Comparing the above annotations with the criteria of CLP regulation, the test chemical cannot be classified for skin irritation.

 

Eye irritation

Based on the available data for the various test chemicals and applying the weight of evidence approach, it can be concluded that the test chemical will also tend to behave in a similar manner. Therefore, the test chemical was considered to be not irritating to eyes. Comparing the above annotations with the criteria of CLP regulation, the test chemical cannot be 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:
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 from various test chemicals
Justification for type of information:
Data is summarized based on the available information from various test chemicals.
Reason / purpose:
read-across: supporting information
Reason / purpose:
read-across: supporting information
Qualifier:
according to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
WoE report is based on 2 skin irritation studies as- WoE-2 and WoE-3.
Skin irritation study of test chemical was conducted on rabbits and guinea pigs to assess its skin irritating effects.
GLP compliance:
not specified
Species:
other: 2. rat 3. rabbit
Strain:
other: 2. Sprague-Dawley 3. New Zealand White
Details on test animals and environmental conditions:
2. TEST ANIMALS
- Source: National Institute of Biosciences, Pune.
- Females (if applicable) nulliparous and non-pregnant: No data available
- Age at study initiation: Young adult male and female rats aged between 6 – 9 weeks were used.
- Weight at study initiation: The weight ranges of approximately 239.3 to 272.5 grams at initiation of dosing were used.
Body weights at the start : Male Mean : 270.14 g (= 100 %); Minimum : 267.1 g (- 1.13 %); Maximum : 272.5 g (+ 0.87 %) Total No. of animals : 5
Female Mean: 243.94 g (= 100 %); Minimum : 239.3 g (- 1.90 %); Maximum : 250.1 g (+ 2.53 %) Total No. of animals : 5
- Fasting period before study: No data available
- Housing: The rats were individually housed in polycarbonate cages with paddy husk as bedding.
- Diet (e.g. ad libitum): Rodent feed supplied by the Nutrivet Life Sciences, Pune, was provided ad libitum from individual feeders.
- Water (e.g. ad libitum): Water was provided ad libitum from individual bottles attached to the cages. All water was from a local source and passed through the reverse osmosis membrane before use.
- Acclimation period: 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.1 to 22.3 degree centigrade.
- Humidity (%): 55.7% to 59.6%.
- Air changes (per hr): Ten to fifteen air changes per hour.
- Photoperiod (hrs dark / hrs light): An artificial light and dark cycle of 12 hours each was provided to the room.

IN-LIFE DATES: 30-09-2016 to 15-10-2016
3. TEST ANIMALS
Source: No data
Age at study initiation: No data
Weight at study initiation: 3 kg
Fasting period before study: No data
Housing: singly housed, in suspended cages
Diet (e.g. ad libitum): Purina Rabbit Chow, ad libitum
Water (e.g. ad libitum): water, ad libitum
Acclimation period: No data
ENVIRONMENTAL CONDITIONS
Temperature (°C): No data
Humidity (%):No data
Air changes (per hr): No data
Photoperiod (hrs dark / hrs light): 12 hour light and 12 hr dark cycle

IN-LIFE DATES: From: No data To: No data
Type of coverage:
other: 2. semiocclusive 3. Entire inner surface of one ear
Preparation of test site:
other: 2. clipped 3. A colony of rabbits that had genetically good ears and which were free from mites were used for the assay
Vehicle:
other: 2. Distilled water 3. The test chemical was mixed in propylene glycol at a 9 to 1 dilution for testing.
Controls:
yes
not specified
Amount / concentration applied:
2. TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Concentration (if solution): No data available

VEHICLE
- Amount(s) applied (volume or weight with unit): No data available
- Concentration (if solution): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

NEGATIVE CONTROL
- Amount(s) applied (volume or weight): No data available
- Concentration (if solution): No data available

POSITIVE CONTROL
- Amount(s) applied (volume or weight): No data available
- Concentration (if solution): No data available
3. Dose of 1ml of the test material was applied once daily for five days per week for 2 weeks.
Duration of treatment / exposure:
2. 24 hrs.
3. once daily for five days per week for 2 weeks.
Observation period:
2. 14 days
3. 2 weeks
Number of animals:
2. 10 (5/sex).
3. 3 rabbits
Details on study design:
2. TEST SITE
- Area of exposure: Trunk (dorsal surface and sides from scapular to pelvic area)
- % coverage: Approximately 10% of the body surface area.
- Type of wrap if used: Porous gauze dressing and non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Distilled water was used to remove residual test item.

OBSERVATION TIME POINTS
(indicate if minutes, hours or days) : Dermal reaction was observed daily for study period of 14 days.

SCORING SYSTEM: Draize Method.

OTHER OBSERVATIONS
Type and Frequency of Tests, Analyses and Measurements

Viability: Twice daily.

Clinical Observations and General Appearance: Animals were observed for clinical signs, mortality, until sacrifice.
Onset, duration and severity of any sign were recorded. The clinical signs and mortality observations were conducted at 10, 30, 60 minutes, 2, 4 and 6 hours on the day of dosing and once daily thereafter for 14 day. Daily observation was done as far as possible at the same time. The observations were included general clinical signs, observations of eyes, mucous membranes, respiratory, circulatory system and behavior pattern.

Body weights: Individual animal body weights were recorded pre-test (prior to administration of the test item), day 7 and at termination on day 14.

Gross Pathology: Necropsy was performed on animals surviving at the end of the study. Macroscopic examination of all the orifices, cavities and tissues were made and the findings were recorded. All animals surviving the study period were sacrificed by the carbon dioxide asphyxiation technique (day 15).

Histopathology: No gross abnormalities were observed in animals sacrificed terminally hence, no histopathology was performed.
3. TEST SITE
Area of exposure: Ear
% coverage: A dose of 1ml of the test chemical is applied and spread once daily to the entire inner surface of one ear five days per week for 2 weeks.
Type of wrap if used: No data

REMOVAL OF TEST SUBSTANCE
Washing (if done): No data
Time after start of exposure: No data

SCORING SYSTEM: The irritancy produced by repeated application of a chemical or skin care product on the surface epidermis in the rabbit ear is evaluated on a scale of 0 to 5. The grades are summarized as follows:
0 = No irritation
1 = few scales, no Erythema
2 = diffuse scaling, no Erythema
3 = Generalized scaling with Erythema
4 = Scaling, Erythema and Edema
5 = Epidermal necrosis and slough
Irritation parameter:
erythema score
Remarks:
2
Basis:
mean
Time point:
14 d
Score:
0
Max. score:
4
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Remarks:
2
Basis:
mean
Time point:
14 d
Score:
0
Max. score:
4
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritation parameter:
overall irritation score
Remarks:
3
Basis:
mean
Time point:
other: 2 weeks
Score:
0
Max. score:
5
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
2. Overall result:
Sex : Male Group I - Animal treated at the dose level of 2000 mg/kg body weight did not result in any skin reaction during the study period of 14 days.
Sex : Female Group I - Animal treated at the dose level of 2000 mg/kg body weight did not result in any skin reaction during the study period of 14 days.
3. No erythema observed.
Other effects:
2. Clinical Signs of Toxicity and Mortality
Sex : Male Group I - Animal treated at the dose level of 2000 mg/kg body weight did not result in any signs of toxicity during the study period of 14 days. All animals survived through the study period of 14 days.
Sex : Female Group I - Animal treated at the dose level of 2000 mg/kg body weight did not result in any signs of toxicity during the study period of 14 days. All animals survived through the study period of 14 days.

Body Weight
Sex : Male Group I (2000 mg/kg) - Percent body weight gain after 7 days and 14 days was found to be 9.74% and 17.37% respectively.
Sex : Female Group I (2000 mg/kg) - Percent body weight gain after 7 days and 14 days was found to be 4.89% and 9.61% respectively.

Gross Pathological Findings: Gross pathological examination did not reveal any abnormalities in animals from 2000 mg/kg dose group.
3. No data
Interpretation of results:
other: not irritating
Conclusions:
Based on the available data for the various test chemicals and applying the weight of evidence approach, it can be concluded that the test chemical will also tend to behave in a similar manner. Therefore, the test chemical was considered to be not irritating to skin. Comparing the above annotations with the criteria of CLP regulation, the test chemical cannot be classified for skin irritation.
Executive summary:

In different studies, the given test chemical has been investigated for the dermal irritation potential to a greater or lesser extent. The studies are based on in-vivo experiments conducted in rodents which have been summarized as below -

 

A study was designed and conducted to determine the dermal reaction profile of the test chemical in Sprague Dawley rats. The study was performed as per OECD Guidelines 402 and complying to the GLP procedures. Ten rats (5 male and 5 female) were used for conducting dermal irritation /corrosion study at 2000 mg/kg. The animals were kept in their cages for at least 5 days prior to administration for acclimatization to the laboratory condition and after acclimatization period, animals were randomly selected. Approximately 24 hours before application, the hair of each rat was closely clipped from the trunk (dorsal surface and sides from scapular to pelvic area) with an electric clipper, so as to expose at least 10% of the body surface area. The test chemical was moistened with distilled water and applied onto the exposed skin of the animal, taking care to spread it evenly. The test chemical was held in contact with the skin using a porous gauze dressing and non irritating tape around the animal to cover the exposure site for first 24 hours exposure period. Elizabethan collar was placed on each animal for first 24 hours after application to prevent ingestion. Following 24 hours of exposure, the wrapping was removed and the test site wiped free of excess test chemical by using Distilled water. Administration at 2000 mg/kg did not result in any skin reaction at the site of application during the study period of 14 days. The overall irritation score of the substance was determined to be 0 and no erythema and edema (skin irritation) were observed at the end of 14 days observation period after patch removal. Hence, it was concluded that the test chemical was Non-Irritating to the skin of Sprague Dawley rats under the experimental conditions tested and not classified as per CLP Classification.

 

The above study was supported with another skin irritation test performed to determine the Comedogenicity and irritancy potential of the test chemical. The dyes were mixed in propylene glycol at a 9 to 1 dilution for testing unless otherwise indicated (10% concentration). Colonies of New Zealand albino rabbits that have genetically good ears and free from mites were used. Three rabbits, weighing two to three kilograms, were used for each assay. Animals were housed singly in suspended cages and fed Purina Rabbit Chow and water ad libitum. Animals were maintained on a 12-hour light and 12-hour dark cycle. A dose of 1 ml of the test material was applied and spread once daily to the entire inner surface of once for five days per week for two weeks. The opposite untreated ear of each animal served as an untreated control. The irritancy produced by repeated application of the chemical on the surface epidermis in the rabbit ear is evaluated on a scale of 0 to 5. The grades are summarized as follows: 0 = No irritation; 1 = few scales, no Erythema; 2 = diffuse scaling, no Erythema; 3 = Generalized scaling with Erythema; 4 = Scaling, Erythema and Edema; 5 = Epidermal necrosis and slough. The test chemical falls under Grade 0 (no irritation observed).Hence it can be concluded that the test chemical was not irritating to rabbit ears.

 

Based on the available data for the various test chemicals and applying the weight of evidence approach, it can be concluded that the test chemical will also behave in similar manner and was considered to be not irritating to skin. Thus it cannot be classified for skin irritation.

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 from various test chemicals
Justification for type of information:
Data is summarized based on the available information from various test chemicals.
Reason / purpose:
read-across: supporting information
Reason / purpose:
read-across: supporting information
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 on guinea pigs and rabbits to assess its eye irritating effects.
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Details on test animals or tissues and environmental conditions:
2. not specified
3. not specified
Vehicle:
other: 2. aqueous suspension 3. water
Controls:
not specified
Amount / concentration applied:
2. 2 instillations of 10% (0.2ml)
3. 0.2 ml of a 10% aqueous solution (20 mg)
Duration of treatment / exposure:
2. The test substance was installed into conjunctival sac of rabbits 5 times per week for 4 weeks.
3. test material was applied twice daily, five times weekly
Observation period (in vivo):
2. 4 weeks
3. four weeks
Number of animals or in vitro replicates:
2. no data available
3. six or more albino rabbits
Details on study design:
2. - Area of exposure: conjunctival sac of rabbits
3. SCORING SYSTEM: Draize
Irritation parameter:
overall irritation score
Remarks:
2
Basis:
mean
Time point:
other: 4 weeks
Reversibility:
fully reversible within: 24 hours
Remarks on result:
no indication of irritation
Irritation parameter:
overall irritation score
Remarks:
3
Basis:
mean
Time point:
other: 20 days
Score:
0
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
2. Only minimal irritative effects after 2 hours.
3. not irritating to the rabbit eye
Other effects:
2. No data
3. No data
Interpretation of results:
other: Not irrtating
Conclusions:
Based on the available data for the various test chemicals and applying the weight of evidence approach, it can be concluded that the test chemical will also tend to behave in a similar manner. Therefore, the test chemical was considered to be not irritating to eyes. Comparing the above annotations with the criteria of CLP regulation, the test chemical cannot be classified for eye irritation.
Executive summary:

The ocular irritation potential was assessed based on the available results from the various test chemicals.These studies have been summarized as below -

 

The local eye irritative potential of test chemical was investigated in rabbits’ eye to assess the degree of eye irritancy caused by the chemical. Each rabbit received 2 installations of 0.2 ml of a 10% aqueous suspension of the test chemical into the conjunctival sac of rabbits 5 times per week for 4 weeks. The chemical produced only minimal irritative effects after 2 hours which could not confirmed the irritation potential. Hence, on the basis of findings, the test chemical can be considered as not irritating to the rabbits’ eye.

 

The above study was supported by the results of an eye irritation study conducted to determine the irritation potential of the test chemical on rabbit eyes. 0.2 ml of a 10% aqueous solution (20 mg) or suspension of the test material was applied twice daily, five times weekly, for four weeks to the conjunctival sac of one eye of each of a group of six or more albino rabbits (40 applications). One hour after each application, the eyes were examined for evidence of staining and the irritation was scored according to Draize. The test material caused intense colouring of the iris, lasting for 2 to 7 days. The overall irritation score after 20 days of observation was 0. Hence, the test chemical was considered to be not irritating to rabbit eyes.

 

Based on the available data, it can be concluded that the given test chemical cannot cause irritation to rodent’s eyes. Comparing the above annotations with the criteria of CLP regulation, the test chemical cannot be classified for eye irritation.

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 given test chemical has been investigated for the dermal irritation potential to a greater or lesser extent. The studies are based on in-vivo experiments conducted in rodents which have been summarized as below -

 

A study was designed and conducted to determine the dermal reaction profile of the test chemical in Sprague Dawley rats. The study was performed as per OECD Guidelines 402 and complying to the GLP procedures. Ten rats (5 male and 5 female) were used for conducting dermal irritation /corrosion study at 2000 mg/kg. The animals were kept in their cages for at least 5 days prior to administration for acclimatization to the laboratory condition and after acclimatization period, animals were randomly selected. Approximately 24 hours before application, the hair of each rat was closely clipped from the trunk (dorsal surface and sides from scapular to pelvic area) with an electric clipper, so as to expose at least 10% of the body surface area. The test chemical was moistened with distilled water and applied onto the exposed skin of the animal, taking care to spread it evenly. The test chemical was held in contact with the skin using a porous gauze dressing and non irritating tape around the animal to cover the exposure site for first 24 hours exposure period. Elizabethan collar was placed on each animal for first 24 hours after application to prevent ingestion. Following 24 hours of exposure, the wrapping was removed and the test site wiped free of excess test chemical by using Distilled water. Administration at 2000 mg/kg did not result in any skin reaction at the site of application during the study period of 14 days. The overall irritation score of the substance was determined to be 0 and no erythema and edema (skin irritation) were observed at the end of 14 days observation period after patch removal. Hence, it was concluded that the test chemical was Non-Irritating to the skin of Sprague Dawley rats under the experimental conditions tested and not classified as per CLP Classification.

 

The above study was supported with another skin irritation test performed to determine the Comedogenicity and irritancy potential of the test chemical. The dyes were mixed in propylene glycol at a 9 to 1 dilution for testing unless otherwise indicated (10% concentration). Colonies of New Zealand albino rabbits that have genetically good ears and free from mites were used. Three rabbits, weighing two to three kilograms, were used for each assay. Animals were housed singly in suspended cages and fed Purina Rabbit Chow and water ad libitum. Animals were maintained on a 12-hour light and 12-hour dark cycle. A dose of 1 ml of the test material was applied and spread once daily to the entire inner surface of once for five days per week for two weeks. The opposite untreated ear of each animal served as an untreated control. The irritancy produced by repeated application of the chemical on the surface epidermis in the rabbit ear is evaluated on a scale of 0 to 5. The grades are summarized as follows: 0 = No irritation; 1 = few scales, no Erythema; 2 = diffuse scaling, no Erythema; 3 = Generalized scaling with Erythema; 4 = Scaling, Erythema and Edema; 5 = Epidermal necrosis and slough. The test chemical falls under Grade 0 (no irritation observed).Hence it can be concluded that the test chemical was not irritating to rabbit ears.

 

Based on the available data for the various test chemicals and applying the weight of evidence approach, it can be concluded that the test chemical will also behave in similar manner and was considered to be not irritating to skin. Thus it cannot be classified for skin irritation.

 

Eye irritation

The ocular irritation potential was assessed based on the available results from the various test chemicals.These studies have been summarized as below -

 

The local eye irritative potential of test chemical was investigated in rabbits’ eye to assess the degree of eye irritancy caused by the chemical. Each rabbit received 2 installations of 0.2 ml of a 10% aqueous suspension of the test chemical into the conjunctival sac of rabbits 5 times per week for 4 weeks. The chemical produced only minimal irritative effects after 2 hours which could not confirmed the irritation potential. Hence, on the basis of findings, the test chemical can be considered as not irritating to the rabbits’ eye.

 

The above study was supported by the results of an eye irritation study conducted to determine the irritation potential of the test chemical on rabbit eyes. 0.2 ml of a 10% aqueous solution (20 mg) or suspension of the test material was applied twice daily, five times weekly, for four weeks to the conjunctival sac of one eye of each of a group of six or more albino rabbits (40 applications). One hour after each application, the eyes were examined for evidence of staining and the irritation was scored according to Draize. The test material caused intense colouring of the iris, lasting for 2 to 7 days. The overall irritation score after 20 days of observation was 0. Hence, the test chemical was considered to be not irritating to rabbit eyes.

 

Based on the available data, it can be concluded that the given test chemical cannot cause irritation to rodent’s eyes. Comparing the above annotations with the criteria of CLP regulation, the test chemical cannot be classified for eye irritation.

 

Justification for classification or non-classification

Based on the available data for the various test chemicals and applying the weight of evidence approach, it can be concluded that the test chemical will also tend to behave in a similar manner. Therefore, the test chemical was considered to be not irritating to skin and eye. Comparing the above annotations with the criteria of CLP regulation, it cannot be classified for skin and eye irritation.