1,3-Benzenedimethanamine, reaction products with polyethylene glycol mono-Bu ether and TDI

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study was conducted according to internationally accepted technical guidelines and in compliance with GLP in a contract research organization. The study is scientifically valid and the report is fully adequate for assessment, despite some minor restrictions (e.g. due to limited reporting).

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1996

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

of 1981

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, Division of Pharmacology, FDA

Deviations:

not specified

GLP compliance:

yes (incl. QA statement)

Remarks:

Certified by BAM according to DIN EN 45001.

Test material

Test material information

Constituent 1

Test material form:

other: The test material contained 50% WS400517 in organic solvent

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

- Number: 3 animals,
- Average bodyweight: 3.2 kg
- Housing: Individual housing in cages.
- Diet: Commercially available standard laboratory diet for rabbits ( Altromin, Lage, Germany).
Prior to dosing the animals were starved for 16 hours.
- Water: Ad libitum

ENVIRONMENTAL CONDITIONS

Room temperature kept constant at 18±2°C, the relative humidity at 50-60%. 12 hours illumination per day.

Test system

Vehicle:

other: The test material contained 50% WS400517 in organic solvent and was used after warming to 37°C

Controls:

not required

Amount / concentration applied:

After warming undiluted test material (no vehicle) to 37°C, 0.1 ml of it was instilled into the conjunctival sac of one eye per rabbit. The contralateral eye remained untreated to serve as a control.

Duration of treatment / exposure:

There was no mentioning in the report that eyes were rinsed after treatment. Consequently the treatment/exposure period was equivalent to the entire observation period following administration, which was 7 days, or lasted until removal of the test material by physiological mechanisms, whichever happened sooner.

Observation period (in vivo):

7 days post instillation

Number of animals or in vitro replicates:

3 adult rabbits

Details on study design:

Eyes were evaluated for occular lesions using ultraviolet light. The numerical scoring system listed in Table 1 in the field below was adopted. Time points of evaluation were: Pretest (prior to treatment), 1, 2, 4, 8, 24, 48, 72 and 96 hours after administration and daily thereafter until 7 days after administration. Grades attained at 24, 48 and 72 hours after administration were included in the mean gradings of ocular lesions for each animal.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

over 3 animals and 3 time points

Time point:

24/48/72 h

Score:

0.2

Max. score:

4

Reversibility:

fully reversible within: 7 days post instillation

Remarks on result:

other: Only 1 animal with corneal lesions, i.e. opacity

Results 2

Irritation parameter:

iris score

Basis:

mean

Remarks:

over 3 animals and 3 time points

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: Iridal changes were not evident during the study

Results 3

Irritation parameter:

conjunctivae score

Remarks:

(redness)

Basis:

mean

Remarks:

over 3 animals and 3 time points

Time point:

24/48/72 h

Score:

1.9

Max. score:

3

Reversibility:

not fully reversible within: 7 days post instillation

Remarks on result:

other: fully reversible in 2 animals, whereas in the other animal still grade 1 at 7 days post instillation

Results 4

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

over 3 animals and 3 time points

Time point:

24/48/72 h

Score:

1.6

Max. score:

4

Reversibility:

fully reversible within: 6 days post instillation

Results 5

Irritation parameter:

other: lacrimation score

Basis:

mean

Remarks:

over 3 animals and 3 time points

Time point:

24/48/72 h

Score:

0.9

Max. score:

3

Reversibility:

fully reversible within: 5 days post instillation

Irritant / corrosive response data:

Adverse effects on the iris were not evident during the 7-day observation period. Corneal findings (opacity and area affected, grade 1 to 2) were confined to one animal (No. 2) and occurred rather late during the observation period (from 3 to 6 days post test material instillation). By 7 days post instillation, the corneal finding was no longer evident. Conjunctival redness, chemosis and lacrimation, grade 1 to 2, were seen in all animals and had completely resolved in two animals (Nos. 1 and 3) within 5 days after instillation. In the other animal (No. 2) a trend to reversibility was evident during the observation period with chemosis and lacrimation having completely resolved and conjunctival redness, grade 1, still present by 7 days post instillation. The ocular findings in treated eyes are detailed in Table 2.

Other effects:

Daily determination of bodyweight did not reveal any test related changes. Bodyweight gain was normal.

Any other information on results incl. tables

Table 2: Ocular Lesions of each Animal
			Cornea			Iris		Conjunctivae
Animal	Time after dosing		Opacity (0-4)	Area (0-4)		(0-2)		Redness (0-3)	Chemosis (0-4)	Lacrimation (0-3)
1	1 hour		0	0		0		2	2	1
	2 hours		0	0		0		2	2	2
	4 hours		0	0		0		2	2	2
	8 hours		0	0		0		2	2	2
	24 hours		0	0		0		2	2	1
	48 hours		0	0		0		2	1	1
	72 hours		0	0		0		1	1	0
	96 hours		0	0		0		1	0	0
	5 days		0	0		0		0	0	0
	6 days		0	0		0		0	0	0
	7 days		0	0		0		0	0	0
2	1 hour		0	0		0		1	1	1
	2 hours		0	0		0		2	2	2
	4 hours		0	0		0		2	2	2
	8 hours		0	0		0		2	2	2
	24 hours		0	0		0		2	2	2
	48 hours		0	0		0		2	2	1
	72 hours		2	2		0		2	2	1
	96 hours		2	2		0		2	2	1
	5 days		2	2		0		1	1	0
	6 days		1	1		0		1	0	0
	7 days		0	0		0		1	0	0
3	1 hour		0	0		0		1	1	1
	2 hours		0	0		0		2	2	1
	4 hours		0	0		0		2	2	1
	8 hours		0	0		0		2	2	2
	24 hours		0	0		0		2	2	1
	48 hours		0	0		0		2	1	1
	72 hours		0	0		0		2	1	0
	96 hours		0	0		0		1	0	0
	5 days		0	0		0		0	0	0
	6 days		0	0		0		0	0	0
	7 days		0	0		0		0	0	0

Applicant's summary and conclusion

Interpretation of results:

other: not irritating, see explanation in conclusion

Remarks:

expert judgment

Conclusions:

According to European classification rules [REGULATION (EC) 1272/2008] the degree and incidence of conjunctival redness seen in the present study could lead to classification as an eye irritant Category 2. However, the material tested in the present study contained a substantial amount of at least one formulation constituent classified as skin and eye irritant Category 2 [REGULATION (EC) 1272/2008]. Therefore and because of the absence of any relevant toxicity or indication of an irritating potential in all other toxicity studies performed with neat WS400517 or with any of its formulations, the eye irritation seen in the present study is attributed to the irritating formulation constituent and not to WS400517. Consequently, it is proposed not to classify WS400517 as an eye irritant according to EU classification rules [REGULATION (EC) 1272/2008].