Prometryn

Endpoint summary

Description of key information

- Skin irritation: not irritating, male/female, New-Zealand White rabbit, OECD 404, Moore 2004

- Eye irritation: not irritating, male/female, New-Zealand White rabbit, OECD 405, Moore 2004

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:

10 Aug 2004 to 13 Aug 2004

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

Version / remarks:

January 29, 1985

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Remarks:

albino

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.
- Diet: Pelleted Rabbit Chow
Water: Filtered tap water was supplied ad-libitum by an automatic water dispensing system.
- Acclimation period: 6 days

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

IN-LIFE DATES: From: 10 Aug 2004 To: 13 Aug 2004

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

water

Controls:

not required

Amount / concentration applied:

Five-tenths of a gram of the test substance (1.11 g of the test mixture)

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

1 male and 2 females

Details on study design:

PREPARATION AND SELECTION OF ANIMALS
On the day before application, a group of animals was prepared by clipping the dorsal area and the trunk. On the day of dosing, but prior to application, the animals were examined for health and the skin checked for any abnormalities. Three healthy animals without pre-existing skin irritation were selected for test.

APPLICATION OF TEST SUBSTANCE
Prior to application, the test substance was moistened with distilled water to achieve a dry paste by preparing a 45% w/w mixture. Five-tenths of a gram of the test substance (1.11 g of the test mixture) was placed on a 1 inch x 1 inch, 4-ply gauze pad and applied to one 6 cm2 intact dose site on each animal. The pad and entire trunk of each animal were then wrapped with semi-occlusive 3 inch Micropore tape to avoid dislocation of the pad. Elizabethan collars were placed on each rabbit and they were returned to their designated cages. 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.

EVALUATION OF TEST SITES
individual dose sites were scored according to the Draize scoring system (see Table 1 in 'Any other information on materials and methods incl. tables') at approximately 1, 24, 48, and 72 hours after patch removal.

CAGE SIDE OBSERVATIONS
The animals were observed for signs of gross toxicity and behavioural changes at least once daily during the test period. Observations included gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea and coma.

Irritation parameter:

erythema 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:

edema 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:

One hour after patch removal, very slight erythema was noted for all three treated sites. The overall incidence and severity of irritation decreased with time. All animals were free from dermal irritation within 24 hours.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of the study (OECD 404, GLP), the mean erythema and oedema scores of all three animals for the 24/48/72 hours time points were determined to be 0.

Executive summary:

A primary skin irritation test was conducted with rabbits, in accordance with GLP and OECD guideline 404, to determine the skin irritation potential of the substance after a single topical application. An aliquot of 0.5 g test substance was moistened with distilled water and applied to the skin of three healthy rabbits for 4 hours under semi-occlusive conditions. Following exposure, dermal irritation was evaluated by the method of Draize et al.

One hour after patch removal, very slight erythema was noted for all three treated sites. The overall incidence and severity of irritation decreased with time. All animals were free from dermal irritation within 24 hours. The mean erythema and oedema scores of all three animals for the time points after 24/48/72 hours were determined to be 0.

Under the conditions of this study, the substance was considered to be not irritating to the skin of rabbits.

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:

19 Aug 2004 to 22 Aug 2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Version / remarks:

1998

Qualifier:

according to guideline

Guideline:

other: JMAFF 59 NohSan No. 4200

Version / remarks:

January 28, 1985

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Remarks:

albino

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Age at study initiation: 12 weeks
- 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.
- Diet: Pelleted Rabbit Chow
- Water: Filtered tap water was supplied ad-libitum by automatic water dispensing system.
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-22
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 19 Aug 2004 To: 22 Aug 2004

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- One-tenth of a millilitre (0.03 grams)

Duration of treatment / exposure:

single treatment

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

3 males

Details on study design:

PREPARATION AND SELECTION OF ANIMALS
Prior to instillation, both eyes of a number of animals were examined using a fluorescein dye procedure. One drop of 2% ophthalmic fluorescein sodium was instilled into both eyes of each rabbit. The eyes were rinsed with physiological saline (0.9% NaCl) approximately 30 seconds after instillation of the fluorescein. Using an ultraviolet light source, the eyes were checked for gross abnormalities. Three healthy animals without pre-existing ocular irritation were selected for test.

INSTILLATION
Prior to use, the test substance was ground with a mortar and pestle. One-tenth of a milliliter (0.03 grams) of the test substance was instilled into the conjunctival sac of the right eye of each rabbit by pulling the lower lid away from the eyeball. The upper and lower lids were then gently held together for about one second before releasing to minimize loss of the test substance. The other eye of each rabbit remained untreated with the test substance and served as a control. The rabbits were then returned to their designated cages.

OCULAR SCORING
Ocular irritation was evaluated using a high-intensity white light in accordance with Draize et al. (see Table 1 at ‘Any other information on methods and materials incl. tables’) at 1, 24, 48, and 72 hours post-instillation. The fluorescein dye evaluation procedure described above was used at 24 hours to verify the absence of corneal damage. In addition to observations of the cornea, iris and conjunctivae, any other observed lesions were noted. The average score for all rabbits at each scoring period was calculated to aid in data interpretation.

CAGE SIDE OBERVATIONS
The animals were observed for signs of gross toxicity and behavioural changes at least once daily during the test period. Observations included gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea and coma.

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

Basis:

animal: #1, #2, #3

Time point:

24/48/72 h

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 48 hours

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 the first hour following test substance instillation, “positive” conjunctivitis was observed in all three treated eyes. The overall incidence and severity of irritation decreased with time. All animals were free of ocular irritation within 48 hours.

Other effects:

All animals appeared active and healthy. There were no signs of gross toxicity, adverse pharmacologic effects or abnormal behaviour.

Table 1. Individual eye irritation scores

	Rabbit #1				Rabbit #2				Rabbit #3
	Hours				Hours				Hours
	1	24	48	72	1	24	48	72	1	24	48	72
I. Cornea
A. Opacity	0	0*	0	0	0	0*	0	0	0	0*	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	0	0	0	0	0	0	0	0	0	0	0	0
Ax5	0	0	0	0	0	0	0	0	0	0	0	0
III. Conjunctivae
A. Redness	2	1	0	0	2	1	0	0	2	1	0	0
B. Chemosis	0	0	0	0	0	0	0	0	0	0	0	0
C. Discharge	1	0	0	0	0	0	0	0	1	0	0	0
(A+B+C)x2	6	2	0	0	4	2	0	0	6	2	0	0
Total	6	2	0	0	4	2	0	0	6	2	0	0

* 2% ophthalmic fluorescein sodium used to verify the absence of corneal opacity.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of the study (OECD 405, GLP), the mean irritation scores for the 24/48/72 hour time points were determined to be 0 for all animals for corneal opacity, iritis and chemosis. The mean irritation scores for the 24/48/72 hour time points for conjunctival redness was determined to be 0.33 for all animals.

Executive summary:

A primary eye irritation test was conducted with rabbits, in accordance with GLP and OECD guideline 405, to determine the irritation potential of the substance after a single instillation into the eye. An aliquot of 0.1 mL (0.03 grams) test substance was instilled into the right eye of three healthy rabbits. The left eye remained untreated and served as a control. Ocular irritation was evaluated by the method of Draize et al.

Within the first hour following test substance instillation, “positive” conjunctivitis was observed in all three treated eyes. The overall incidence and severity of irritation decreased with time. All animals were free from ocular irritation within 48 hours. The mean irritation scores for the time points after 24/48/72 hours were determined to be 0 for all animals for corneal opacity, iritis and chemosis. The mean irritation scores for the time points after 24/48/72 hours for conjunctival redness were determined to be 0.33 for all animals.

Under the conditions of this study, the test substance was considered to be not irritating to the eyes of rabbits.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation 

A primary skin irritation test was conducted with rabbits, in accordance with GLP and OECD guideline 404, to determine the skin irritation potential of the substance after a single topical application. An aliquot of 0.5 g test substance was moistened with distilled water and applied to the skin of three healthy rabbits for 4 hours under semi-occlusive dressing. Following exposure, dermal irritation was evaluated by the method of Draize et al. One hour after patch removal, very slight erythema was noted for all three treated sites. The overall incidence and severity of irritation decreased with time. All animals were free from dermal irritation within 24 hours. The mean erythema and oedema scores of all three animals for the time points after 24/48/72 hours were determined to be 0. Under the conditions of this study, the substance was considered to be not irritating to the skin of rabbits.

 

Eye irritation 

A primary eye irritation test was conducted with rabbits, in accordance with GLP and OECD guideline 405, to determine the irritation potential of the substance after a single instillation into the eye. An aliquot of 0.1 mL (0.03 grams) test substance was instilled into the right eye of three healthy rabbits. The left eye remained untreated and served as a control. Ocular irritation was evaluated by the method of Draize et al. Within the first hour following test substance instillation, “positive” conjunctivitis was observed in all three treated eyes. The overall incidence and severity of irritation decreased with time. All animals were free from ocular irritation within 48 hours. The mean irritation scores for the time points after 24/48/72 hours were determined to be 0 for all animals for corneal opacity, iritis and chemosis. The mean irritation scores for the time points after 24/48/72 hours for conjunctival redness were determined to be 0.33 for all animals. Under the conditions of this study, the test substance was considered to be not irritating to the eyes of rabbits.

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.