Ethyl 3-[[bis(1-methylethoxy)phosphinothioyl]thio]propionate

Endpoint summary

Description of key information

Treatment of rabbit skin with the test substance resulted in minimal erythema and edema formations, reversible within 72h. Treatment of rabbit eyes with the test substance caused minimal conjunctival effects in all animals and minimal corneal opacity in one animal; all effects were reversible within 48 hours. Therefore, the substance is considered to be not irritating to skin or eyes.

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:

1976

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

other: "Hazardous Substances Regulations" under the U.S. Federal Hazardous Substances Labelling Act Sect. 191.11 (February 1955).

Principles of method if other than guideline:

Two test sites lateral to the mid line of the back were used on each rabbit. Immediately before the application of the test compound, the right hand site was abraded. Assessments of skin reactions were made after 24 hrs and 72 hrs and for any further period considered necessary up to 14 days.

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 12-14 weeks
- Weight at study initiation: 2.32 kg (males) and 2.57 kg (females)
- Housing: caged individually
- Diet: A commercial irradiated diet (Styles-Oxoid) ad libitum
- Water: Sterile filtered waterad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 1
- Humidity (%): 50-70
- Photoperiod (hrs dark / hrs light): 14 / 10

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.5 mL

Duration of treatment / exposure:

24 h

Observation period:

14 d

Number of animals:

6 (3 male and 3 female)

Details on study design:

TEST SITE
- Area of exposure: The backs of the rabbits, shaved over an area of at least 10% of the total body surface. Two test sites lateral to the mid line of
the back were used on each rabbit. Immediately before the application of the test compound, the right hand site was abraded with the point of a sterile hypodermic needle. The left hand sit's remained intact.
- % coverage: 2.5 cm2
- Type of wrap if used: gauze covered with aluminum foil secured with "Sleek" adhesive tape (Smith and Nephew, Hull, England). The test sites were then covered by a 6" wide "Coban" self adhesive bandage (3M Company, Wigmore Street, London)

REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: 24 h

SCORING SYSTEM: Draize et al. (1944) J. Pharmac. Exp. Ther. 82:377

Irritation parameter:

overall irritation score

Basis:

mean

Remarks:

intact skin

Time point:

72 h

Score:

1.42

Max. score:

8

Reversibility:

fully reversible within: 72 h

Remarks on result:

probability of weak irritation

Irritation parameter:

erythema score

Basis:

animal #1

Remarks:

intact skin

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

probability of weak irritation

Irritation parameter:

erythema score

Basis:

animal #2

Remarks:

intact skin

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

probability of weak irritation

Irritation parameter:

erythema score

Basis:

animal #3

Remarks:

intact skin

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

probability of weak irritation

Irritation parameter:

erythema score

Basis:

animal #4

Remarks:

intact skin

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

probability of weak irritation

Irritation parameter:

erythema score

Basis:

animal #5

Remarks:

intact skin

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

probability of weak irritation

Irritation parameter:

erythema score

Basis:

animal #6

Remarks:

intact skin

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

probability of weak irritation

Irritation parameter:

erythema score

Basis:

mean

Remarks:

intact skin

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Remarks:

intact skin

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

animal #2

Remarks:

intact skin

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

animal #3

Remarks:

intact skin

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

animal #4

Remarks:

intact skin

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

animal #5

Remarks:

intact skin

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

animal #6

Remarks:

intact skin

Time point:

24 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 h

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Basis:

mean

Remarks:

intact skin

Time point:

72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible within:

Remarks:

72 h

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

mean

Remarks:

intact skin

Time point:

48 h

Remarks on result:

not measured/tested

Irritation parameter:

edema score

Basis:

mean

Remarks:

intact skin

Time point:

48 h

Remarks on result:

not measured/tested

Erythema formation

No/ Sex	Intact		Abraded		total
	24 h	72 h	24 h	72 h
11/male	1	0	1	0
13	1	0	1	0
15	2	0	2	0
12/female	1	0	1	0
14	2	0	2	0
16	1	0	1	0
Mean	1.33	0.00	1.33	0.00	2.67

Oedema formation

No/ Sex	Intact		Abraded		total
	24 h	72 h	24 h	72 h
11/male	1	0	1	0
13	1	0	2	0
15	2	0	1	0
12/female	2	0	1	0
14	2	0	2	0
16	1	0	2	0
Mean	1.50	0.00	1.50	0.00	3.00

Erythema + Oedema = 5.67

Primary Irritation Score = 1.42

Mean erythema score of 24 and 72 hour readings, mean of all animals = 0.67

Mean edema score of 24 and 72 hour readings, mean of all animals = 0.75

Interpretation of results:

GHS criteria not met

Conclusions:

Treatment with the test substance resulted in minimal erythema and edema formations, reversible within 72h. Therefore, the substance is considered to be not irritating.

Executive summary:

In a pre-GLP study performed to assess the primary irritation potential of the test substance, six New Zealand White rabbits (three males and three females) were treated dermally with the test compound. Twenty-four hours prior to treatment, the the backs of the rabbits were shaved over an area consisting of at least 10% of the total body surface. Two test sites lateral to the mid line of the back were used on each rabbit. Immediately before the application of the test compound, the right hand site was abraded with the point of a sterile hypodermic needle. The left hand sites remained intact. 0.5 ml of the test compound was applied to each test site on a 2.5 cm² gauze patch and covered occlusively. After 24 hours the dressing was removed and the intact and abraded application sites were assessed for oedema and erythema, a further assessment was made after 72 hours and for any further period considered necessary up to 14 days. Only minimal irritation was observed, the mean values for erythema and edema after 24 and 72 hour timepoints (all animals) were 0.67 and 0.75, respecitvely. All effects were fully reversible within 72 hours.Based on this result, the test substance is considered not irritating to the skin and does not require classification.

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:

1976

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

non GLP, body weight development not recorded, no clinical signs recorded, observation period only 3 days (effects were reversible within two days)

Qualifier:

according to guideline

Guideline:

other: "Hazardous Substances Regulations" under the U.S.A. Federal Hazardous Substances Labelling Act Sect. 191.12 (February 1965)

Principles of method if other than guideline:

0.1 ml of the test compound were instilled into the conjunctival sac of the left eye of six rabbits. The eyelids were then held closed for 1 second. The right eye served as a control. After 30 seconds the compound was, as far as possible, flushed out of the eyes of three of the rabbits with approximately 200 ml. of warm water. The rabbits were examined 1, 24, 48 and 72 hours after application.

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Age at study initiation: 12-14 weeks
- Weight at study initiation: males: 2.32 kg; females: 2.57
- Housing: individually
- Diet: commercial irradiated diet (Styles-Oxoid) ad libitum
- Water: Sterile filtered water, ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 1
- Humidity (%): 50-70
- Photoperiod (hrs dark / hrs light): 14 / 10

Vehicle:

unchanged (no vehicle)

Controls:

other: Left eye served as control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL

Duration of treatment / exposure:

In three rabbits, the eyes were rinsed after 30 seconds. The test eye of the other three rabbits remained unwashed.

Observation period (in vivo):

72 h

Number of animals or in vitro replicates:

6 (3 male and 3 female)

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After 30 seconds the compound was, as far as possible, flushed out of the eyes of three of the rabbits with approximately 200 ml of warm water.

SCORING SYSTEM: method described in "Appraisal of the Safety of Chemicals in Food, Drugs, and Cosmetics" page 51, published by the Association of Food and Drug Officials of the U.S.A. (see appendix 1)

TOOL USED TO ASSESS SCORE: Corneal damage was assessed after staining with fluorescein.

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

unwashed eyes

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: minimal effects observed in one rinsed eye

Irritation parameter:

iris score

Basis:

mean

Remarks:

unwashed eyes

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

other: no effects

Irritation parameter:

conjunctivae score

Basis:

mean

Remarks:

unwashed eyes

Time point:

24/48/72 h

Score:

0.2

Max. score:

3

Reversibility:

fully reversible within: 48 h

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

unwashed eyes

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

fully reversible within: 24 h

Remarks on result:

other: minimal chemosis observed after 1 h

Irritant / corrosive response data:

Minimal conjunctival redness was observed in both rinsed and unrinsed eyes at the 1h and 24 h timepoint. In addition, in on rinsed eye minimal corneal opacity was observed. All effects were reversible within 48 hours the latest.

EXPERIMENTAL RESULT

Animal Number	11				13				15 (rinsed)				12				14 (rinsed)				16 (rinsed)
Timepoint (hrs)	1	24	48	72	1	24	48	72	1	24	48	72	1	24	48	72	1	24	48	72	1	24	48	72
Cornea
Opacity	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Area	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Iris	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Conjunctivae
Redness	1	1	0	0	1	0	0	0	2	0	0	0	2	1	0	0	1	1	0	0	1	0	0	0
Chemosis	0	0	0	0	1	0	0	0	1	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Discharge	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 values after 24, 48 and 72 hours for animals with non-rinsed eyes are:

Iris: 0

Corneal Opacity: 0

Conjunctival Redness: 0.2

Chemosis: 0

Interpretation of results:

GHS criteria not met

Conclusions:

The test substance caused minimal conjunctival effects in all animals and minimal corneal opacity in one animal; all effects were reversible within 48 hours.

Executive summary:

The occular irritation potential of the test substance was assessed in an in vivo study performed with six New Zealand White rabbits. The eyes of the experimental animals were examined and found normal prior to the test. 0.1 mL of the test compound were instilled into the conjunctival sac of the left eye. The eyelids were then held closed for 1 second. The right eye served as a control. After 30 seconds the compound was, as far as possible, flushed out of the eyes of three of the rabbits with approximately 200 ml of warm water. The rabbits were examined 1, 24, 48 and 72 hours after application of the test compound and for any further period that was considered necessary. The ocular reactions were scored by the method described in "Appraisal of the Safety of Chemicals in Food Drugs and Cosmetics" page 51, published by the Association of Food and Drug Officials of the USA. Corneal damage was assessed after staining with fluorescein. A very slight to slight conjunctival reaction was seen in all treated eyes one hour after application of the compound. This was still present in three eyes (2 unwashed, 1 washed) at 24 hours. Damage to the surface epithelium of the cornea with slight opacity was seen at 24 hours only in one washed eye. After 48 hours, all occular effects had reversed. Therefore, the substance was considered to be not irritating to eyes.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

Skin Irritation

In a pre-GLP study (Ciba Pharmaceuticals, 1976), the potential of the test substance to cause acute dermal irritation or corrosion was assessed by single topical application to the shaved skin of 6 New Zealand White rabbits (3 males and 3 females). Two test sites lateral to the mid line of the back were used on each rabbit, the right hand sites were abraded, the left hand sites remained intact. An amount of 0.5 ml of the test compound was applied to each test site under occlusive conditions. After 24 hours the dressing was removed and the intact and abraded application sites were assessed for oedema and erythema, a further assessment was made at 72 hours. Only minimal irritation was observed, the mean 24 -72 -hour scores for erythema and edema were 0.67 and 0.75, respectively. The effects were fully reversible within 72 hours. Based on this result, the test substance is considered not irritating to the skin and does not require classification according to EU and GHS criteria.

Eye Irritation

In a pre-GLP study (Ciba Pharmaceuticals, 1976) the ocular irritation potential of the test substance was assessed in six New Zealand White rabbits. An amount of 0.1 mL of the test compound was instilled into the conjunctival sac of the left eye, the right eye served as a control. In three rabbits, the compound was washed out of the eyes with warm water, the eyes of the remaining rabbits were not rinsed. The rabbits were examined 1, 24, 48 and 72 hours after application of the test compound and the ocular reactions were scored. Corneal damage was assessed after staining with fluorescein. A very slight to slight conjunctival reaction was seen in all treated eyes one hour after application of the compound. This was still present in three eyes (2 unwashed, 1 washed) at the 24 hour time point. Damage to the surface epithelium of the cornea with slight opacity was seen at 24 hours only in one washed eye. After 48 hours, all ocular effects had reversed. The mean 24 -72 hour scores for iris lesions, corneal opacity, conjunctival redness and chemosis were 0, 0.06, 0.17 and 0 and thus far below the regulatory threshold for classification. Therefore, the substance is considered to be not irritating to eyes.

Respiratory Irritation

no data available

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for the purpose of classification under Regulation (EC) No.1272/2008. Based on the data, classification for irritation is not warranted under Regulation (EC) No.1272/2008.