Registration Dossier

The skin and eye irritation potential of IPHA was examined in GLP-compliant studies following similar priciples as in the OECD guidelines. IPHA did not meet the CLP classification criteria for skin or eye irritation.

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

April 1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was not conducted according to guidelines but was conducted according to GLPs and the report contains sufficient data for interpretation of study results

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Principles of method if other than guideline:

Essentially followed the Draize test.

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Young adult New Zealand,hnite rabbits (Ace Animals, Inc., Boyertown, PAl were acclimated to the FDRL laboratory environment for a minimum of 5 days. They were observed daily during the acclimation period to assure their sui tabU i ty as test animals. All' housing and care conformed to the standards established in "Guide for the Care and Use of Laboratory Animals" DHEW Publication No. (NIH) 85-23. The animals were individually housed in wire-mesh cages. Food (NIH 09 Rabbit Ration, Zeigler Brothers, Inc., Gardners, PA) and fresh tap water were supplied ad libitum. Animals were identified with ear tags and color coded cage cards. Six animals weighing between two and three kilograms were randomly selected from the acclimating animals and assigned to the test group.

Type of coverage:

semiocclusive

Preparation of test site:

other: The back of each rabbit was clipped with an electric clipper on the day prior to dosing.

Vehicle:

physiological saline

Remarks:

Applied to the test material following applicaton on rabbit skin.

Controls:

not specified

Amount / concentration applied:

Each rabbit was administered 0.5 g of the test article moistened with 0.5 ml of physio]ogical saline to two non-abraded test sites.

Duration of treatment / exposure:

The binders and collars were removed four hours post-dose administration and the exposure sites gently wiped with gauze to remove as much non-absorbed test article as possible.

Observation period:

Test Site Evaluation
Dermal irritation was evaluated at 4.5, 28, 52 and 76 hours as well as 4, 7 and 10 days post-dose administration. Erythema and edema were scored
separately according to the Draize method.

Observations
The animals were observed daily for mortality and overt pharmacotoxic signs. Body weights were obtained on study day 1, prior to dose . administration. At study termination, the animals were euthanized by intracardiac injection of sodium pentobarbital and discarded.

Number of animals:

6 rabbits

Details on study design:

Dose Administration
The back of each rabbit was clipped with an electric clipper on the day prior to dosing. The test article was topically applied to two non-abraded dorsal test sites per rabbit and moistened with physiological saline. The test sites were wrapped with semi-occlusive binders consisting of a one-inch square gauze patch and Micropore® tape immediately after dosing. The animals were fitted with circular collars during the exposure period to prevent removal of the patches. The binders and collars were removed four hours post-dose administration and the exposure sites gently wiped with gauze to remove as much non-absorbed test article as possible.

Irritation parameter:

edema score

Basis:

animal: all

Time point:

other: all timepoints

Score:

0

Max. score:

0

Irritation parameter:

erythema score

Basis:

mean

Remarks:

all animals

Time point:

other: mean across 28/52/76 hrs

Score:

0.9

Max. score:

2

Reversibility:

fully reversible within: 10 days

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: mean across 28/52/76 hrs

Score:

0

Max. score:

0

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

other: mean across 28/52/76 hrs

Score:

1

Max. score:

1

Reversibility:

fully reversible within: 10 days

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

other: mean across 28/52/76 hrs

Score:

0

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

other: mean across 28/52/76 hrs

Score:

1

Max. score:

1

Reversibility:

fully reversible within: 10 days

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

other: mean across 28/52/76 hrs

Score:

1.7

Max. score:

2

Reversibility:

fully reversible within: 10 days

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

other: mean across 28/52/76 hrs

Score:

1.7

Max. score:

2

Reversibility:

fully reversible within: 10 days

Irritant / corrosive response data:

Dermal irritation was not noted in any animal 4.5 hours post-dose. At 24 hours, four animals exhibited slight erythema. Irritation was still evident at 52, 76 hours and day 4. At day 7, slight erythema was noted in one animal. There was no evidence of edema at any time through the 10 day observation period. All test sites appeared normal at day 10 and the study was terminated.

Other effects:

No overt pharmacotoxic signs were noted in any animal.

Animal number	Scoring	Test site	28 hr	52 hr	76 hr
1	Erythema	left	0	0	0
	Erythema	right	0	0	0
1	Edema	left	0	0	0
	Edema	right	0	0	0
2	Erythema	left	1	1	1
	Erythema	right	1	1	1
	Edema	left	0	0	0
	Edema	right	0	0	0
3	Erythema	left	0	0	0
	Erythema	right	0	0	0
3	Edema	left	0	0	0
	Edema	right	0	0	0
4	Erythema	left	1	1	1
	Erythema	right	1	1	1
4	Edema	left	0	0	0
	Edema	right	0	0	0
5	Erythema	left	1	2	2
	Erythema	right	1	1	1
5	Edema	left	0	0	0
	Edema	right	0	0	0
6	Erythema	left	1	2	2
	Erythema	right	1	1	1
6	Edema	left	0	0	0
	Edema	right	0	0	0

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: OECD GHS

Conclusions:

N-Isopropylhydroxylamine was slightly irritating to the skin of six New Zealand White rabbits following four-hour, semi-occlusive topical exposure. The mean primary dermal irritation score of the test group was 0.78. All edema scores were 0. Erythema mean scores across all animals and the 28, 52 and 76 hr readings were 0.9. The test sites showed normal by day 10.

Executive summary:

N-Isopropylhydroxylamine was evaluated for potential primary dermal irritation using six New Zealand White rabbits. Each rabbit was administered 0.5 g of the test article moistened with 0.5 ml of physiological saline to two non-abraded test sites. The test sites were semi-occlusively wrapped for four hours following dose administration. Dermal irritation was scored at 4.5, 28, 52 and 76 hours as well as 4, 7 and 10 days post-administration according to the Draize method.

Under the conditions of this study, the mean primary dermal irritation score was 0.78 based on Draize methodolgy. All edema scores were 0. Erythema mean scores across all animals and the 28, 52 and 76 hr readings were 0.9. The test sites showed normal by day 10. According to Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, N-Isopropylhydroxylamine is not classified for skin irritation.

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:

6 - 9 April 1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was not conducted according to guidelines but was conducted according to GLPs and the report contains sufficient data for interpretation of study results

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

may have used more animals

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

Young adult New Zealand White rabbits (Ace Animals Inc., Boyertown, PA) were acclimated to the FDRL laboratory environment for a minimum of 5 days. They were observed daily during the acclimation period to assure their suitability as test animals. All housing and care conformed to the standards established in "Guide for the Care and Use of Laboratory Animals" DHEW Publication No. (NIH) 85-23. The animals were individually housed in wire-mesh cages. Food (NIH 09 Rabbit Ration, Zeigler Brothers, Inc., Gardners, PA) and fresh tap water were supplied ad libitum. Animals were identified with ear tags and color coded cage cards. Nine animals weighing between two and three kilograms were randomly selected from the acclimating animals and assigned to either the non-irrigated or irrigated test group (six and three animals, respectively). The eyes of each rabbit were examined with
sodium fluorescein and an ultraviolet lamp on the day prior to dosing to verify the absence of preexisting ocular lesions.

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

The test article (0.1 g) was instilled into one eye of each rabbjt.

Duration of treatment / exposure:

The lower eyelid was gently pulled away from the eyeball to form a cup (conjunctival sac) and the test article inserted therein. The lids were then held together for one secotld and released. The treated eye of six animals remajned non-irrigated. The treated eyes of the remaining three animals were thoroughly irrigated with physiological saline beginning thirty seconds after test article instillation.

Observation period (in vivo):

Primary eye irritation was evaluated at 1, 24, 48 and 72 hours post-dose administration. The cornea, iris and conjunctiva were scored separately according to the Draize system (Draize, 1959).

Reference
Draize, J.H., 1959, Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, In: Association of Food and Drug Officials in the United States, Austin, Texas.

Number of animals or in vitro replicates:

Nine rabbits were used. The treated eye of six animals remajned non-irrigated. The treated eyes of the remaining three animals were thoroughly irrigated with physiological saline beginning thirty seconds after test article instillation.

Details on study design:

No additional information available.

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

all animals

Time point:

other: 24/48/72

Score:

0.28

Max. score:

1

Reversibility:

fully reversible within: 72 hrs

Irritation parameter:

iris score

Basis:

mean

Remarks:

all animals

Time point:

other: 24/48/72

Score:

0

Max. score:

0

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

mean

Remarks:

all animals

Time point:

other: 24/48/72

Score:

0.89

Max. score:

2

Reversibility:

fully reversible within: 72 hrs

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

all animals

Time point:

other: 24/48/72

Score:

0.28

Max. score:

1

Reversibility:

fully reversible within: 48 hrs

Irritant / corrosive response data:

Non-Irrigated Group:
All animals exhibited slight to moderate conjunctival redness, swelling, blistering and discharge at 1 hour post-dose. Corneal opacity was noted in four of six animals at 24 hours post-dose. These effects were reversible by 72 hours post-dose.
Irrigated Group:
At 1- hour post-dose administration all animals exhibited slight conjunctival redness. In addition, conjunctival swelling, blistering and discharge were noted in two animals. At 24 hours, corneal opacity was noted in two animals. These effects were reversible by 72 hours post-dose administration.

Other effects:

Observations
No overt pharmacotoxic signs were noted in any animal.

Animal Number	Tissue	24 hr	48 hr	72 hr	Comment
1	Corneal opacity	1	0	0	unrinsed
	Iris	0	0	0	unrinsed
	Conjunctiva redness	2	1	0	unrinsed
	Conjunctiva chemosis	1	0	0	unrinsed
2	Corneal opacity	1	0	0	unrinsed
	Iris	0	0	0	unrinsed
	Conjunctiva redness	2	1	0	unrinsed
	Conjunctiva chemosis	1	0	0	unrinsed
3	Corneal opacity	1	1	0	unrinsed
	Iris	0	0	0	unrinsed
	Conjunctiva redness	2	1	0	unrinsed
	Conjunctiva chemosis	1	0	0	unrinsed
4	Corneal opacity	0	0	0	unrinsed
	Iris	0	0	0	unrinsed
	Conjunctiva redness	2	1	0	unrinsed
	Conjunctiva chemosis	1	0	0	unrinsed
5	Corneal opacity	0	0	0	unrinsed
	Iris	0	0	0	unrinsed
	Conjunctiva redness	1	0	0	unrinsed
	Conjunctiva chemosis	0	0	0	unrinsed
6	Corneal opacity	1	0	0	unrinsed
	Iris	0	0	0	unrinsed
	Conjunctiva redness	2	1	0	unrinsed
	Conjunctiva chemosis	1	0	0	unrinsed
7	Corneal opacity	0	0	0	rinsed 30 seconds after instillation
	Iris	0	0	0	rinsed 30 seconds after instillation
	Conjunctiva redness	1	1	0	rinsed 30 seconds after instillation
	Conjunctiva chemosis	0	0	0	rinsed 30 seconds after instillation
8	Corneal opacity	1	1	0	rinsed 30 seconds after instillation
	Iris	0	0	0	rinsed 30 seconds after instillation
	Conjunctiva redness	2	0	0	rinsed 30 seconds after instillation
	Conjunctiva chemosis	1	0	0	rinsed 30 seconds after instillation
9	Corneal opacity	1	0	0	rinsed 30 seconds after instillation
	Iris	0	0	0	rinsed 30 seconds after instillation
	Conjunctiva redness	1	1	0	rinsed 30 seconds after instillation
	Conjunctiva chemosis	0	0	0	rinsed 30 seconds after instillation

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: OECD GHS

Conclusions:

N-Isopropylhydroxylamine produced corneal opacity and conjunctival irritation to rabbits' eyes without irrigation. These effects were reversible in both groups by 72 hours post-dose administration. The mean scores across timepoints per animal and across all scores were below the GHS/CLP classification thresholds for all endpoints.

Executive summary:

N-Isopropylhydroxylamine was evaluated for potential primary eye irritation using nine New Zealand White rabbits. Each rabbit was administered 0.1 g of the test article to the conjunctival sac of one eye. The untreated contralateral eye of each rabbit served as a control. The treated eye of three rabbits was irrigated with physiological saline thirty seconds after test article administration.

Treated and untreated eyes were examined at 1, 24, 48 and 72 hours post-administration and ocular irritation scored according to the Draize method.

Under the conditions of this study, N-Isopropylhydroxylamine produced corneal opacity and conjunctival irritation to rabbits' eyes without irrigation. Corneal opacity and conjunctival irritation was produced by N-Isopropylhydroxylamine to the rabbits' eyes irrigated thirty seconds after instillation. These effects were reversible in both groups by 72 hours post-dose administration.

According to Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, the test material would not be classified for eye irritation.

Endpoint conclusion:

no adverse effect observed (not irritating)

Endpoint conclusion:

no study available

Skin Irritation:

N-Isopropylhydroxylamine was evaluated for potential primary dermal irritation using six New Zealand White rabbits. Each rabbit was administered 0.5 g of the test article moistened with 0.5 ml of physiological saline to two non-abraded test sites. The test sites were semi-occlusively wrapped for four hours following dose administration. Dermal irritation was scored at 4.5, 28, 52 and 76 hours as well as 4, 7 and 10 days post-administration according to the Draize method.

Under the conditions of this study, the mean primary dermal irritation score was 0.78 based on Draize methodolgy. All edema scores were 0. Erythema mean scores across all animals and the 28, 52 and 76 hr readings were 0.9. The test sites showed normal by day 10. According to Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, N-Isopropylhydroxylamine is not classified for skin irritation.

Eye Irritation:

N-Isopropylhydroxylamine was evaluated for potential primary eye irritation using nine New Zealand White rabbits. Each rabbit was administered 0.1 g of the test article to the conjunctival sac of one eye. The untreated contralateral eye of each rabbit served as a control. The treated eye of three rabbits was irrigated with physiological saline thirty seconds after test article administration.

Treated and untreated eyes were examined at 1, 24, 48 and 72 hours post-administration and ocular irritation scored according to the Draize method.

Under the conditions of this study, N-Isopropylhydroxylamine produced slight corneal opacity and slight to minimal conjunctival irritation to rabbits' eyes without irrigation. Corneal opacity and conjunctival irritation was produced by N-Isopropylhydroxylamine to the rabbits' eyes irrigated thirty seconds after instillation. These effects were reversible in both groups by 72 hours post-dose administration.

According to Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, the test material would not be classified for eye irritation.

Justification for selection of skin irritation / corrosion endpoint:
The study was not conducted according to guidelines but was conducted according to GLPs and the report contains sufficient data for interpretation of study results

Justification for selection of eye irritation endpoint:
The study was not conducted according to guidelines but was conducted according to GLPs and the report contains sufficient data for interpretation of study results

Effects on skin irritation/corrosion: slightly irritating

According to the criteria of Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, IPHA is not classificable regarding its skin or eye irritancy.