Carbamic acid, N-[[5-[[[2-[2-(dimethylamino)ethoxy]ethoxy]carbonyl]amino]-1,3,3-trimethylcyclohexyl]methyl]-, 2-[2-(dimethylamino)ethoxy]ethyl ester

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

26 Mar - 05 Apr 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-Guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

EEC Directive 92/69, B.5

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Remarks:

incl. certificate for RCC Ltd Itingen from Swiss Federal Office of Public Health

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

441-100-8

EC Name:

-

Cas Number:

351197-46-1

Molecular formula:

Hill formula: C24 H48 N4 O6 CAS formula: C24 H48 O6 N4

IUPAC Name:

2-[2-(dimethylamino)ethoxy]ethyl N-{[1,3,3-trimethyl-5-(9-methyl-2-oxo-3,6-dioxa-1,9-diazadecan-1-yl)cyclohexyl]methyl}carbamate

Details on test material:

- Name of test material (as cited in study report): UAX-1179
- Physical state / appearance: pale, amber liquid
- Analytical purity: >99% proproetary tertiary amines
- Lot/batch No.: M. 17-08.01
- Expiration date of the lot/batch: 19-Sep-2003
- Storage condition of test material: In the original container, at room temperature (range of 20 +/- 3 °C), away from direct sunlight, heat and moisture. The sample was stored under dry air (nitrogen).
- Safety precautions: Routine hygienic procedures were used to ensure the health and safety of the personnel.

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Elevage Scientifique des Dombes, F-01400 Chatillon sur Chalaronne 1, France
- Age at study initiation: 11-12 weeks (male)
- Weight at study initiation: 1995g at first day of acclimatization and 2183g at day of treatment (male)
- Housing: Individually in stainless steel cages equipped with feed hoppers, drinking water bowls, with wood blocks (RCC Ltd, Füllinsdorf) and haysticks for gnawing. Haysticks (batch no. 1201) provided by Provimi Kliba AG, CH-4303 Kaiseraugst.
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3418 rabbit maintenance diet ad libitum (batch no. 116101) provided by Provimi Kliba AG, CH-4303 Kaiseraugst. Results of analysis are archived at RCC Ltd, Itingen.
- Water (e.g. ad libitum): Community tap water from Füllinsdorf, ad libitum. Results of bacteriological, chemical and contaminant analyses are archived at RCC Ltd, Itingen.
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 23 °C
- Humidity (%): 30 - 70%
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12
- Music was played during the daytime light period

Test system

Vehicle:

unchanged (no vehicle)

Controls:

other: right eye remained untreated

Amount / concentration applied:

0.1 mL

Duration of treatment / exposure:

no data

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

1 (3, but only one was treated)

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not rinsed after instillation

SCORING SYSTEM: The ocular reaction was assessed according to the numerical scoring system listed in the EEC Commission Directive 92/69/EEC, July 31, 1992 at approximately 1, 24, 48 and 72 hours after application. The degree of ocular discharge was assessed in accordance with the Draize scoring system.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

conjunctivae score

Remarks:

(redness)

Basis:

animal #1

Remarks:

(mean score 1)

Time point:

other: 24-48-72 h

Score:

2

Max. score:

3

Reversibility:

not reversible

Results 2

Irritation parameter:

chemosis score

Basis:

animal #1

Remarks:

(mean score 1)

Time point:

other: 24-48-72 h

Score:

2

Max. score:

4

Reversibility:

not reversible

Results 3

Irritation parameter:

cornea opacity score

Basis:

animal #1

Remarks:

(mean score 1)

Time point:

other: 24-48-72 h

Score:

3

Max. score:

4

Reversibility:

not reversible

Results 4

Irritation parameter:

iris score

Basis:

animal #1

Remarks:

(mean score 1)

Time point:

other: 24-48-72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Irritant / corrosive response data:

Reversibility of any observed effect: There was no indication of reversibility within 3 days.
Swelling with lids more than half closed was observed at 1h, obvious swelling with partial eversion of lids was present throughout the observation period. Assessment of the sclera was not possible at 1 hour due to the swelling of the conjunctivae but moderate reddening was subsequently observed from 24 to 72 hours. Increased ocular discharge was observed from 1 to 24 hours, and discharge with moistening of the lids and hair just adjacent to the lids was apparent from 48 to 72 hours. Blood was also present around the eye at the 1-hour reading and ruptured blood vessels were evident during the observation period.

Other effects:

The animal displayed signs of distress and pain during the examination. Based on the results the animal was prematurely sacrificed at the request of the Study Director and no further animals were treated.

Any other information on results incl. tables

Corrosion could not be fully assessed due to the premature termination of the study. Based upon the referred classification criteria (EEC Commission Directive 93/21/EEC of April 27, 1993), UAX-1179 is considered to be "R41 -Risk of serious damage to eyes" ( 67/548/EEC) and has to be classified as category 1 for eye damage (1272/2008/EC).

Table 1: Eye irritation scores - individual values

Animal Number	Sex	Evaluation Interval	Corneal Opacity	Area of Corneal Opacity	Iris	Conjuntivae Conjunctivae		Cumulative Cumulative		Sclera
						Redness	Chemosis	Score	Mean
97	M	1 hour	3	4	2	2	4	11	11	n.a.
97	M	24 hours	3	4	1	2	2	8	8	2
97	M	48 hours	3	4	1	2	2	8	8	2
97	M	72 hours	3	4	1	2	2	8	8	2

n.a. = not assessable due to swelling of the conjunctivae

Applicant's summary and conclusion

Interpretation of results:

highly irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

risk of serious damage to eyes

Executive summary:

The primary eye irritation potential of UAX-1179 was investigated by instillation of 0.1 mL into the left eye of one young adult New Zealand White rabbit in a GLP-Guideline study. The instillation of UAX-1179 into the eye of a single male rabbit resulted in moderate to severe ocular changes.The eye reactions (mean values from 24 to 72 hours) consisted of grade 3.00 corneal opacity, grade 1.00 iris lesions, grade 2.00 redness of the conjunctivae and grade 2.00 chemosis of the conjunctivae. Blood was also present around the eye at the 1-hour reading and ruptured blood vessels were evident during the observation period. There was no indication of reversibility of the effects at the 72-hour reading. Because of signs of distress and pain the animal was prematurely sacrified and no further animals were treated. Based upon the classification criteria of EEC Commission Directive 93/21/EEC, UAX-1179 is considered to be “R41- Risk of serious damage to eyes” and category 1 "cause serious eye damage" according to GHS, respectively.