1-methylpiperidin-4-ol

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data from peer reviewed journal

Data source

Reference

Reference Type:

publication

Title:

Treatment of Ocular Tissues Exposed to Nitrogen Mustard: Beneficial Effect of Zinc Desferrioxamine Combined with Steroids

Author:

Yair Morad, Eyal Banin, Edward Averbukh, Eduard Berenshtein, Alexey Obolensky and Mordechai Chevion

Year:

2005

Bibliographic source:

Invest Ophthalmol Vis Sci. 2005; 46:1640–1646

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

To assess the extent of ocular injury caused by the test chemical in animals.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Chlormethine

EC Number:

200-120-5

EC Name:

Chlormethine

Cas Number:

51-75-2

Molecular formula:

C5H11Cl2N

IUPAC Name:

bis(2-chloroethyl)(methyl)amine

Test material form:

liquid

Details on test material:

Name of test material (as cited in study report):2,2'-Dichloro-N-methyldiethylamine
Common name: nitrogen mustard(NM)
Molecular formula : C5H11Cl2N
Molecular weight : 156.055 g/mol
InChI: 1S/C5H11Cl2N/c1-8(4-2-6)5-3-7/h2-5H2,1H3
Subsatnce type: Organic
Physical State: Liquid

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

A total of 56 New Zealand Albino rabbits weighing 2.5 to 3.5 kg were used. All animal experiments were conducted in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

Test system

Vehicle:

other: saline

Controls:

other: control eyes (four additional animals, eight eyes), saline solution (instead of NM) was applied to the cornea for 5 minutes

Amount / concentration applied:

NM (mechlorethamine), at a concentration of 2% in saline

Duration of treatment / exposure:

5 minutes

Observation period (in vivo):

Slit lamp observations were performed 24 hours after exposure and subsequently after 4,7,10,14,17,21,25,29 days

Number of animals or in vitro replicates:

One eye in each of 52 rabbits was exposed to 2% nitrogen mustard (NM).

Details on study design:

TEST SITE
- Area of exposure: the test chemical was applied to the cornea of one eye of each animal (the experimental eye) for 5 minutes within a trephine
- % coverage:
- Type of wrap if used: NM was quickly absorbed from within the trephine with small Weck-cell sponges (Invotec International, Inc., Jacksonville, FL), followed by washing of the eye with copious amounts of normal saline

REMOVAL OF TEST SUBSTANCE
- Washing (if done): followed by washing of the eye with copious amounts of normal saline
- Time after start of exposure: after 5 minutes

SCORING SYSTEM:
Slit-lamp examinations were performed at 24 hours after exposure, and subsequently at days 4, 7, 10, 14, 17, 21, 25, and 29. In each examination, the following parameters were recorded:
1. Area of corneal epithelial loss (corneal erosion): The average horizontal and vertical linear dimensions of the epithelial defect as stained by locally applied fluorescein were measured with the adjustable slit lamp beam and the area computed in square millimeters.
2. Degree of corneal opacity: grade 0, clear cornea with details of iris observed clearly; grade 1, mild blurring of iris details; grade 2, moderate opacity with blurred iris crypts; and grade 3, severe corneal opacity, no iris details visible.
3. Degree of iris pigmentation: grade 0, no pigmentation; grade 1, mild; grade 2, moderate; grade 3, severe iris pigmentation.
4. Degree of corneal neo-vascularization (CNV): grade 0, no pigmentation; grade 1, mild; grade 2, moderate; grade 3, severe iris pigmentation.
Additional observations included extent of eyelid and conjunctiva swelling and injection; anterior chamber reaction; iris atrophy and, when present, hyphema, corneal ectasia, perforation, and the resultant endophthalmitis.

Results and discussion

In vivo

Results

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 1 day after exposure

Reversibility:

not specified

Remarks on result:

other: Exposure to the test chemical causes severe and long lasting injury

Irritant / corrosive response data:

Exposure to NM causes severe and long-lasting injury to ocular anterior segment structures.

Other effects:

Injury to the conjunctiva and cornea in a saline-administered eye 1 day after exposure to 2% NM was noted. Conjunctival and corneal injury, scarring, and neo-vascularization evolved over the entire duration of the experiment (4 weeks) in such eyes. Corneal Neo- vascularization developed to various degrees in all groups after exposure to NM. An increase in Intra Ocular Pressure occurred after exposure to NM, peaking at day 4 in all study groups. Exposure to NM caused iris atrophy and pigmentation together with pupil dilation in all study groups.

Applicant's summary and conclusion

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

An ocular irritation study was performed to assess the level of ocular injury caused due to exposure to Nitrogen mustard. Exposure to NM causes severe and long-lasting injury to ocular anterior segment structures. Injury to the conjunctiva and cornea in a saline-administered eye 1 day after exposure to 2% NM was noted. Corneal Neo- vascularization developed to various degrees in all groups after exposure to NM. An increase in Intra Ocular Pressure occurred after exposure to NM, peaking at day 4 in all study groups. Exposure to NM caused iris atrophy and pigmentation together with pupil dilation in all study groups.
On the basis of these observations, we can consider Nitrogen mustard to be irritating to eyes.

Executive summary:

An ocular irritation study was performed to assess the level of ocular injury caused due to exposure to Nitrogen mustard (NM). A total of 52 New Zealand Albino rabbits weighing 2.5 to 3.5 kg were used. All animal experiments were conducted in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. One eye in each of 52 rabbits was exposed to 2% nitrogen mustard (NM).Eight eyes (four animals) that were not exposed to NM served as the control. Animals were anesthetized with ketamine HCl (Ketalar, 50mg/kg) injected intramuscularly in combination with the relaxing agent xylazine (0.5 mg/kg). Local anesthetic drops (benoxinate HCl 0.4) were administered. Briefly, NM (mechlorethamine), at a concentration of 2% in saline, was applied to the cornea of one eye of each animal (the experimental eye) for 5 minutes within a trephine. Immediately after application, NM was quickly absorbed from within the trephine with small Weck-cell sponges, followed by washing of the eye with copious amounts of normal saline. In control eyes (four additional animals, eight eyes), saline solution (instead of NM) was applied to the cornea for 5 minutes, also within the trephine. Incontrol experiments, the vehicle (saline) was used as eye drops after exposure to NM. During the experiment and follow-up, intramuscular dipyrone injections (10 mg/kg) were given to animals showing pain or distress. Slit-lamp examinations were performed at 24 hours after exposure, and subsequently at days 4, 7, 10, 14, 17, 21, 25, and 29. In each examination, the following parameters were recorded: Area of corneal epithelial loss (corneal erosion), Degree of corneal opacity, Degree of iris pigmentation, Degree of corneal neo-vascularization (CNV).

Exposure to NM causes severe and long-lasting injury to ocular anterior segment structures. Injury to the conjunctiva and cornea in a saline-administered eye 1 day after exposure to 2% NM was noted. Conjunctival and corneal injury, scarring, and neo-vascularization evolved over the entire duration of the experiment (4 weeks) in such eyes. Corneal Neo- vascularization developed to various degrees in all groups after exposure to NM. An increase in Intra Ocular Pressure occurred after exposure to NM, peaking at day 4 in all study groups. Exposure to NM caused iris atrophy and pigmentation together with pupil dilation in all study groups.

On the basis of these observations, we can consider Nitrogen mustard to be irritating to eyes.