cyproconazole (ISO); (2RS,3RS;2RS,3SR)-2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Endpoint summary

Description of key information

- Skin irritation: not irritating, male/female, New Zealand White rabbit, OECD TG 404, Durando 2005

- Eye irritation: not irritating, male/female, New Zealand White rabbit, OECD TG 405, Durando 2005

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:

26 Jul 2005 to 1 Aug 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Version / remarks:

1998

Qualifier:

according to guideline

Guideline:

other: JMAFF 59 NohSan No. 4200, January 28, 1985

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Young adult
- Housing: The animals were singly housed in suspended stainless steel caging with mesh floors which conform to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals DHEW (NIH). Litter paper was placed beneath the cage and was changed at least three times per week
- Water: ad libitum
- Acclimation period: 9 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-22
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 26 Jul 2005 to 1 Aug 2005

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

water

Remarks:

Distilled

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.71 g of the test mixture

Duration of treatment / exposure:

4 hours

Observation period:

1, 24, 48, and 72 hour

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: The test substance was applied by placing it on a 1 inch x 1 inch, 4-ply gauze pad .
- % coverage: 6 cm^2 intact dose site
- Type of wrap if used: The pad and entire trunk of each animal were wrapped with semi-occlusive 3 inch Micropore tape to avoid dislocation of the pad.

REMOVAL OF TEST SUBSTANCE
- Washing: After 4 hours of exposure to the test substance, the pads and collars were removed and the test sites were gently cleansed of any residual test substance.

OBSERVATION TIME POINTS
1, 24, 48, and 72 hours after patch removal

SCORING SYSTEM:
- Method of calculation: The classification of irritancy was obtained by adding the average erythema and edema scores for the 1, 24, 48, and 72-hour scoring intervals and dividing by the number of evaluation intervals

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

other: 1, 24, 48 and 72h

Score:

0.3

Reversibility:

fully reversible within: 24h

Irritation parameter:

erythema score

Basis:

animal: #1, #2, #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal: #1, #2, #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

One hour after patch removal, very slight erythema was noted for all three treated dose sites. All animals were free from dermal irritation within 24 hours.

Other effects:

All animals appeared active and healthy during the study. Apart from the skin irritation noted below, there were no other signs of gross toxicity, adverse pharmacologic effects or abnormal behaviour

Table 1. Individual skin irritation scores, erythema/oedema

Animal No.	Sex	Hours After Patch Removal
		1	24	48	72
#1	M	1/0	0/0	0/0	0/0
#2	F	1/0	0/0	0/0	0/0
#3	M	1/0	0/0	0/0	0/0
Total		3/0	0/0	0/0	0/0
Mean		1.0/0.0	0.0/0.0	0.0/0.0	0.0/0.0

Table 2. Summary of primary skin irritation scores

	Hours
	1	24	48	72
Erythema	1.0	0.0	0.0	0.0
Oedema	0.0	0.0	0.0	0.0
TOTAL (PDI)^2	1.0	0.0	0.0	0.0

Primary Dermal Irritation Index (PDII) : (PDI for 1, 24, 48 and 72 hours) /4=0.3

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study, the test substance is slightly irritating to the skin, but not sufficient for classification under CLP.

Executive summary:

In a primary skin irritation test that was performed in accordance with OECD TG 404 and GLP principles, 2 males and 1 female New Zealand White rabbit were used to determine the potential for the test substance to produce irritation after a single topical application. Five-tenths of a gram of the test substance was moistened with distilled water and then applied to the skin for 4 hours using a semi-occlusive dressing. Following exposure, dermal irritation was evaluated by the method of Draize et al. Observations were done at 1, 24, 48, and 72 hour after patch removal.

Results showed that one hour after patch removal, very slight erythema was noted for all three treated dose sites. All animals were free from dermal irritation within 24h. The Primary Dermal Irritation Index (PDII) calculated for this substance was 0.3. The mean average scores for oedema and erythema was 0 for all the animals for 24, 48, and 72h.

Under the conditions of this study, the test substance is slightly irritating to the skin, but not sufficient for classification under CLP.

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:

26 Jul 2005 to 4 Aug 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Version / remarks:

1998

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

other: JMAFF 59 NohSan No. 4200, January 28

Version / remarks:

1985

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Age at study initiation: Young adults
- Housing: The animals were singly housed in suspended stainless steel caging with mesh floors which conform to the size recommendations in the most recent Guide for the Care and Use of Laboratory Animals DHEW (NIH). Litter paper was placed beneath the cage and was changed at least three times per week.
- Water: Ad libitum
- Acclimation period: 40 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 22
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 26 Jul 2005 to 4 Aug 2005

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.06 g

Duration of treatment / exposure:

Single treatment

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

2 females and 1 male

Details on study design:

SCORING SYSTEM: Draize scale for scoring eye lesions and Kay and Calandra scheme for classifying eye irritants. Observations were made at 1, 24, 48 and 72 hours.

TOOL USED TO ASSESS SCORE: Fluorescein

OTHER EXAMINATIONS:
- General health

Irritation parameter:

cornea opacity score

Basis:

animal: #1, #2, #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal: #1, #2, #3

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Remarks:

Redness

Basis:

animal: #1, #2

Time point:

24/48/72 h

Score:

0.67

Max. score:

3

Reversibility:

fully reversible within: 72h

Irritation parameter:

conjunctivae score

Remarks:

Redness

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 48h

Irritation parameter:

chemosis score

Basis:

animal: #1, #2, #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

Within one hour after test substance instillation, “positive” iritis and conjunctivitis were noted for all three treated eyes. The overall incidence and severity of irritation decreased with time. All animals were free of ocular irritation within 72 hours. Mean scores following grading at 24, 48 and 72 hours were below 1 in all animals.

Other effects:

- Other observations: There were no other signs of gross toxicity, adverse pharmacologic effects or abnormal behaviour.

Table 1. Individual scores for ocular irritation

	Rabbit #1 (Female)				Rabbit #2 (Female)				Rabbit #3 (Male)
	Hours				Hours				Hours
	1	24	48	72	1	24	48	72	1	24	48	72
I. Cornea
A. Opacity	0	01	0	0	0	01	0	0	0	01	0	0
B. Area	4	4	4	4	4	4	4	4	4	4	4	4
(AxB)x5	0	0	0	0	0	0	0	0	0	0	0	0
II. Iris
A. Values	1	0	0	0	1	0	0	0	1	0	0	0
Ax5	5	0	0	0	5	0	0	0	5	0	0	0
III. Conjunctivae
A. Redness	2	1	1	0	2	1	1	0	2	1	0	0
B. Chemosis	1	0	0	0	1	0	0	0	1	0	0	0
C. Discharge	2	1	0	0	2	1	0	0	2	1	0	0
(A+B+C)x2	10	4	2	0	10	4	2	0	10	4	0	0
Total	15	4	2	0	15	4	2	0	15	4	0	0

Interpretation of results:

GHS criteria not met

Conclusions:

Based on these results, the test substance is mildly irritating to the eye, but not sufficient for classification under CLP.

Executive summary:

In accordance with OECD TG 405 and GLP principles, a primary eye irritation test was conducted with 1 male and 2 females New Zealand White rabbits to determine the potential for the test substance to produce irritation from a single instillation via the ocular route. One-tenth of a mL (0.06 grams) of the test substance was instilled into the right eye of three healthy rabbits. The left eye remained untreated and served as a control. Observations were made 1 hour, 24 hours, 48 hours and 72 hours after instillation of the test substance. Ocular irritation was evaluated by the Draize scale method.

Results showed that within one hour after test substance instillation, “positive” iritis and conjunctivitis were noted for all three treated eyes. The mean average score (24, 48, and 72h) for cornea opacity, chemosis and the iris was 0 for all the animals. The mean average score for conjunctivae redness (24, 48, and 72h) was 0.67 for animal #1, #2 and 0.33 for animal #3. The overall incidence and severity of irritation decreased with time. All animals were free of ocular irritation within 72 hours.

Based on these results, the test substance is mildly irritating to the eye, but not sufficient for classification under CLP.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

All available data was assessed and the studies representing the worst-case effects were included as key studies. The in vitro data requirements were waived based on the availability of adequate in vivo data. Dosing with the test material in rabbits resulted in slight irritation to the skin and to the eye, but no sufficient effect for classification under CLP.

 

Skin irritation/corrosion

In a primary skin irritation test (Durando 2005) that was performed in accordance with OECD TG 404 and GLP principles, 2 males and 1 female New Zealand White rabbit were used to determine the potential for the test substance to produce irritation after a single topical application. Five-tenths of a gram of the test substance was moistened with distilled water and then applied to the skin for 4 hours using a semi-occlusive dressing. Following exposure, dermal irritation was evaluated by the method of Draize et al. Observations were done at 1, 24, 48, and 72 hour after patch removal. Results showed that one hour after patch removal, very slight erythema was noted for all three treated dose sites. All animals were free from dermal irritation within 24 hr. The Primary Dermal Irritation Index (PDII) calculated for this substance was 0.3. The mean average scores for oedema and erythema was 0 for all the animals for 24, 48, and 72 hr.

 

Another OECD 404 study (Hamburger et al. 1985) was performed under GLP and showed no signs of either erythema or oedema in rabbits at any point throughout the course of the study. Under the conditions of this study, the test substance is slightly irritating to the skin, but not sufficient for classification under CLP.

 

Eye irritation

In accordance with OECD TG 405 and GLP principles, a primary eye irritation test (Durando 2005) was conducted with 1 male and 2 females New Zealand White rabbits to determine the potential for the test substance to produce irritation from a single instillation via the ocular route. One-tenth of a mL (0.06 grams) of the test substance was instilled into the right eye of three healthy rabbits. The left eye remained untreated and served as a control. Observations were made 1 hour, 24 hours, 48 hours and 72 hours after instillation of the test substance. Ocular irritation was evaluated by the Draize scale method. Results showed that within one hour after test substance instillation, “positive” iritis and conjunctivitis were noted for all three treated eyes. The mean average score (24, 48, and 72 hr) for cornea opacity, chemosis and the iris was 0 for all the animals. The mean average score for conjunctivae redness (24, 48, and 72h) was 0.67 for animal #1, #2 and 0.33 for animal #3. The overall incidence and severity of irritation decreased with time. All animals were free of ocular irritation within 72 hours.

 

Another OECD TG 405 study (Hamburger et al. 1985) was performed under GLP. Slight redness (grade 1) of the conjunctivae was noted at 0.5 h after treatment in all animals tested. No other findings were noted at all thereafter: the mean average score (24, 48, and 72 hr) for cornea opacity, chemosis, conjunctivae redness and the iris was 0 for all the animals. Based on these results, the test substance is mildly irritating to the eye, but not sufficient for classification under CLP.

Justification for classification or non-classification

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