dinotefuran (ISO); 1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

05/04/1997 - 11/06/1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP, Guideline study: Nine rabbits instead of 3 (92/69/EEC B.5) were used, the eyes of 6 rabbits remaining unwashed (regulatory requirement in US) and the eyes of 3 animals washed 30 seconds after instillation of test article. Clinical signs and body weights (after treatment) not reported.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

(1987)

Deviations:

no

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPP 81-4 (Acute Eye Irritation)

Version / remarks:

(1982)

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: JMAFF 59 NohSan no. 4200 (1985)

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(RS)-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine

EC Number:

605-399-0

Cas Number:

165252-70-0

Molecular formula:

C7H14N4O3

IUPAC Name:

(RS)-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine

Test material form:

solid: particulate/powder

Remarks:

powder

Test animals / tissue source

Species:

rabbit

Strain:

other: New Zealand White (Hra:(NZW)SPF)

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Age at study initiation: 14-18 weeks old
- Weight at study initiation: 2334 - 2694 g
- Sex: males and females

Test system

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.1 g

Duration of treatment / exposure:

- Exposure period: Washed group: 3 rabbits 30-second exposure; Unwashed group: 6 rabbits 96 h
- Post-exposure period: 14-days

Observation period (in vivo):

- The treated eyes of all animals were examined for ocular irritation reactions 1, 24, 48, 72 and 96 hours and 7 and 14 days after instillation.

Number of animals or in vitro replicates:

9 rabbits, 6 males and 3 females

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: With water (both eyes of 3 rabbits for 1 minute)
- Time after start of exposure: 30 seconds

SCORING SYSTEM: Irritation reactions were graded and scored according to the Draize technique. Sodium fluorescein examinations were performed to assist the visualisation of possible corneal lesions

- pH: no data
- Statistics: no statistical analyses were employed

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

overall irritation score

Remarks:

according to the method of Kay & Calandra

Basis:

mean

Remarks:

total eye irritation score at each interval for all animals / no. animals in the group

Time point:

other: 1 hour

Score:

13

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: unwashed group

Results 2

Irritation parameter:

overall irritation score

Remarks:

according to the method of Kay & Calandra (1962)

Basis:

mean

Remarks:

total eye irritation score at each interval for all animals / no. animals in the group

Time point:

other: 24 hours

Score:

14.8

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: unwashed group

Results 3

Irritation parameter:

overall irritation score

Remarks:

according to the method of Kay & Calandra (1962)

Basis:

mean

Remarks:

total eye irritation score at each interval for all animals / no. animals in the group

Time point:

other: 48 hours

Score:

6.7

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: unwashed group

Results 4

Irritation parameter:

overall irritation score

Remarks:

according to the method of Kay & Calandra (1962)

Basis:

mean

Remarks:

total eye irritation score at each interval for all animals / no. animals in the group

Time point:

other: 72 hours

Score:

3.2

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: unwashed group

Results 5

Irritation parameter:

overall irritation score

Remarks:

according to the method of Kay & Calandra (1962)

Basis:

mean

Remarks:

total eye irritation score at each interval for all animals / no. animals in the group

Time point:

other: 96 hours

Score:

1.8

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: unwashed group

Results 6

Irritation parameter:

overall irritation score

Remarks:

according to the method of Kay & Calandra (1962)

Basis:

mean

Remarks:

total eye irritation score at each interval for all animals / no. animals in the group

Time point:

other: 7 days

Score:

2.2

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: unwashed group

Results 7

Irritation parameter:

overall irritation score

Remarks:

according to the method of Kay & Calandra (1962)

Basis:

mean

Remarks:

total eye irritation score at each interval for all animals / no. animals in the group

Time point:

other: 14 days

Score:

0

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: unwashed group

Results 8

Irritation parameter:

overall irritation score

Remarks:

according to the method of Kay & Calandra (1962)

Basis:

mean

Remarks:

total eye irritation score at each interval for all animals / no. animals in the group

Time point:

other: 1 hour

Score:

12

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: washed group

Results 9

Irritation parameter:

overall irritation score

Remarks:

according to the method of Kay & Calandra (1962)

Basis:

mean

Remarks:

total eye irritation score at each interval for all animals / no. animals in the group

Time point:

other: 24 hours

Score:

14.7

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: washed group

Results 10

Irritation parameter:

overall irritation score

Remarks:

according to the method of Kay & Calandra (1962)

Basis:

mean

Remarks:

total eye irritation score at each interval for all animals / no. animals in the group

Time point:

other: 48 hours

Score:

8.3

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: washed group

Results 11

Irritation parameter:

overall irritation score

Remarks:

according to the method of Kay & Calandra (1962)

Basis:

mean

Remarks:

total eye irritation score at each interval for all animals / no. animals in the group

Time point:

other: 72 hours

Score:

4

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: washed group

Results 12

Irritation parameter:

overall irritation score

Remarks:

according to the method of Kay & Calandra (1962)

Basis:

mean

Remarks:

total eye irritation score at each interval for all animals / no. animals in the group

Time point:

other: 96 hours

Score:

3.3

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: washed group

Results 13

Irritation parameter:

overall irritation score

Remarks:

according to the method of Kay & Calandra (1962)

Basis:

mean

Remarks:

total eye irritation score at each interval for all animals / no. animals in the group

Time point:

other: 7 days

Score:

1.3

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: washed group

Results 14

Irritation parameter:

overall irritation score

Remarks:

according to the method of Kay & Calandra (1962)

Basis:

mean

Remarks:

total eye irritation score at each interval for all animals / no. animals in the group

Time point:

other: 14 days

Score:

0

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: washed group

Results 15

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24 h

Score:

0

Results 16

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

48 h

Score:

0

Results 17

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

72 h

Score:

0

Results 18

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24 h

Score:

0

Results 19

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

48 h

Score:

0

Results 20

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

72 h

Score:

0

Results 21

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24 h

Score:

1

Reversibility:

fully reversible within: 24 h

Results 22

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

48 h

Score:

0

Results 23

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

72 h

Score:

0

Results 24

Irritation parameter:

cornea opacity score

Basis:

animal #4

Time point:

24 h

Score:

1

Reversibility:

fully reversible within: 24 h

Results 25

Irritation parameter:

cornea opacity score

Basis:

animal #4

Time point:

48 h

Score:

0

Results 26

Irritation parameter:

cornea opacity score

Basis:

animal #4

Time point:

72 h

Score:

0

Results 27

Irritation parameter:

cornea opacity score

Basis:

animal #5

Time point:

24 h

Score:

1

Reversibility:

fully reversible within: 24 h

Results 28

Irritation parameter:

cornea opacity score

Basis:

animal #5

Time point:

48 h

Score:

0

Results 29

Irritation parameter:

cornea opacity score

Basis:

animal #5

Time point:

72 h

Score:

0

Results 30

Irritation parameter:

cornea opacity score

Basis:

animal #6

Time point:

24 h

Score:

1

Reversibility:

fully reversible within: 14 d

Results 31

Irritation parameter:

cornea opacity score

Basis:

animal #6

Time point:

48 h

Score:

1

Reversibility:

fully reversible within: 14 d

Results 32

Irritation parameter:

cornea opacity score

Basis:

animal #6

Time point:

72 h

Score:

1

Reversibility:

fully reversible within: 14 d

Results 33

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

0

Results 34

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Results 35

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

> 0 - < 2

Max. score:

1

Reversibility:

fully reversible within: 24 h

Results 36

Irritation parameter:

iris score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Results 37

Irritation parameter:

iris score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0

Results 38

Irritation parameter:

iris score

Basis:

animal #6

Time point:

24/48/72 h

Score:

> 0 - < 2

Max. score:

1

Reversibility:

fully reversible within: 48 h

Results 39

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

> 0 - < 3

Max. score:

2

Reversibility:

fully reversible within: 96 h

Results 40

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

> 0 - < 3

Max. score:

2

Reversibility:

fully reversible within: 96 h

Results 41

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

> 0 - < 3

Max. score:

2

Reversibility:

fully reversible within: 96 h

Results 42

Irritation parameter:

conjunctivae score

Basis:

animal #4

Time point:

24/48/72 h

Score:

> 0 - < 3

Max. score:

2

Reversibility:

fully reversible within: 14 d

Results 43

Irritation parameter:

conjunctivae score

Basis:

animal #5

Time point:

24/48/72 h

Score:

> 0 - < 3

Max. score:

2

Reversibility:

fully reversible within: 7 d

Results 44

Irritation parameter:

conjunctivae score

Basis:

animal #6

Time point:

24/48/72 h

Score:

> 0 - < 2

Max. score:

2

Reversibility:

fully reversible within: 14 d

Results 45

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

> 0 - <= 1

Reversibility:

fully reversible within: 72 h

Results 46

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

> 0 - <= 2

Max. score:

2

Reversibility:

fully reversible within: 96 h

Results 47

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

> 0 - <= 1

Reversibility:

fully reversible within: 72 h

Results 48

Irritation parameter:

chemosis score

Basis:

animal #4

Time point:

24/48/72 h

Score:

> 0 - <= 1

Reversibility:

fully reversible within: 72 h

Results 49

Irritation parameter:

chemosis score

Basis:

animal #5

Time point:

24/48/72 h

Score:

> 0 - <= 1

Reversibility:

fully reversible within: 96 h

Results 50

Irritation parameter:

chemosis score

Basis:

animal #6

Time point:

24/48/72 h

Score:

> 0 - <= 3

Reversibility:

fully reversible within: 14 d

Irritant / corrosive response data:

The unwashed eyes of 4 of 6 animals showed slight (grade 1) corneal opacity with epithelial peeling, and iridial irritation in 2 of 6 animals within 24 hours of instillation of dinotefuran (Table 1 and Table 2). The reaction was accompanied by slight to moderate (grade 1 or 2) erythema, chemosis and clear or purulent discharge in all 6 animals. The eyes of 4 of the animals had returned to normal appearance within 96 hours of instillation and the remaining 2 animals had returned to normal 14 days after instillation. A positive reaction occurred in 3 of 3 animals in the washed group and was characterised by slight corneal opacity and slight to moderate erythema, chemosis and discharge. With the exception of one of 3 animals that showed slight erythema and chemosis on day 7, the washed eyes of all animals returned to normal appearance by 96 hours. The appearance of the eyes of the 3rd animal had returned to normal on day 14. The mean irritation scores for all ocular reactions according to Commission Directive 93/21/EEC (Annex VI) were greatest at 24 hours in both the washed and unwashed groups (Table 1). Thereafter, they progressively declined until day 14 at which time all animals in the washed and unwashed eye groups were free of all ocular irritation reactions. None of the individual animal or group mean irritation scores exceeded the EU criteria for classification as “irritating to eyes”.

Any other information on results incl. tables

Table 1: Group mean irritation scores according to Commission Directive 93/21/EEC (Annex VI)

Observation	Mean irritation scores in the:
	Unwashed group at:					Washed group at:
	1hr	24hr	48hr	72hr	96hr	1hr	24hr	48hr	72hr	96hr
Corneal opacity	0.2	0.7	0.2	0.2	0.2	0.0	1.0	0.0	0.0	0.0
Iris lesion	0.2	0.3	0.2	0.0	0.0	0.0	0.0	0.0	0.0	0.0
Erythema	2.0	2.0	1.3	0.8	0.3	2.0	2.0	1.7	1.3	1.0
Edema	2.0	1.5	1.2	0.3	0.2	2.3	1.7	1.3	0.7	0.7

Table 2: Individual irritation scores

Observation	Time	Individual scores
		unwashed group						washed group
		1	2	3	4	5	6	7	8	9
Cornea	1hr	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
(severity/area)	24hr	0 / 0	0 / 0	1^a/ 1	1^a/ 1	1^a/ 1	1^a/ 2	1^a/ 1	1^a/ 1	1^a/ 2
(A / B)	48hr	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1^a/ 1	0 / 0	0 / 0	1^a/ 1
	72hr	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1^a/ 1	0 / 0	0 / 0	0 / 0
	96hr	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
	7days	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
	14days	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Iris	1hr	0	0	1^b	0	0	0	0	0	0
(C)	24hr	0	0	1^b	0	0	1^b	0	0	0
	48hr	0	0	0	0	0	1^b	0	0	0
	72hr	0	0	0	0	0	0	0	0	0
	96hr	0	0	0	0	0	0	0	0	0
	7days	0	0	0	0	0	0	0	0	0
	14days	0	0	0	0	0	0	0	0	0
Redness	1hr	2^c	2^c	2^c	2^c	2^c	2^c	2^c	2^c	2^c
(D)	24hr	2^c	2^c	2^c	2^c	2^c	2^c	2^c	2^c	2^c
	48hr	1	1	1	1	2^c	2^c	2	1	2^c
	72hr	0	1	0	1	1	2	1	1	2^c
	96hr	0	0	0	1	0	1	1	0	2
	7days	0	0	0	1	0	2	0	0	1
	14days	0	0	0	0	0	0	0	0	0
Chemosis	1hr	2	2	2	2	2	2	2	2	3
(E)	24hr	1	2	1	1	1	3	2	1	2
	48hr	1	1	1	1	1	2	1	1	2
	72hr	0	0	0	0	1	1	0	0	2
	96hr	0	0	0	0	0	1	0	0	2
	7days	0	0	0	0	0	1	0	0	1
	14days	0	0	0	0	0	0	0	0	0
Discharge	1hr	1^d	1^d	2^d	2^e	2^e	2^d	0	0	1^e
(F)	24hr	0	1^d	1^d	1^d	1^d	2^d	0	0	0
	48hr	0	0	0	0	0	0	0	0	0
	72hr	0	0	0	0	0	0	0	0	0
	96hr	0	0	0	0	0	0	0	0	0
	7days	0	0	0	0	0	0	0	0	0
	14days	0	0	0	0	0	0	0	0	0

^acorneal epithelial peeling;

^binjected;

^cblanching;

^dclear discharge;

^epurulent discharge

Applicant's summary and conclusion

Interpretation of results:

slightly irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Dinotefuran is slightly irritating to the eyes of the rabbit but does not require classification in the EU according to the CLP regulation.