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Administrative data

Description of key information

Skin irritation: The test substance is not a dermal irritant.
Eye irritation: The test substance produced conjunctival irritation which cleared by day 7.

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:
Experimental start date: 11/13/07. Experimental termination date: 11/27/07
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Animals were received from Millbrook Breeding Labs.
- Age at study initiation: Approximately 3 months.
- Weight at study initiation: The pretest bodyweight range was 2.5 - 3.0 kg.
- Housing: 1 animal per cage in suspended wire cages. Bedding was placed beneath the cages and changed at least three times per week.
- Diet (e.g. ad libitum): Fresh PMI Rabbit Chow was provided daily.
- Water (e.g. ad libitum): Water was available ad libitum.
- Acclimation period: At least five days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): The animal room was temperature controlled.
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle.

Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
other: The test article was moistened with 0.5 ml of distilled water to form a paste
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): The test article was individually weighed, 0.5 g/site and moistened with 0.5 ml of distilled water to form a pasty consistency.


Duration of treatment / exposure:
Exposure periods of 3 minutes (for initial animal), 1 hour (for initial animal) and 4 hours (all animals)
Observation period:
Up to 7 days.
Number of animals:
3 (1 initial animal (male) and 2 subsequent animals (females)).
Details on study design:
SITE PREPARATION:
The day prior to application of the test article, the dorsal area of the trunk of each animal was clipped free of hair. The prepared site was approximately 10 x 10 cm and remained intact.

DOSING
Initially, one rabbit was dosed on sites #1, 2 and 3 with 0.5 g/site of the test article. The test article was individually weighed, 0.5 g/site and moistened with 0.5 ml of distilled water to form a pasty consistency. The test article was applied under a 2.5 x 2.5 cm gauze patch. Gentle pressure was applied to aid in the distribution of the test article over the prepared site. Each patch was secured with non-irritating tape. Site 1 was covered with a piece of plastic and held in place manually for the three-minute exposure. This method allowed partial removal of the wrapping to expose site #1 at 3 minutes post dose without disturbing sites #2 and 3. Sites 2 and 3 were wrapped with another piece of plastic in a semi-occlusive manner and secured with non-irritating tape. This method of wrapping aids in retaining the test patch in position and retards evaporation of volatile substances.

The wrapping and test article patch covering site #1 was removed at 3 minutes postdose and the site was gently washed with distilled water. A window was cut in the wrapping over site #2 at 1 hour after dosing. The patch was removed and the site gently washed with distilled water. At 4 hours postdose, the torso wrappings and patch covering site #3 were removed and the site gently washed with distilled water.

Since no evidence of a corrosive or severely irritating effect was observed in the initial animal, two additional animals were added to the study. The animals (females) were dosed with 0.5 g of the test article at site #3. After an exposure period of four hours, the wrappings and patches were removed and the sites gently washed with distilled water.


TYPE AND FREQUENCY OF OBSERVATIONS:
The test sites of all animals were scored for dermal irritation at 60 minutes after removal of wrappings. Site #3 (four-hour exposure) was scored at 24, 48 and 72 hours. Reactions were scored again on day 7 following patch removal.

Erythema and edema were scored according to teh numerical Driaze technique. The skin was also evaluated for ulceration and necrosis or any evidence of tissue destruction.

Draize scoring scheme:

Erythema & Eschar
No erythema: 0
Very slight erythema (barely perceptible): 1
Well defined erythema: 2
Moderate to severe erythema: 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth): 4

Edema
No edema: 0
Very slight edema (barely perceptible): 1
Slight edema (edges of area well-defined by definite raising): 2
Moderate edema (raised approximately 1.0 mm): 3
Severe edema (raised more than 1.0 mm, extending beyond the area of exposure): 4

Body weights of all animals were recorded pre-test, 72 hours and at termination.

The general health of the animals was monitered at each observation time. All animals were sacrificed using CO2 following study termination.
Irritation parameter:
erythema score
Basis:
mean
Remarks:
(Animal H510 - initial animal)
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: 24 hours
Remarks on result:
other: Results from 4-hour exposure
Irritation parameter:
erythema score
Basis:
mean
Remarks:
(Animal H599)
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Results from 4-hour exposure
Irritation parameter:
erythema score
Basis:
mean
Remarks:
(Animal H527)
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: Results from 4-hour exposure
Irritation parameter:
edema score
Basis:
mean
Remarks:
(Animal H510 - initial animal))
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: Results from 4-hour exposure
Irritation parameter:
edema score
Basis:
mean
Remarks:
(Animal H599)
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: Results from 4-hour exposure
Irritation parameter:
edema score
Basis:
mean
Remarks:
(Animal H527)
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: Results from 4-hour exposure
Irritant / corrosive response data:
Dermal Observations:
Initial animal:
Erythema was absent at 60 minutes following patch removal following the 3 minute exposure and very slight at 60 minutes following the 1 and 4 hour exposures. Erythema was absent at 24, 48 and 72 hours following the 4 hour exposure. Edema was absent at 60 minutes after patch removal following the 3 minute exposure and following the 1 and 4 hour exposures. Edema was also absent at 24, 48 and 72 hours. On day 7, erythema and edema were absent.

Two additional animals:
Erythema was absent at 60 minutes following the 4 hour exposure and absent to slight at 24, 48 and 72 hours following the 4 hour exposure. On day 7, erythema was absent. Edema was absent at all observation points.
Other effects:
Systemic Observations:
There were no abnormal physical signs noted during the observation period.
All body weight changes were normal.

See attached background material for Table 1: Dermal Observations, Body Weights and Systemic Observations.

Interpretation of results:
GHS criteria not met
Conclusions:
The test substance is not a dermal irritant.
Executive summary:

Objective:

To determine the irritant or corrosive effects, if any, of a test article when applied dermally. The study was designed to comply with the standards set forth in OECD Guidelines for Testing Chemicals, Number 404, adopted April 24, 2002.

Method Synopsis:

Since the test article was suspected to be a severe dermal irritant, one healthy male New Zealand White rabbit was dosed dermally with NIPMMA Technical Grade. The test article (0.5 g) was applied dermally to three intact sites for an exposure period of three minutes on site #1, one hour on site #2 and four hours on site #3. Dermal reactions were scored at 60 minutes after each patch removal on all three sites. Site #3 was scored again at 24, 48 and 72 hours. Reactions were scored again on day 7 following patch removal. The skin was also evaluated for ulceration and necrosis or any evidence of tissue destruction at these time periods. Since the reaction of the initial animal did not produce a corrosive or severely irritating effect, two additional animals (females) were added to the study. The two animals were dosed at site #3 for a four hour exposure. Dermal reactions were scored at 60 minutes, 24, 48 and 72 hours and day 7 after patch removal. Body weights of all animals were recorded pretest, at 72 hours and at termination.

Summary:

Initial animal:

Erythema was absent at 60 minutes following patch removal following the 3 minute exposure and very slight at 60 minutes following the 1 and 4 hour exposures. Erythema was absent at 24, 48 and 72 hours following the 4 hour exposure. Edema was absent at 60 minutes after patch removal following the 3 minute exposure and following the 1 and 4 hour exposures. Edema was also absent at 24, 48 and 72 hours. On day 7, erythema and edema were absent.

Two additional animals:

Erythema was absent at 60 minutes following the 4 hour exposure and absent to slight at 24, 48 and 72 hours following the 4 hour exposure. On day 7, erythema was absent. Edema was absent at all observation points.

Systemic Observations:

There were no abnormal physical signs noted during the observation period.

All body weight changes were normal.

Conclusion:

The test substance is not a dermal irritant.

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:
Experimental Start Date: 11/06/07. Experimental Termination Date: 11/20/07
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: New Zealand White rabbits were received from Millbrook Breeding Labs, MA.
- Age at study initiation: Approximately 3 months old.
- Weight at study initiation: The pretest body weight was 2.6 - 3.1 kg.
- Housing: The animals were housed 1 per cage in suspended cages. Bedding was placed beneath the cages and changed at least three times per week.
- Diet (e.g. ad libitum): Fresh PMO Rabbit Chow was provided daily.
- Water (e.g. ad libitum): Water was available ad libitum.
- Acclimation period: At least five days.
Three animals (1 male, 2 females), free from evidence of occular irritation or abnormalities, were assigned to the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): The animal room was temperature controlled.
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle.

Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml (equivalent 68.3 mg).
Duration of treatment / exposure:
Single exposure
Observation period (in vivo):
Up to 7 days.
Number of animals or in vitro replicates:
3 (1 male, 2 females)
Details on study design:
DOSING:
One eye of each rabbit was dosed. The contralateral eye served as a control. The test article (0.1 ml (equivalent (68.3 mg)) was placed by syringe-type applicator into the conjunctival sac, which was formed by gently pulling the lower eyelid away from the eye. After instillation, the lids were held together for approximately one second to ensure adequate distribution of the test article.

TYPE AND FREQUENCY OF OBSERVATIONS:
Using a Mini-Maglite flashlight equipped with a high intensity bulb, the treated eye of each rabbit was examined for irritation of the cornea, iris and conjunctiva at 1, 24, 48 and 72 hours in all three animals and to day 7 in the two additional animals. Sodium fluorescein dye procedures were used at the 24 and 48 hour observation intervals for the initial animal and at the 24 hour observation interval for the two additional animals. The eye was examined with the aid of an ultraviolet light source.
Ocular reactions were graded according to the numerical Draize technique (see attached background matertial). Additional signs were described.

Body weights were recorded pretest and at termination.

The general health of the animals was monitered at each observation time. All animals were humanely sacrificed using CO2 following study termination.




Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
(Animal 1 - H504)
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: lack of normal luster observed at 24 hour observation
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
(Animal 2 - H512)
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
(Animal 3 - H526)
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Remarks:
(Animal 1 - H504)
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
mean
Remarks:
(Animal 2 - H512)
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
mean
Remarks:
(Animal 3 - H526)
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
(Animal 1 - H504)
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
(Animal 2 - H512)
Time point:
24/48/72 h
Score:
0.67
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
(Animal 3 - H526)
Time point:
24/48/72 h
Score:
1.67
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
(Animal 1 - H504)
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
(Animal 2 - H512)
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
(Animal 3 - H526)
Time point:
24/48/72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritant / corrosive response data:
Ocular Findings (see Table 1 - attached back ground material).
There was no corneal opacity or iritis noted at any observation period. Conjunctival irritation was noted in 3/3 eyes and cleared by day 7.
Other effects:
Systemic Observations (see Table 1 - attached back ground material).
All animals appeared normal during the observation period.
Interpretation of results:
GHS criteria not met
Conclusions:
The test substance produced conjunctival irritation which cleared by day 7.
Executive summary:

Objective:

To determine the irritant and/or corrosive effects, if any, of a test article when instilled into the rabbit eye. The study was designed to comply with the standards set forth in OECD Guidelines For Testing Chemicals, Number 405, adopted April 24, 2002.

Method Synopsis:

Initially, one healthy New Zealand White rabbit (female), free from evidence of ocular irritation and corneal abnormalities, was dosed with NIPMAA Technical Grade. The test article (0.1 ml (equivalent (68.3 mg)) was placed into the conjuctival sac of one eye. Based on the reactions of the initial animal, two additional animals (1 male, 1 female) were added to the study and dosed in the same manner. The eyes were examined and scored by the Draize technique at 1, 24, 48 and 72 hours in all three animals and to day 7 in the two additional animals. Sodium fluorescein dye procedures were used at the 24 and 48 hour observation intervals for the initial animal and at the 24 hour observation interval for the two additional animals. The primary eye irritation score for each rabbit, each day, was calcuated. Body weights were recorded pretest and at termination.

Summary:

There was no corneal opacity or iritis noted at any observation period. Conjunctival irritation was noted in 3/3 eyes and cleared by day 7.

All animals appeared normal during the observation period.

Conclusion:

NIPMAA Technical Grade produced conjunctival irritation which cleared by day 7.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin Irritation/Corrosion:

Objective:

To determine the irritant or corrosive effects, if any, of a test article when applied dermally. The study was designed to comply with the standards set forth in OECD Guidelines for Testing Chemicals, Number 404, adopted April 24, 2002.

Method Synopsis:

Since the test article was suspected to be a severe dermal irritant, one healthy male New Zealand White rabbit was dosed dermally with the test item. The test article (0.5 g) was applied dermally to three intact sites for an exposure period of three minutes on site #1, one hour on site #2 and four hours on site #3. Dermal reactions were scored at 60 minutes after each patch removal on all three sites. Site #3 was scored again at 24, 48 and 72 hours. Reactions were scored again on day 7 following patch removal. The skin was also evaluated for ulceration and necrosis or any evidence of tissue destruction at these time periods. Since the reaction of the initial animal did not produce a corrosive or severely irritating effect, two additional animals (females) were added to the study. The two animals were dosed at site #3 for a four hour exposure. Dermal reactions were scored at 60 minutes, 24, 48 and 72 hours and day 7 after patch removal. Body weights of all animals were recorded pretest, at 72 hours and at termination.

Summary:

Initial animal:

Erythema was absent at 60 minutes following patch removal following the 3 minute exposure and very slight at 60 minutes following the 1 and 4 hour exposures. Erythema was absent at 24, 48 and 72 hours following the 4 hour exposure. Edema was absent at 60 minutes after patch removal following the 3 minute exposure and following the 1 and 4 hour exposures. Edema was also absent at 24, 48 and 72 hours. On day 7, erythema and edema were absent.

Two additional animals:

Erythema was absent at 60 minutes following the 4 hour exposure and absent to slight at 24, 48 and 72 hours following the 4 hour exposure. On day 7, erythema was absent. Edema was absent at all observation points.

Systemic Observations:

There were no abnormal physical signs noted during the observation period.

All body weight changes were normal.

Conclusion:

The test substance is not a dermal irritant.

Eye Irritation/Corrosion:

Objective:

To determine the irritant and/or corrosive effects, if any, of a test article when instilled into the rabbit eye. The study was designed to comply with the standards set forth in OECD Guidelines For Testing Chemicals, Number 405, adopted April 24, 2002.

Method Synopsis:

Initially, one healthy New Zealand White rabbit (female), free from evidence of ocular irritation and corneal abnormalities, was dosed with NIPMAA Technical Grade. The test article (0.1 ml (equivalent (68.3 mg)) was placed into the conjuctival sac of one eye. Based on the reactions of the initial animal, two additional animals (1 male, 1 female) were added to the study and dosed in the same manner. The eyes were examined and scored by the Draize technique at 1, 24, 48 and 72 hours in all three animals and to day 7 in the two additional animals. Sodium fluorescein dye procedures were used at the 24 and 48 hour observation intervals for the initial animal and at the 24 hour observation interval for the two additional animals. The primary eye irritation score for each rabbit, each day, was calcuated. Body weights were recorded pretest and at termination.

Summary:

There was no corneal opacity or iritis noted at any observation period. Conjunctival irritation was noted in 3/3 eyes and cleared by day 7.

All animals appeared normal during the observation period.

Conclusion:

The test substance produced conjunctival irritation which cleared by day 7.


Justification for selection of skin irritation / corrosion endpoint:
The study has been conducted according to OECD Guideline 404 and GLP and is adequately reported. The study has been assigned a reliability 1.

Justification for selection of eye irritation endpoint:
The study has been conducted according to OECD Guideline 405 and GLP and is adequately reported. The study has been assigned a reliability 1.

Justification for classification or non-classification

The results from skin irritation and eye irritation studies were evaluated according to the Classification, Labelling and Packaging Regulation (CLP).

Skin irritation:

The test item produced a maximum individual mean score of 1 for erythema (based on scores at 24, 48 and 72) in one animal only and therefore does not meet the criteria for classification according to the Classification, Labelling and Packaging Regulation (CLP).

Eye irritation:

The test item does not meet the criteria for classification according to the Classification, Labelling and Packaging Regulation (CLP), as although some minor conjunctival irritation was observed, all effects cleared by day 7 for 1 animal and by 72 hours for 2 animals. The effects were insufficient to meet the criteria for classification according to the Classification, Labelling and Packaging Regulation.