pymetrozine (ISO); (E)-4,5-dihydro-6-methyl-4-(3-pyridylmethyleneamino)-1,2,4-triazin-3(2H)-one

Endpoint summary

Description of key information

- Skin irritation: non-irritating, male/female, New-Zealand White rabbit, EPA 81-5, Glaza 1991

- Eye irritation: non-irritating, male/female, New-Zealand White rabbit, EPA 81-4, Glaza 1991

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24 Jul 1991 to 27 Jul 1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OPP 81-5 (Acute Dermal Irritation)

Version / remarks:

1982

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Remarks:

Hra:(NZW)SPF

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: adult
- Weight at study initiation: 2402 to 2590 g (for males), 2278 to 2598 g (for females).
- Housing: maintained individually in screen-bottom cages in temperature- and humidity-controlled quarters.
- Diet: a measured amount of High Fiber Rabbit Chow
- Water: ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
Animal husbandry and housing comply with standards outlined in the "Guide for the Care and Use of Laboratory Animals" (NIH publication number No. 86-23, revised 1985). Variations from the prescribed environmental conditions existed and were considered to have had no effect on the study outcome. No contaminants were expected to have been present in the feed or water which would have interfered with or affected the results of the study.

IN-LIFE DATES:
July 24 to July 27, 1991

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

physiological saline

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.5 g of the moistened test material

VEHICLE
- Amount applied: moistened with 0.9% saline

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3 animals/sex

Details on study design:

TEST SITE
- Area of exposure: back, shaved skin
- % coverage: not reported
- Type of wrap if used: The area of application was covered with a 2.5 x 2.5 cm gauze patch secured with paper tape, loosely overwrapped with Saran Wrap and secured with Elastoplast tape to provide a semi occlusive dressing.

REMOVAL OF TEST SUBSTANCE
- Washing: At the end of the 4 hour exposure period, the patches were removed and the test sites were washed using tap water and disposable paper towels. The test material was removed from the test sites as thoroughly as possible without irritating the skin.
- Time after start of exposure: 4 hours

OBSERVATION TIME POINTS
Thirty minutes after removal of the test material, the degree of erythema and oedema was read according to the Draize technique (recorded as the 4-hour score). Subsequent examinations were made at 24, 48, and 72 hours.

SCORING SYSTEM:
Method of calculation: see field ‘any other information on materials methods incl. tables’.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

The average and individual values of the 4-, 24-, 48-, and 72-hour scores is 0.0.

Interpretation of results:

GHS criteria not met

Conclusions:

In this EPA 81-5 study, the test substance was determined to be non-irritating to the skin of albino rabbits (Hra: New-Zealand White SPF).

Executive summary:

The skin irritation potential of the test substance was determined in vivo according to the EPA OPP 81-5 test guideline and GLP principles. 0.5 g moistened test substance was administered to the shaved back of 3 male and 3 female adult albino rabbits (Hra: New-Zealand White SPF) for 4 hours under semi-occlusive conditions. After 4 hours the test item was removed using tap water and disposable paper towels. Scoring was performed at 0, 24, 48 and 72 hours after application according to the Draize system. No erythema or Oedema reactions were observed (the average of the 24-, 48- and 72-hour scores is 0.0). Therefore the test substance is considered to be not irritating to the skin.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

23 Jul 1991 to 29 Jul 1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OPP 81-4 (Acute Eye Irritation)

Deviations:

no

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

yes

Remarks:

Nine instead of 3 rabbits (92/69/EEC B.5.) were used; the eyes of six rabbits remained unwashed for 24 hours, the eyes of the remaining 3 animals were washed 30 seconds after instillation of the test-article

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Remarks:

Hra:(NZW) SPF

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Age at study initiation: adult
- Weight at study initiation: 2116 to 2278 g (for males), 2060 to 2158 (for females in group 1), 2036 to 2238 g (for females in group 2)
- Housing: maintained individually in screen-bottom cages in temperature- and humidity-controlled quarters.
- Diet: a measured amount of High Fiber Rabbit Chow
- Water: ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
Animal husbandry and housing comply with standards outlined in the "Guide for the Care and Use of Laboratory Animals" (NIH publication number No. 86-23, revised 1985). Variations from the prescribed environmental conditions existed and were considered to have had no effect on the study outcome. No contaminants were expected to have been present in the feed or water which would have interfered with or affected the results of the study.

IN-LIFE DATES:
July 25 to July 29, 1991

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.03 g (weight equivalent of 100 μL) placed into the everted lower lid of the right eye.

Duration of treatment / exposure:

The eyes of the Group 1 rabbits (6 animals) remained unflushed for 24 hours following instillation of the test material. After 24 hours, the eyes were flushed with lukewarm tap water.
The eyes of the Group 2 rabbits (3 animals) were flushed in the same manner for 1 minute starting 30 seconds after test material instillation.

Observation period (in vivo):

The treated eyes of both groups were observed for ocular irritation at 1, 24, 48, and 72 hours after treatment. Additional observations were made at 96 hours after treatment for the animals in Group 1.

Number of animals or in vitro replicates:

6 animals (group 1) and 3 animals (group 2)

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: lukewarm tap water
- Time after start of exposure: The eyes of the Group 1 rabbits remained unflushed for 24 hours following instillation of the test material. After 24 hours, the eyes were flushed. The eyes of the Group 2 animals were flushed in the same manner for 1 minute starting 30 seconds after test material instillation.

SCORING SYSTEM:
See ‘any other information on materials and methods incl. tables’.

TOOL USED TO ASSESS SCORE: A sodium fluorescein examination was used to aid in revealing possible corneal injury at 72 hours.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

cornea opacity score

Basis:

animal: 1, 2, 3, 4, 5, 6

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

iris score

Basis:

animal: 1, 2, 3, 4, 5, 6

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

1.22

Max. score:

3

Reversibility:

fully reversible within: 96 hours

Irritation parameter:

conjunctivae score

Basis:

animal: 1, 6

Time point:

24/48/72 h

Score:

1.6

Max. score:

3

Reversibility:

fully reversible within: 96 hours

Irritation parameter:

conjunctivae score

Basis:

animal: 4

Time point:

24/48/72 h

Score:

1.3

Max. score:

3

Reversibility:

fully reversible within: 96 hours

Irritation parameter:

conjunctivae score

Basis:

animal: 3, 5

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

conjunctivae score

Basis:

animal: 2

Time point:

24/48/72 h

Score:

0.6

Max. score:

3

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

chemosis score

Basis:

animal: 1, 2, 3, 4, 5, 6

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Irritant / corrosive response data:

Under both conditions the test material produced iridal involvement (grade 1 injection) limited to 1 hour after instillation observation. Also observed was slight to moderate conjunctival irritation, but no corneal changes. In group 1 the conjunctiva reactions cleared by 96 hours, and in group 2 by 48 hours after instillation. An overview of the data of group 1 can be found in 'any other information on results incl. tables'. Group 2 data is not considered in the final conclusion.

Table 1. Eye irritation scores according to the Draize scheme - unwashed eyes (group 1)

Time	Cornea opacity						Iris						Conjunctiva - redness						Conjunctiva - chemosis
Rabbit:	1	2	3	4	5	6	1	2	3	4	5	6	1	2	3	4	5	6	1	2	3	4	5	6
1 hour	0	0	0	0	0	0	1	1	1	1	0	1	2	1	2	2	2	2	1	1	1	1	1	1
24 hours	0	0	0	0	0	0	0	0	0	0	0	0	2	1	2	2	2	2	1	1	1	1	1	1
48 hours	0	0	0	0	0	0	0	0	0	0	0	0	2	1	1	1	1	2	0	0	0	0	0	0
72 hours	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1	0	1	0	0	0	0	0	0
96 hours	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
mean scores 24-72h	0.0						0.0						1.22						0.33
mean scores 24-72h	0	0	0	0	0	0	0	0	0	0	0	0	1.6	0.6	1	1.3	1	1.6	0.3	0.3	0.3	0.3	0.3	0.3

Interpretation of results:

GHS criteria not met

Conclusions:

This GLP compliant EPA 81-4 study in New-Zealand White rabbits, the averages over 72 hours did not reach irritative thresholds for cornea opacity (score 0), iris (score 0), conjunctivae (score <2) and chemosis (score <2)

Executive summary:

The primary eye irritation potential of the test substance was evaluated according to US EPA test guideline 81-4 and GLP principles. 0.03 g (100 μL) of test substance was instilled into the eyes of nine New-Zealand White rabbits, six of which received a washout 24 hours after instillation (Group 1) and three of which received a washout 30 seconds after instillation (Group 2). The left eye served as untreated control. In both conditions the test material produced iridal involvement and slight to moderate conjunctival irritation. Under the conditions of the study, no cornea opacity was observed. Slight iris reactions were seen 1 hour after instillation but iris was normal at the 24 hours scoring. Moderate conjunctival redness (score 2) was observed up to 48 hours after instillation but was normal 96 hours post instillation. Moderate conjunctival chemosis (score 1) was observed up to 24 hours after instillation but was normal 48 hours post instillation. Mean scores (24-72 hours) were 1.2 for conjunctival redness (no individual mean ≥ 2) and 0.3 for conjunctival chemosis (no individual mean ≥ 2). The eyes of the Group 1 animals cleared of irritation by 96 hours after instillation. The eyes of the rabbits in Group 2 cleared of irritation by 48 hours after instillation. Based on these results, the substance is considered to be not irritating to the eyes.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation

The skin irritation potential of the test substance was determined in vivo according to the EPA OPP 81-5 test guideline and GLP principles (Glaza, 1991). 0.5 g moistened test substance was administered to the shaved back of 3 male and 3 female adult albino rabbits (Hra: New-Zealand White SPF) for 4 hours under semi-occlusive conditions. After 4 hours the test item was removed using tap water and disposable paper towels. Scoring was performed at 0, 24, 48 and 72 hours after application according to the Draize system. No erythema or oedema reactions were observed (the average of the 24-, 48- and 72-hour scores is 0.0). Therefore the test substance is considered to be not irritating to the skin.

Eye irritation

The primary eye irritation potential of the test substance was evaluated according to US EPA test guideline 81-4 and GLP principles (Glaza, 1991). 0.03 g (100 μL) of test substance was instilled into the eyes of nine New-Zealand White rabbits, six of which received a washout 24 hours after instillation (Group 1) and three of which received a washout 30 seconds after instillation (Group 2). The left eye served as untreated control. In both conditions the test material produced iridal involvement and slight to moderate conjunctival irritation. Under the conditions of the study, no cornea opacity was observed. Slight iris reactions were seen 1 hour after instillation but iris was normal at the 24 hours scoring. Moderate conjunctival redness (score 2) was observed up to 48 hours after instillation but was normal 96 hours post instillation. Moderate conjunctival chemosis (score 1) was observed up to 24 hours after instillation but was normal 48 hours post instillation. Mean scores (24-72 hours) were 1.2 for conjunctival redness (no individual mean ≥ 2) and 0.3 for conjunctival chemosis (no individual mean ≥ 2). The eyes of the Group 1 animals cleared of irritation by 96 hours after instillation. The eyes of the rabbits in Group 2 cleared of irritation by 48 hours after instillation. Based on these results, the substance is considered to be not irritating to the eyes.

Justification for classification or non-classification

Based on the available information, classification for skin and eye irritation is not warranted in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation No. (EC) 1272/2008.