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Description of key information

Skin: 
The test material caused slight to well-defined erythema and oedema through 24 hours after the test material was removed. On Days 2 and 3, slight to moderate erythema was observed. Slight erythema was observed in some animals on Day 7. All sites were clear of irritation on Day 14. The primary irritation score was 1.6.
The mean value of the scores for erythema and edema formation for 24, 48 and 72 hours was calculated to be 1 and so will not be classified as irritating according to the dangerous substances directive, 67/548/EEC.
Eye:
Conjunctival irritation, including positive irritation (grade 2) for four rabbits, was noted for all animals. There were no iridal or corneal findings in the treated eyes. All conjunctival irritation completely subsided by day 7.
The Maximum Average Score for the test material was 5.3 at one-hour post-instillation.
The mean value of the scores for cornea opacity, iris lesions, redness & oedema of the conjuctivae, for 24, 48 and 72 hours was calculated and was considered to be non-irritating according to the dangerous substances directive, 67/548/EEC.

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:
3rd to 17th December 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Not conducted to a recognised guideline however methods well written and look similar to OECD 404. Conducted to GLP.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
not specified
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: L.I.T. Rabbitry, Whitehall, Montana
- Age at study initiation: The animals were 17-19 weeks of age at the time of dosing.
- Housing: The animals were housed individually in wire-bottom cages in an air conditioned room.
- Diet (e.g. ad libitum): The animals were fed a daily ration of Purina Laboratory Rabbit Chow HF #5326.
- Water (e.g. ad libitum): Free access to water.
- Acclimation period: Conditioning period of nine weeks prior to dosing.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.8-22.3°C
- Humidity (%): 18.2-62.7%
- Photoperiod (hrs dark / hrs light): The photoperiod was a 12-hour light/dark cycle: lights on at 0630 and off at 1830.

Type of coverage:
semiocclusive
Preparation of test site:
other: shaved and both abraded and unabraded
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
The test material was delivered neat.
Duration of treatment / exposure:
4 hours
Observation period:
1, 24, 48 and 72 hours, 7 and 14 days
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure: One-half milliliter of the test material was applied to each of two intact and two abraded sites on the back of each rabbit.
- Type of wrap if used: After application, each treated site was covered with a gauze patch secured in place by porous tape. The trunk of each animal was loosely wrapped in a plastic sheet, and paper toweling was wrapped around the plastic sheet to prevent tearing. A collar was also placed on each animal to protect the wrappings during the exposure period.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped with mineral oil and a gauze pad to remove any remaining test material.
- Time after start of exposure: 4 hours

SCORING SYSTEM:
Irritation was scored at 1, 24, 48, and 72 hours after removal of the test material and at 7 and 14 days, using the modified scoring method of Draize et al.
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Score:
1.6
Remarks on result:
other: Sum of the combined individual scores for erythema and edema at each site at 1, 24, and 72 hours divided by 72 observations.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 hours
Score:
1.6
Max. score:
2
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: Intact Skin
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 48 hours
Score:
0.9
Max. score:
2
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: Intact Skin
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 72 hours
Score:
0.6
Max. score:
2
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: Intact Skin
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 hours
Score:
0
Reversibility:
fully reversible within: 24 hours
Remarks on result:
other: Intact Skin
Irritant / corrosive response data:
The test material caused no to well-defined erythema and edema one hour after the test material was removed. Slight to well-defined erythema was observed at 24 hours; slight edema was also seen at one treatment site. No to moderate erythema was observed 48 and 72 hours after removal of the test material. On Day 7, slight erythema was observed at four sites. Flakiness was seen at the majority of the application sites. All sites were clear of irritation on Day 14. However, one animal had flaky skin at all four application sites.There was no difference in irritation between intact and abraded sites.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The primary irritation score was 1.6.
Executive summary:

One-half milliliter of the test material was applied to two intact and two abraded areas on the back of each of six rabbits for four hours. The test material caused slight to well-defined erythema and edema through 24 hours after the test material was removed. On Days 2 and 3, slight to moderate erythema was observed. Slight erythema was observed in some animals on Day 7. All sites were clear of irritation on Day 14. The primary irritation score was 1.6.

The mean value of the scores for erythema and edema formation for 24, 48 and 72 hours was calculated to be 1 and so will not be classified as irritating according to the dangerous substances directive, 67/548/EEC.

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:
16th to 25th December 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study following GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
not specified
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
not specified
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Covance Research Products, Inc. Denver, PA
- Age at study initiation: Young adult
- Weight at study initiation: 2746 to 2999 grams at initiation of dosing
- Housing: Individual suspended wire mesh cages. The animals were maintained by the animal husbandry staff of WIL Research Laboratories, Inc. in accordance with standard operating procedures.
- Diet (e.g. ad libitum): PMI Nutrition International, Inc. Certified Rabbit LabDiet® 5322 was offered at approximately 150 g per day during the study. Analysis of feed was performed and provided by the manufacturer.
- Water (e.g. ad libitum): Municipal water was provided ad libitum. Water was analyzed in accordance with standard operating procedures. Contaminants were not present in animal feed or water at levels expected to interfere with the objective of this study.
- Acclimation period: The animals were acclimated to laboratory conditions for a minimum of seven days prior to initiation of dosing.

ENVIRONMENTAL CONDITIONS
- Temperature: 68.2-68.8°F
- Humidity (%): 30.2-44.1%
- Photoperiod (hrs dark / hrs light): 12 hours light/12 hours dark

Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.1 ml/right eye
Duration of treatment / exposure:
The test article was placed directly into the cupped lower conjunctival sac of each rabbit's right (test) eye. The eyelids were held closed for approximately one second after instillation. Left eyes were manipulated in an identical manner to simulate the dosing of the right eyes.
Observation period (in vivo):
Treated eyes were examined at 24, 48 and 72 hours and on Days 4 and 7 following treatment according to the Draize methodology. The rabbits were observed twice daily (morning and afternoon) for mortality for the duration of the study.
Number of animals or in vitro replicates:
six, 2 males/4 females
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): Unwashed exposure.

SCORING SYSTEM:
Both eyes of all rabbits were examined macroscopically for ocular irritation in accordance with the method of Draize at approximately one, 24, 48 and 72 hours after dosing and on days 4 and 7 if irritation persisted.

TOOL USED TO ASSESS SCORE:
An ophthalmoscope was used during these observations to examine the corneal tissue. In addition, both eyes were further examined at 72 hours and on day 7 with sodium fluorescein.
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 1 hour after instillation of test material
Score:
5.3
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24, 48 & 72 hours
Score:
0
Max. score:
0
Reversibility:
other: no effects seen
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48 & 72 hours
Score:
0
Max. score:
0
Reversibility:
other: no effetcs seen
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24 hours
Score:
1.5
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 48 hours
Score:
1.3
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 72 hours
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24 hours
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 48 hours
Irritant / corrosive response data:
Conjunctival irritation, including positive irritation (grade 2) for four rabbits, was noted for all animals. There were no iridal or corneal findings in the treated eyes. All conjunctival irritation completely subsided by day 7.
M.A.S. - Maximum Average Score for 1 hour was 5.3.

There were no deaths during the study.

The left (control) eyes were free of evidence of ocular irritation and other findings for the duration of the study.

There were no remarkable body weight changes noted during the study.

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Conjunctival irritation, including positive irritation (grade 2) for four rabbits, was noted for all animals. There were no iridal or corneal findings in the treated eyes. All conjunctival irritation completely subsided by day 7.
Executive summary:

In an eye irritation study conducted to OED method 405 in compliance with GLP, the primary ocular irritation potential of the test material was evaluated with New Zealand White rabbits.

There was one group of six albino rabbits that received a single, unwashed exposure. Each 0.1-m1 dose of the test article was instilled into the lower conjunctival sac of the right eye. The eyelid was held closed for approximately one second and released. The left eye was manipulated in a similar manner as the right eye and served as a contralateral control.

The eyes were examined for ocular reactions in accordance with the method of Draize at approximately one, 24, 48 and 72 hours after dosing and on days 4 and 7 if irritation persisted. Sodium fluorescein was used to aid in revealing possible corneal damage at 72 hours and on day 7.

Conjunctival irritation, including positive irritation (grade 2) for four rabbits, was noted for all animals. There were no iridal or corneal findings in the treated eyes. All conjunctival irritation completely subsided by day 7.

The Maximum Average Score for the test material was 5.3 at one-hour post-instillation.

The mean value of the scores for cornea opacity, iris lesions, redness & oedema of the conjuctivae, for 24, 48 and 72 hours was calculated and was considered to be non-irritating according to the dangerous substances directive, 67/548/EEC.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin:

The key study Brorby, 1986 (Chevron report number: SOCAL 2503) was comparable to the OECD Guideline 404 (Acute Dermal Irritation / Corrosion) and was conducted to GLP. Although there was no guideline stated, the study predates OECD 404 and basic scientific principles are similar to recognised guidelines.

A reliability rating of 1 was assigned according to the criteria of Klimisch, 1997. This was considered to be the most reliable study and is also the most recent study available. Classification has been based on the results from this study.

- The Hirose et al study, 1986 (Chevron report number: SOCAL 2433A) was identical in methodology to the above key study. Although there was no guideline stated, the study predates OECD 404 and basic scientific principles are similar to recognised guidelines. The study was considered to have a reliability rating of 1, according to the criteria of Klimisch, 1997.

The primary irritation score was 1.3. The mean value of the scores for erythema and edema formation for 24, 48 and 72 hours was calculated to be 0.2 and so will not be classified as irritating according to the dangerous substances directive, 67/548/EEC.

- The Meyding et al study, 1962a (Hazleton report number: 20-0169-33) was not conducted according to a recognised guideline or GLP. There are also significant deviations affecting this study such as the test substance being left on for 24 hours rather than 4 hours as suggested in recognised guidelines, and also the test material was not removed with an appropriate solvent after exposure. The study was therefore considered to have a reliability rating of 3, according to the criteria of Klimisch, 1997.

The test material produced a moderate degree of irritation characterized by erythema and edema involving both intact and abraded skin areas. Little improvement was observed at the 72-hour observation for although the edema had significantly subsided, erythema increased and substantial drying of the skin occurred. The primary dermal irritation index of the test material was 3.8.

The test material could not be classified according to the dangerous substances directive, 67/548/EEC as only 24 and 72 hour readings were available.

- The Meyding et al study, 1962b (Hazleton report number: 20-0169-33) was not conducted according to a recognised guideline or GLP. There are also significant deviations affecting this study such as the test substance being left on for 24 hours rather than 4 hours as suggested in recognised guidelines, and also the test material was not removed with an appropriate solvent after exposure. The study was therefore considered to have a reliability rating of 3, according to the criteria of Klimisch, 1997.

The primary dermal irritation index of the test material is 6.2.

The test compound produced a severe reaction on both the intact and abraded surfaces. Maximum scores for edema and erythema were frequently observed; the irritation had not subsided appreciably by the 72-hour observation period.

The test material could not be classified according to the dangerous substances directive, 67/548/EEC as only 24 and 72 hour readings were available.

- The Brett, 1975 study was conducted according to the Federal Hazardous Substance Act (16 CFR 1500). A reliability rating of 3 was assigned according to the criteria of Klimisch, 1997 due to the following deviations: The study employed a 24 hour exposure instead of the standard 4 hour exposure. No details of test material removal from the skin. The information was obtained from the peer reviewed, 2006 OECD SIDS dossier due to the original report being unavailable. The test material could not be classified according to the dangerous substances directive, 67/548/EEC as only 24 and 72 hour readings were available, however it was considered not irritating according to the FSHA.

Irritation Index = 3.7

- The Exxon Biomedical Sciences study, 1992 was comparable to the OECD Guideline 404 (Acute Dermal Irritation / Corrosion) and was conducted to GLP.

The test substance was removed using water and due to the low solubility of the test material it is unlikely that this method will have fully removed the test material from the test sites, therefore a reliability rating of 3, according to the criteria of Klimisch, 1997 was assigned.

primary irritation index = 2.42.

The mean value of the scores for erythema and edema formation for 24, 48 and 72 hours was calculated to be 1.1 and so will not be classified as irritating according to the dangerous substances directive, 67/548/EEC.

- The Exxon Biomedical Sciences study, 1986 was comparable to the OECD Guideline 404 (Acute Dermal Irritation / Corrosion) and was conducted to GLP.

The test substance was removed using water and due to the low solubility of the test material it is unlikely that this method will have fully removed the test material from the test sites, therefore a reliability rating of 3, according to the criteria of Klimisch, 1997 was assigned.

primary irritation index = 5.33.

The mean value of the scores for erythema and edema formation for 24, 48 and 72 hours was calculated to be 2.6 and so will be classified as irritating according to the dangerous substances directive, 67/548/EEC, however this study was not considered reliable and so will not be taken into account when classifying the substance.

Eye:

The Kern, 2000 study (Report number: WIL-168178) was chosen as the key study for skin irritation as it was conducted to the OECD Guideline 405 (Acute Eye Irritation / Corrosion) and GLP. A reliability rating of 1 was assigned according to the criteria of Klimisch, 1997. This was considered to be the most reliable study and is also the most recent study available. Classification has been based on the results for this study.

The other supporting studies available are as follows:

- The Brorby et al study, 1986 (Chevron report number: SOCAL 2325) was not considered the key study as it was conducted less recently than the above key study. There was no guideline stated, however the study predates OECD 405 and basic scientific principles look comparable to recognised guidelines. A reliability rating of 1 was assigned according to the criteria of Klimisch, 1997.

The mean value of the scores for cornea opacity, iris lesions, redness & oedema of the conjuctivae, for 24, 48 and 72 hours was calculated and was considered to be non-irritating according to the dangerous substances directive, 67/548/EEC.

- The Meyding et al study, 1962b (Hazleton report number: 20-0169-33) was not considered the key study as it was conducted less recently than the above key study and was not conducted according to a recognised guideline or GLP. Methods and results were reported. The study was considered to have a reliability rating of 4, according to the criteria of Klimisch, 1997 as observations were not carried out for long enough to enable revesibility of irritation and although methods and results were reported the conjunctivae scores were combined in the results and therefore it was not possible to classify according to current labelling guides and so this study was considered unassignable.

The test material produced a significant degree of eye irritation in rabbits which has not completely subsided within 72 hours following instillation. The test material could not be classified according to the dangerous substances directive, 67/548/EEC as information was limited.

- The Meyding et al study, 1962a (Hazleton report number: 20-0169-33) was not considered the key study as it was conducted less recently than the above key study and was not conducted according to a recognised guideline or GLP. Methods and results were reported. The study was considered to have a reliability rating of 4, according to the criteria of Klimisch, 1997 as observations were not carried out for long enough to enable revesibility of irritation and although methods and results were reported the conjunctivae scores were combined in the results and therefore it was not possible to classify according to current labelling guides and so this study was considered unassignable.

The test material produced a significant degree of eye irritation in rabbits which has not completely subsided within 72 hours following instillation. The test material could not be classified according to the dangerous substances directive, 67/548/EEC as information was limited.

- The Brett, 1975 study was conducted according to the Federal Hazardous Substance Act (16 CFR 1500.42). A reliability rating of 4 was assigned according to the criteria of Klimisch, 1997 due to the following deviations: The information was obtained from the peer reviewed, 2006 OECD SIDS dossier due to the original report being unavailable. The test material could not be classified according to the dangerous substances directive, 67/548/EEC as no individual animal data was available, however it was considered not irritating according to the FSHA.

Mean draize score = 9.0

- The Exxon Biomedical Sciences study, 1984 was comparable to the OECD Guideline 405 (Acute Eye Irritation / Corrosion).

A reliability rating of 1, according to the criteria of Klimisch, 1997 was assigned. Ocular instillation of the test material elicited only conjunctival responses, including redness, chemosis and discharge. All animals were clear of irritation by the Day 7 observation. The mean value of the scores for cornea opacity, iris lesions, redness & oedema of the conjuctivae, for 24, 48 and 72 hours was calculated and was considered to be non-irritating according to the dangerous substances directive, 67/548/EEC.

Justification for selection of skin irritation / corrosion endpoint:
Most reliable of 7 studies

Justification for selection of eye irritation endpoint:
Most reliable of 6 studies

Justification for classification or non-classification

Skin:

The key parameter chosen for skin irritation was less than the criteria set out in Directive 67/548/EEC and also Regulation (EC) 1272/2008, therefore classification for skin irritation was not considered to be necessary.

Eye:

The key parameter chosen for eye irritation was less than the criteria set out in Directive 67/548/EEC and also Regulation (EC) 1272/2008, therefore classification for eye irritation was not considered to be necessary.