L-Glutamic acid, N-acetyl-, compd. with (.alpha.S)-.alpha.-(2-methylpropyl)-2-(1-piperidinyl)benzenemethanamine (1:1)

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

10 November 1998 - 12 January 1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study (OECD 405) and in compliance with GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

(S)-3-Methyl-1-(2-piperidine-1-phenyl)butylamine compound with N-Acetyl-L-glutamic acid

EC Number:

606-883-4

Cas Number:

219921-94-5

Molecular formula:

C16-H26-N2 x C7-H11-N-O5

IUPAC Name:

(S)-3-Methyl-1-(2-piperidine-1-phenyl)butylamine compound with N-Acetyl-L-glutamic acid

Details on test material:

- Name of test material (as cited in study report): AGEE 623 Glutaminate; L-Glutamic acid, N-acetyl, compd. with (S)-alpha-(2-methylpropyl)-2-(1-piperidinyl)-benzenemethanamine
- Physical state: White solid
- Analytical purity: 100% (4% of (R)-(-)-enantiomer) measured peak HPLC
- Lot/batch No.: T29725
- Expiration date of the lot/batch: 31 December 1999
- Stability under test conditions: pure: at least 20 months; in solvent: stable for at least 2 hours in water and organic solvents
- Storage condition of test material: room temperature, light protected
- Other: Routine hygienic procedures will be sufficient to assure personnel health and safety

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Charles River Germany GmbH, 88353 Kißlegg
- Weight at study initiation: 3.2 kg, 3.7 kg, 5.0 kg
- Housing: individually housed in ABS - plastic rabbit cages
- Diet (e.g. ad libitum): ad libitum, Altromin 2123 maintenance diet rabbit
- Water (e.g. ad libitum): ad libitrum, tap water
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 +- 3°C
- Humidity (%): 55 +- 10 %
- Air changes (per hr): at least x 10/ hour
- Photoperiod (hrs dark / hrs light): 12 : 12 hours, light/dark

Test system

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

A dose of 0.1 g was applied to the test site.

Duration of treatment / exposure:

72 hours

Observation period (in vivo):

1, 24, 48 and 72 hours after start of the treatment.

Number of animals or in vitro replicates:

3

Details on study design:

SCORING SYSTEM:
The eye irritation scored were evaulated according to the scoring system by Draize (1959) and OECD 405 ( 24 April 2002).

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

other: 1, 24, 48 and 72 hours

Score:

4

Max. score:

4

Results 2

Irritation parameter:

conjunctivae score

Remarks:

Redness

Basis:

mean

Time point:

other: 1, 24, 48 and 72 hours

Score:

3

Max. score:

3

Results 3

Irritation parameter:

conjunctivae score

Remarks:

chemosis

Basis:

mean

Time point:

other: 1, 24, 48 and 72 hours

Score:

4

Max. score:

4

Any other information on results incl. tables

One hour after application all criteria of evaluation were rated at the highest possible score. The iris was not discernible through the opacity of the cornea. The alternations lasted up to the 72 h reading, when the animals were euthanised due to animal welfare. Severe corneal lesions were found upon fluorescein examination at the 72 h reading. The test item produced corrosion the eyes of all test animals. the total mean cumulative scores of the 24, 48 and 72 hour readings did exceed the limit values according to directive 93/21 EEC.

Individual and Total Mean Cumul.Score - 24, 48, 72 hour reading

Animal	Sex	Cornea	Iris	Conjunctivae		Cumul. Score	Primary Irrit. Score
				A	B
1	f	4.00	*	3.00	4.00	11.00*
2	f	4.00	*	3.00	4.00	11.00*
3	f	4.00	*	3.00	4.00	11.00*	11.00*
Total Mean:		4.00	*	3.00	4.00

*Iris not discernible through the opacity of the cornea

A=Redness; B=Chemosis

No other toxic effects were observed.

 

Applicant's summary and conclusion

Interpretation of results:

Category 1 (irreversible effects on the eye)

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test item caused severe erythema and swelling of the conjunctivae, opacity of the comea, the iris not being discernible through the opacity in all
animals at the 1 h reading, lasting up to 72 h after application.
Severe comeallesions were found upon fluorescein examination at the 72 h reading.
The total mean cumulative scores of the 24, 48 and 72 hour readings did exceed the limit values according to Directive 93/21 EEC.