Phosphorothioic acid, O,O-bis(2-methylpropyl) ester, sodium salt (1:1)

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

April 10, 1991 - April 30, 1991

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Limited details on test material and environmental conditions. No controls were avalable as both eyes were dosed with the test substance. Observations were not performed until 21 days but only until 7 days at which irreversibility of the cornea (1 animal) and the conjunctiva (2/3 animals) was observed in the unwashed eyes. In the washed eyes, irreversibility of the cornea (2/3 animals) and conjunctiva (redness) (all animals) was observed until day 7.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

April 10, 1991 - April 30, 1991

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Limited details on test material and environmental conditions.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

Limited details on test material and environmental conditions.

GLP compliance:

yes

Specific details on test material used for the study:

- Name of test material (as cited in study report): CT 473-91
- Name: Sodium diisobutyl monothiophoshate
- CAS: 53378-52-2
- Molecular formula: C8H18O3PS.Na
- Molecular weight: 248.26
- Substance type: Amber liquid
- Physical state: Liquid
- Lot/batch No.: SPS-17220
- Storage condition of test material: Store at room temperature in the dark

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

- Source: Ace animals
- Age at study initiation: no data
- Weight at study initiation: 2.5 - 2.6 kg
- Housing: Animals were housed individually in suspended cages.
- Diet: Free access to fresh purina chow (diet #5321)
- Water: Free access to water.
- Acclimation period: At least 3 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): temperature controlled
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.5 mL/site

Duration of treatment / exposure:

4 hours

Observation period:

Skin reactions were evaluated at 1, 24, 48 and 72 hours after patch removal.

Number of animals:

3

Details on study design:

STUDY DESIGN
The test article was applied to one abraded and one intact site on the cilpped back of each of three rabbits. The treated sites were covered with two 2.5 cm square gauze patches which were secured with adhesive tape. The torso was wrapped with plastic and secured with adhesive tape.

TEST SUBSTANCE PREPARATION
Used as received. 0.5 mL/site, total dose of 0.1 mL/rabbit.

TEST SITE
Prior to application of the test substance, the back and sides of each animal were clipped free of hair. The left side of each animal was abraded with a bent-tip needle. Three abrasions, approximately 2-3 cm apart, extending the length of the exposure site were made. The abrasions were sufficiently deep to penetrate the stratum corneum but not deep enough to produce bleeding.

REMOVAL OF TEST SUBSTANCE
Four hours after the application, the residual test substance was wiped off prior to dermal observations.

OBSERVATIONS
- Mortality/Viability/Toxicity: The general health of the animals was monitored at each dermal irritation observation.
- Body Weight: Body weights were recorded pretest.
- Necropsy: No data.
- Irritation: The skin reactions were assessed at approximately 1, 24, 48 and 72 hours after patch removal. The irritation scores and a description of all other (local) effects were recorded.

SCORING SYSTEM:
The irritation was assessed according to the numerical scoring system according to OECD 404.

Irritation parameter:

erythema score

Remarks:

(Intact skin)

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 24 hours

Irritation parameter:

erythema score

Remarks:

(Intact skin)

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

erythema score

Remarks:

(Intact skin)

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

erythema score

Remarks:

(Abraded skin)

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 24 hours

Irritation parameter:

erythema score

Remarks:

(Abraded skin)

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

erythema score

Remarks:

(Abraded skin)

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Remarks:

(Intact skin)

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Remarks:

(Intact skin)

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Remarks:

(Intact skin)

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Remarks:

(Abraded skin)

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Remarks:

(Abraded skin)

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Remarks:

(Abraded skin)

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

Erythema, slight at 1 hour after patch removal, was absent to slight at 24 hours and absent at 48 and 72 hours both in intact and abraded skin. There was no edema noted at any time point.

Other effects:

There were no abnormal systemic signs noted during the observation period.

Interpretation of results:

GHS criteria not met

Conclusions:

In an skin irritation study with CT-473-91 in rabbits, performed equivalent or similar to OECD 404 test guidelines, no irritation was observed, both in intact and abraded skin.

Executive summary:

Dermal irritation was tested by three rabbits who were exposed to CT-473-91, a 50% solution in water, for 4 hours using a occlusive dressing, equivalent or similar to OECD 404 test guideline and according to GLP principles.

Erythema, slight at 1 hour after patch removal, was absent to slight at 24 hours and absent at 48 and 72 hours, both in intact and abraded skin. There was no edema noted at any time point. There were no abnormal systemic signs noted during the observation period.

Based on the results, CT-473-91, a 50% solution in water, is not considered irritating to both intact and abraded skin and no classification for dermal irritation is needed according to EC regulation 1272/2008.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

Limited details on test material and environmental conditions. No controls were avalable as both eyes were dosed with the test substance. Observations were not performed until 21 days but only until 7 days.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Sodium O,O-diisobutyl phosphorothioate

EC Number:

610-992-2

Cas Number:

53378-52-2

Molecular formula:

C8 H18 O3 P S . Na

IUPAC Name:

Sodium O,O-diisobutyl phosphorothioate

Test material form:

other: grease-like solid

Specific details on test material used for the study:

- Name of test material (as cited in study report): CT 473-91
- Name: Sodium diisobutyl monothiophoshate
- CAS: 53378-52-2
- Molecular formula: C8H18O3PS.Na
- Molecular weight: 248.26
- Substance type: Amber liquid
- Physical state: Liquid
- Lot/batch No.: SPS-17220
- Storage condition of test material: Store at room temperature in the dark

Test animals / tissue source

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

- Source: Ace animals
- Age at study initiation: no data
- Weight at study initiation: 2.5 - 2.6 kg
- Housing: Animals were housed individually in suspended cages.
- Diet: Free access to fresh purina chow (diet #5321)
- Water: Free access to water.
- Acclimation period: At least 3 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

Test system

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied: 0.1 mL

Duration of treatment / exposure:

Single instillation on Day 1.

Observation period (in vivo):

The eyes of each animal were examined approximately 1, 24, 48 and 72 hours and 7 days after instillation of the test substance

Number of animals or in vitro replicates:

3

Details on study design:

STUDY DESIGN
Initially, both eyes of two rabbits were dosed. Due to vocalization noted in two animals post dose, the third animal was not dosed pending consultation with the sponsor. The day following initial administration, the third rabbit was dosed based on the sponsor's instructions.

TREATMENT
The test substance was placed by syringe or syringe-type applicator into the conjunctival sac which was formed by gently pulling the lower eyelid away from the eye. After instillation, the lids were held together briefly to insure adequate distribution of the test substance.

REMOVAL OF TEST SUBSTANCE
-Washing: Twenty to thirty seconds after instillation of the test substance, the left eye of each rabbit was flushed for one minute with lukewarm water. The right eye of each animal remained unwashed.

OBSERVATIONS
- Mortality/Viability/Toxicity: The general health of the animals was monitored at each observation period.
- Body Weight: Body weights were recorded pretest.
- Necropsy: No data.
- Irritation:
The eyes of each animal were examined approximately 1, 24, 48 and 72 hours and 7 days after instillation of the test substance.
The irritation scores and a description of all other (local) effects were recorded. The irritation was assessed according to OECD 405.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

cornea opacity score

Remarks:

(unwashed right eye)

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: vocalization post dose

Results 2

Irritation parameter:

cornea opacity score

Remarks:

(unwashed right eye)

Basis:

animal #2

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Remarks on result:

other: vocalization post dose

Results 3

Irritation parameter:

cornea opacity score

Remarks:

(unwashed right eye)

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.67

Max. score:

4

Reversibility:

fully reversible within: 72 hrs.

Remarks on result:

other: vocalization post dose

Results 4

Irritation parameter:

cornea opacity score

Remarks:

(washed left eye)

Basis:

animal #1

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Results 5

Irritation parameter:

cornea opacity score

Remarks:

(washed left eye)

Basis:

animal #2

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Results 6

Irritation parameter:

cornea opacity score

Remarks:

(washed left eye)

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7 days

Results 7

Irritation parameter:

iris score

Remarks:

(unwashed right eye)

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

other: vocalization post dose

Results 8

Irritation parameter:

iris score

Remarks:

(unwashed right eye)

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

other: vocalization post dose and on day 7 an iris score of 1 was observed

Results 9

Irritation parameter:

iris score

Remarks:

(unwashed right eye)

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.67

Max. score:

2

Reversibility:

fully reversible within: 72 hrs.

Remarks on result:

other: vocalization post dose

Results 10

Irritation parameter:

iris score

Remarks:

(washed left eye)

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

fully reversible within: 7 days

Results 11

Irritation parameter:

iris score

Remarks:

(washed left eye)

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Results 12

Irritation parameter:

iris score

Remarks:

(washed left eye)

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

0

Reversibility:

fully reversible within: 7 days

Results 13

Irritation parameter:

conjunctivae score

Remarks:

(unwashed right eye)

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: vocalization post dose

Results 14

Irritation parameter:

conjunctivae score

Remarks:

(unwashed right eye)

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Remarks on result:

other: vocalization post dose

Results 15

Irritation parameter:

conjunctivae score

Remarks:

(unwashed right eye)

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Remarks on result:

other: vocalization post dose

Results 16

Irritation parameter:

conjunctivae score

Remarks:

(washed left eye)

Basis:

animal #1

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Results 17

Irritation parameter:

conjunctivae score

Remarks:

(washed left eye)

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Results 18

Irritation parameter:

conjunctivae score

Remarks:

(washed left eye)

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Results 19

Irritation parameter:

chemosis score

Remarks:

(unwashed right eye)

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 24 hrs.

Remarks on result:

other: vocalization post dose

Results 20

Irritation parameter:

chemosis score

Remarks:

(unwashed right eye)

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Remarks on result:

other: vocalization post dose

Results 21

Irritation parameter:

chemosis score

Remarks:

(unwashed right eye)

Basis:

animal #3

Time point:

24/48/72 h

Score:

2.67

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: vocalization post dose

Results 22

Irritation parameter:

chemosis score

Remarks:

(washed left eye)

Basis:

animal #1

Time point:

24/48/72 h

Score:

2.33

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Results 23

Irritation parameter:

chemosis score

Remarks:

(washed left eye)

Basis:

animal #2

Time point:

24/48/72 h

Score:

2.33

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Results 24

Irritation parameter:

chemosis score

Remarks:

(washed left eye)

Basis:

animal #3

Time point:

24/48/72 h

Score:

2.67

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritant / corrosive response data:

Unwashed eyes:
Corneal opacity, noted in 2/3 animals, persisted to day 7 in one eye. Iritis was noted in 2/3 animals. Moderate to severe conjunctival irritation, noted in all animals, persisted to day 7 in one animal, improved to slight in another and cleared completely in the third animal.

Washed eyes:
Corneal opacity, noted in all animals, persisted to day 7 in 2/3 animals. Iritis, noted in all animals cleared by day 7. Moderate to severe conjuctival irritation, noted in all animals, persisted to day 7 in two animals and improved to slight in one animal.

Other effects:

Vocalization post dose was observed in all animals.

Any other information on results incl. tables

Tables with results see the attached background material.

Applicant's summary and conclusion

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

In an eye irritation study with CT-473-91 in rabbits, performed equivalent or similar to OECD 405 test guideline and GLP principles, irreversible effects on the eye were observed during the 7 day observation period.

Executive summary:

Eye irritation properties of CT-473 -91, a 50% solution in water, was tested in both eyes of three rabbits, equivalent or similar to OECD 405 test guideline and GLP principles.

No controls were avalable as both eyes were dosed with the test substance. The right eye were unwashed and the left eye was washed twenty to thirty seconds after instillations of the test substance. Vocalization post dose was observed in all animals.

Observations were performed until only 7 days at which irreversibility of the cornea (1 animal) and the conjunctiva (2/3 animals) was observed in the unwashed eyes. In the washed eyes, irreversibility of the cornea (2/3 animals) and conjunctiva (redness) (all animals) was observed until day 7.

Based on the observed irreversibility effects in both the washed and unwashed eyes during the observation period, CT-473 -91, a 50% solution in water, needs to be classified as serious eye damage, category 1 and labelled with H318: Causes serious eye damage, according to EC regulation 1272/2008.