Registration Dossier

Skin irritation/corrosion: Non irittating in rabbits.

Eye irritation: Not irritating in the eyes of rabbits.

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14 August 1989 to 16 October 1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

other: Pesticide Assessment Guidelines, Subdivision F. Hazard Evaluation: Human and Domestic Animals, U. S. Environmental Protection Agency Office of Pesticide and Toxic Substances Series 81-5, pp. 55-59, November 1982.

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Test Animal: Adult albino rabbits, Hra:(NZW)SPF, were procured, maintained individually in screen-bottom cages in temperature- and humidity-controlled quarters, provided access to water ad libitum and a measured amount of High Fiber Rabbit Chow® 5326, Purina Mills, Inc., and held for an acclimation period of at least 7 days. Animal husbandry and housing at HLA comply with standards outlined in the "Guide for the Care and Use of laboratory Animals”. If variations from the prescribed environmental conditions existed, they were documented and considered to have no effect on the study outcome. No contaminants were expected to have been present in the feed or water which would have interfered with or affected the results of the study.
Three male and three female acclimated animals, weighing from 2320 to 2436 g, were chosen at random for the test, and maintained during the observation period as specified for the acclimation period. Test animals were identified by animal number and corresponding ear tag.
Reason for Species Selection: Historically, the New Zealand White albino rabbit has been the animal of choice for evaluating the effect of chemicals on the skin.

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

physiological saline

Controls:

no

Amount / concentration applied:

0.5 g and moistened with 0.9% saline.

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

three males and three females.

Details on study design:

Approximately: 24 hours before treatment the hair was clipped from the back and flanks of each animal.
Preparation of Test Material: The sample was dosed as received.
Treatment: The test material was applied to the intact skin of each rabbit in the amount of 0.5 g and moistened with 0.9% saline. The treated area was covered with a 2.5 x 2.5 cm gauze patch secured with paper tape, loosely overwrapped with Saran Wrap® and secured with Elastoplast® tape to provide a semiocclusive dressing. Collars were applied to restrain the test animals for the 4-hour exposure period.
Reason for Route of Administration: Historically the dermal route is the route of choice based on the method of Draize.
Observations: After the exposure period, the patches were removed. The test sites were washed using lukewarm tap water and disposable paper towels. The test material was removed from the test sites as thoroughly as possible without irritating the skin. Thirty minutes following removal of the test material, the degree of erythema and edema was read according to the Draize technique (recorded as the 4-hour score). Subsequent examinations were made at 24, 48 and 72 hours after patch removal.
Individual body weights were taken just prior to study initiation.
Termination: At study termination all animals were euthanatized and discarded.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

Application of Mark HP-10 to rabbits under 4-hour semi occluded conditions resulted in no dermal irritation in any of the six albino rabbits.

Individual dermal Irritation Scores

Animal Number	Sex	Erythema (hour)				Edema (Hour)
Animal Number	Sex	4	24	48	72	4	24	48	72
F29514	M	0	0	0	0	0	0	0	0
F29498	M	0	0	0	0	0	0	0	0
F29516	M	0	0	0	0	0	0	0	0
F29517	F	0	0	0	0	0	0	0	0
F29518	F	0	0	0	0	0	0	0	0
F29519	F	0	0	0	0	0	0	0	0

Average Primary Dermal Irritation Scores*

Observation Period (Hour)	Average Score
4	0.0
24	0.0
48	0.0
72	0.0

*The average primary dermal irritation score is the total dermal irritation score for all the animals (erythema and edema) divided by the number of test sites at each observation period.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Application of Mark HP-10 to rabbits under 4-hour semi occluded conditions resulted in no dermal irritation in any of the six albino rabbits. The average of the 4-, 24-, 48-, and 72-hour scores is 0.0 (considered to be non irritating).

Executive summary:

To assess the relative level of primary skin irritation of a test material on rabbits under semi occluded conditions according to the U. S. Environmental Protection Agency's Guidelines for Testing Pesticides and Toxic Substances.

Regulatory Compliance: This study was conducted in accordance with the U.S. Environmental Protection Agency Good laboratory Practice Standards, 40 CFR 792 (November 29, 1983), the Food and Drug Administration Good Laboratory Practice Regulati9ns, 21 CFR 58, and the proposed Organisation for Economic Cooperation and Development's Principles of Good Laboratory Practice,

Annex 2, C(81)30. The in-life portion of the study was done before the effective date of the revised EPA standards (September 18, 1989).

The test material, Mark HP-10, was evaluated for its primary dermal irritation potential in male and female albino rabbits. The test material produced no dermal reactions at any of the observations. The average of the 4-, 24-, 48-, and 72-hour scores is 0.0 (considered to be non irritating).

Endpoint conclusion:

no adverse effect observed (not irritating)

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

17 to 20 August 1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study performed in accordance with US EPA test guideline in compliance with GLP

Qualifier:

according to guideline

Guideline:

other: U.S. Environmental Protection Agency Good Laboratory Practice Standards, 40 CFR 792 (November 29, 1983)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

Test Animal: Adult albino rabbits, Hra:(NZW)SPF, were procured, maintained individually in screen-bottom cages in temperature- and humidity-controlled quarters, provided access to water ad libitum and a measured amount of High Fiber Rabbit Chow® 5326, Purina Mills, Inc., and held for an acclimation period of at least 7 days. Animal husbandry and housing at HLA comply with standards outlined in the “Guide for the Care and Use of Laboratory Animals". If variations from the prescribed environmental conditions existed, they were documented and considered to have no effect on the study outcome. No contaminants were expected to have been present in the feed or water which would have interfered with or affected the results of the study.
Three male and three female acclimated animals, weighing from 2020 to 2390 g, were chosen at random for the test.
Reason for Species Selection: Historically, the New Zealand White albino rabbit is the animal of choice based upon its large orbit and non pigmented iris.

Vehicle:

not specified

Controls:

yes, concurrent no treatment

Amount / concentration applied:

0.04 g (0.1 ml weight equivalent)

Duration of treatment / exposure:

Single exposure

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

3 males & 3 females

Details on study design:

The animals' eyes were examined approximately 24 hours prior to test material administration using sodium fluorescein dye procedures. Only those animals with no sign of ocular injury or irritation were used on the test. Test animals were identified by animal number and corresponding ear tag.
Preparation of Test Material: A bulk density determination was made to determine the weight equivalent of a 0.1-ml dose. An individual dose of 0.04 g was weighed out for each animal.
Treatment: Each rabbit received 0.04 g (0.1 ml weight equivalent) of the test material placed into the everted lower lid of one eye, with the contralateral eye serving as the untreated control. The upper and lower lids were gently held together for 1 second to prevent loss of material and then released. The eyes of the rabbits remained unflushed.
Reason for Route of Administration: Historically, the ocular route is the route of choice based on the method of Draize.
Observations: The treated eyes were observed for ocular irritation at 1, 24, 48, and 72 hours after treatment.
At the 72-hour reading, sodium fluorescein was used to aid in revealing possible corneal injury. Irritation was graded and scored according to the Draize technique.
Animals were weighed just prior to test material administration.
Termination: At study termination all animals were euthanatized and discarded.
Statistical Methods: No statistical method was performed.

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other:

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

fully reversible within: 72 h

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.33

Max. score:

1

Reversibility:

fully reversible within: 48 h

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.33

Max. score:

1

Reversibility:

fully reversible within: 48 h

Irritation parameter:

conjunctivae score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0.33

Max. score:

1

Reversibility:

fully reversible within: 48 h

Irritation parameter:

conjunctivae score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0.33

Max. score:

1

Reversibility:

fully reversible within: 48 h

Irritation parameter:

conjunctivae score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0.33

Max. score:

1

Reversibility:

fully reversible within: 48 h

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not apllicable

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: not applicable

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No pain response was elicited from any animal following instillation of the test material.

Other effects:

Blanching of the conjunctivae was seen in one animal at 1 hour.

Table 1 Individual Eye Irritation Scores

Animal Number	Observation Period (Hour)	Cornea		Score AXBX5	Iris A	Score A X 5	Conjunctivae			Score (A+B+C)X2
Animal Number	Observation Period (Hour)	A	B	Score AXBX5	Iris A	Score A X 5	A	B	C	Score (A+B+C)X2
F29713	1	0	0	0	1	5	3	1	3	14
	24	0	0	0	0	0	2	0	0	4
	48	0	0	0	0	0	1	0	0	2
	72	0	0	0	0	0	0	0	0	0
F29714	1	0	0	0	0	0	1	0	0	2
	24	0	0	0	0	0	1	0	0	2
	48	0	0	0	0	0	0	0	0	0
	72	0	0	0	0	0	0	0	0	0
F29715	1	0	0	0	0	0	2	0	1	6
	24	0	0	0	0	0	1	0	0	2
	48	0	0	0	0	0	0	0	0	0
	72	0	0	0	0	0	0	0	0	0
F29722	1	0	0	0	2	5	2	0	1	6
	24	0	0	0	0	0	1	0	0	2
	48	0	0	0	0	0	0	0	0	0
	72	0	0	0	0	0	0	0	0	0
F29717	1	0	0	0	1	5	2	0	1	6
	24	0	0	0	0	0	1	0	0	2
	48	0	0	0	0	0	0	0	0	0
	72	0	0	0	0	0	0	0	0	0
F29718	1	0	0	0	0	0	2	0	1	6
	24	0	0	0	0	0	1	0	0	2
	48	0	0	0	0	0	0	0	0	0
	72	0	0	0	0	0	0	0	0	0

Cornea Conjunctivae

A – Degree of opacity A – Redness

B – Area of involvement B – Chemosis

C – Discharge

Table 2 Sodium Fluorescein Examination

Animal Number	Observation Period
Animal Number	Pre-initiation	72 Hour
F29713	NEG	NEG
F29714	NEG	NEG
F29715	NEG	NEG
F29722	NEG	NEG
F29717	NEG	NEG
F29718	NEG	NEG

NEG – No stain retention

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test material, Mark HP-10, produced iridal involvement and moderate to severe conjunctival irritation when instilled into the eyes of six albino rabbits. All ocular irritation cleared within 72 hours after instillation of the test material.

Executive summary:

Objective: To assess the relative level of irritation produced following a single exposure of a test material to one eye of albino rabbits.

Regulatory Compliance: This study was conducted in accordance withtheU.S. Environmental Protection Agency Good Laboratory Practice Standards, 40 CFR 792 (November 29, 1983), the Food and Drug Administration Good Laboratory Practice Regulations, 21 CFR58,and the proposed Organisation for Economic Cooperation and Development's Principles of Good Laboratory Practice,

Annex 2, C(81)30 . The in-life portion of the study was done before the effective date of the revised EPA standards (September 18, 1989).

The test material, Mark HP-10, produced iridal involvement and moderate to severe conjunctival irritation when instilled into the eyes of six albino rabbits. All ocular irritation cleared within 72 hours after instillation of the test material.

Endpoint conclusion:

no adverse effect observed (not irritating)

Endpoint conclusion:

no study available

Skin Irritation/Corrosion

To assess the relative level of primary skin irritation of a test material on rabbits under semi occluded conditions according to the U. S. Environmental Protection Agency's Guidelines for Testing Pesticides and Toxic Substances. The in-life portion of the study was done before the effective date of the revised EPA standards (September 18, 1989).

The test material, Mark HP-10, was evaluated for its primary dermal irritation potential in male and female albino rabbits. The test material produced no dermal reactions at any of the observations. The average of the 4-, 24-, 48-, and 72-hour scores is 0.0 (considered to be non irritating).

Eye Irritation

To assess the relative level of irritation produced following a single exposure of a test material to one eye of albino rabbits. The in-life portion of the study was done before the effective date of the revised EPA standards (September 18, 1989).

The test material, Mark HP-10, produced iridal involvement and moderate to severe conjunctival irritation when instilled into the eyes of six albino rabbits. All ocular irritation cleared within 72 hours after instillation of the test material.

Justification for selection of skin irritation / corrosion endpoint:

Endpoint conclusion dervied using a GLP compliant study.

Justification for selection of eye irritation endpoint:

Endpoint conclusion dervived using a GLP compliant study.

Based on the avaiable data the substance does not trigger any of the requirements for classification, therefore the substance is Not Classified as a skin or eye irritant.