Registration Dossier

Administrative data

Description of key information

Skin: in vivo study in rabbits (1992, Kr. 1): slightly irritating but does not allow the classification under the current criteria for classification
Eye: in vivo study in rabbits (1992, Kr. 1): irritating to eyes, effects on cornea (fully reversible within 7 days in only 5/6 animals), on iris and conjunctivae (fully reversible within 14 days in all animals).

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:
from 5 October 1992 to 4 November 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study in compliance with the GLP
Qualifier:
according to
Guideline:
other: 16 CFR 1500.41
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
24 hour exposure period, no certificate of analysis
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Ace Animals
- Age at study initiation: no data
- Weight at study initiation: 2.0-2.4 kg
- Fasting period before study: none
- Housing: 2/cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled but conditions not specified
- Humidity (%): no data
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light): 12:12

IN-LIFE DATES: from 6 October 1992 to 9 October 1992
Type of coverage:
occlusive
Preparation of test site:
other: intact clipped skin and abraded clipped skin
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.5 ml applied to 2 sites (abraded and intact)
Duration of treatment / exposure:
24 hours
Observation period:
72 hours
Number of animals:
6 males
Details on study design:
TEST SITE
- Area of exposure: back
- % coverage: 2.5 cm²
- Type of wrap if used: the treated sites were covered with gauze patches which were secured with adhesive tape. The torso was wrapped with plastic which was secured with adhesive tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data

SCORING SYSTEM: Daize scale
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
other: 72 hours
Score:
0.54
Max. score:
0.83
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
erythema score
Remarks:
intact skin
Basis:
mean
Time point:
other: Overall 24 and 72h for each animal
Score:
0 - 0.5
Max. score:
4
Reversibility:
fully reversible within: 3 days
Remarks on result:
other: Mean individual score at 24 and 72h: 0.5/0.5/0.5/0.5/0.5/0.0
Irritation parameter:
edema score
Remarks:
intact skin
Basis:
mean
Time point:
other: Overall 24 and 72h
Score:
0 - 0.5
Max. score:
4
Reversibility:
fully reversible within: 3 days
Remarks on result:
other: Mean individual score at 24 and 72h: 0.0/0.5/0.5/0.0/0.0/0.0
Irritant / corrosive response data:
Erythema, absent to well-defined at 24 hours after test article application, was absent at 72 hours.
Edema, absent to slight at 24 hours after test article application, was absent at 72 hours.
Other effects:
Diarrhoea and ano-genital soiling, noted in one animal.

Table 7.3.1/1 :Irritation scores

 

 

Rabbit No.

Mean Score

 

D4667

D4668

D4669

D4670

D4671

D4672

Erythema/Eschar

Intact 24 h

1

1

1

1

1

0

0.83

Intact 72 h

0

0

0

0

0

0

0.00

Mean (intact skin) 24-72h

0.5

0.5

0.5

0.5

0.5

0.0

0.42

Abraded 24 h

0

1

2

 1

1

0

0.83

Abraded 72 h

0

0

0

0

0

0

0.00

Oedema

Intact 24 h

0

1

1

0

0

0

0.33

Intact 72 h

0

0

0

0

0

0

0.00

Mean (intact skin) 24-72h

0.0

0.5

0.5

0.0

0.0

0.0

0.17

Abraded 24 h

0

0

1

0

0

0

0.17

Abraded 72 h

0

0

0

0

0

-

0.00

Sum of mean scores

2.16

PDII(sum of mean scores/4)

0.54

 

Interpretation of results:
GHS criteria not met
Conclusions:
The test substance was only slightly irritating to the skin. No classification is required according to the criteria of Regulation (EC) 1272/2008 (CLP) and of Directiev 67/548/EEC.
Executive summary:

In a GLP-compliant skin irritation study performed similarly to the OECD 404 Guideline, six maleNew Zealandwhite rabbits were dosed dermally with undilued AWA 1351. 0.5 ml of the test substance was applied to 1 intact and 1 abraded site on the clipped back for a total of 1.0 ml per rabbit. The sites were occluded for 24 hours. Those exposure conditions correspond to a worst case approach as the test guidance recommends an exposure under semi-occlusive patch and for4h. The skin reactions were evaluated by the Draize technique at 24 and 72 hours after the test item application. Body weights were recorded pre-test. The Primary irritation Index was calculated.

Erythema, absent to well-defined at 24 hours after test article application, was absent at 72 hours. Edema, absent to slight at 24 hours after test article application, was absent at 72 hours. Diarrhoea and ano-genital soiling, noted in one animal, was the only abnormal systemic sign observed during the study.

The Primary Irritation Index was 0.54.The mean individual scores calculated within 2 scoring times (24 and 72 hrs) for the unabraded skin were 0.5/0.5/0.5/0.5/0.5/0.0 for erythema and 0.0/0.5/0.5/0.0/0.0/0.0 for edema.

Under the test conditions, the test item is not classified as skin irritant when applied topically to rabbits according to the criteria of the Regulation (EC) 1272/2008 (CLP) and to the criteria of the Directive 67/548/EEC.

This study is considered as acceptable and satisfies the requirement for skin irritation endpoint.

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:
from 15 September 1992 to 4 November 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study in compliance with the GLP
Qualifier:
according to
Guideline:
other: 16 CFR 1500.42
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Ace Animals
- Age at study initiation: no data
- Weight at study initiation: 2.7-3.1 kg
- Fasting period before study: none
- Housing: 2/cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled but conditions not specified
- Humidity (%): no data
- Air changes (per hr): not stated
- Photoperiod (hrs dark / hrs light): 12:12

IN-LIFE DATES: from 5 October 1992 to 26 October 1992
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.1 mL
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
21 days
Number of animals or in vitro replicates:
6 females
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

SCORING SYSTEM: Draize scale

TOOL USED TO ASSESS SCORE: no data
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
of each animal
Time point:
other: overall 24-48-72 h
Score:
0.67 - 2.33
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Remarks on result:
other: fully reversed within 7 days in 5/6 animals. Mean individual score at 24, 48, 72hrs :0.67, 2.33, 2.0, 2.0, 1.33, 2.0
Irritation parameter:
iris score
Basis:
mean
Remarks:
of each animal
Time point:
other: overall 24-48-72 h
Score:
0.33 - 1
Max. score:
2
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: Mean individual score at 24, 48, 72 hrs: 0.33, 1.0, 1.0, 0.33, 0.33, 0.33
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
of each animal
Time point:
other: overall 24-48-72 h
Score:
1.67 - 2.33
Max. score:
3
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: Mean individual score at 24, 48, 72 hrs: 2.0, 2.0, 2.33, 1.67, 2.33, 2.0
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24-48-72 h
Score:
1.67 - 2.67
Max. score:
4
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: Mean individual score at 24, 48, 72 hrs: 1.67, 2.33, 2.0, 1.67, 2.0, 2.0
Irritant / corrosive response data:
Corneal opacity, noted in 6/6 eyes, persisted to 21 days in one eye rabbit. Iritis and moderate conjunctival irritation, noted in 6/6 eyes, cleared by day 14. See details in Table 7.3.2/1.
Other effects:
No abnormal systemic signs noted

Table 7.3.2/1:Irritant/corrosive response data for each animal at each observation time up to removal of each animal from the test. 

Score at time point / Reversibility

Cornea

Iris

Conjunctivae

Chemosis

Max. score: 4

Max. score: 2

Max. score: 3

Max. score: 4

24 h

2/2/2/2/2/2

1/1/1/1/0/1

3/2/3/2/2/2

2/2/2/3/2/2

48 h

0/2/2/2/2/2

0/1/1/0/0/0

2/2/2/2/3/2

2/3/2/2/2/2

72 h

0/3/2/2/0/2

0/1/1/0/0/0

1/2/2/1/2/2

1/3/2/0/2/2

7 days

0/3/0/0/0/0

0/1/0/0/0/0

0/2/0/0/1/0

0/3/0/0/1/0

14 days

0/2/0/0/0/0

0/0/0/0/0/0

0/0/0/0/0/0

0/0/0/0/0/0

21 days

0/2/0/0/0/0

0/0/0/0/0/0

0/0/0/0/0/0

0/0/0/0/0/0

Average 24h, 48h, 72h

0.67/2.33/2.0/ 2.0/1.33/2.0

0.33/1.0/1.0/0.33/0.33/0.33

2.0/2.0/2.33/1.67/2.33/2.0

1.67/2.33/2.0/1.67/2.0/2.0

Reversibility*)

nc

c

c

c

Average time (day) for reversion

N/A

14

14

14

 *) Reversibility: c. = completely reversible;n.c.= not completely reversible; n. = not reversible

Interpretation of results:
Category 2A (irritating to eyes) based on GHS criteria
Conclusions:
Under the test conditions, Triethyl phosphonoacetate is irritating to the eye rabbit and required the classification as Eye Irr. 2 (H319) according to the Regulation (EC) 1272/2008 (CLP) and as Xi, R36 according to the Directive 67/548/EEC.
Executive summary:

In an eye irritation study performed similarly to the OECD No. 405 guideline, 0.1 mL of undiluted Triethyl phosphonoacetate was instilled into the right eye of 6 female New Zealand White Rabbits. After the instillation the substance was not remained. Animals were then observed for 21 days for eye edema and erythema of the conjunctive, corneal opacity and iris lesion. 

Eye irritation was assessed and scored according to the Draize scale at 24, 48 and 72 hrs after the instillation of the substance and then at days 7, 14 and 21. The mean individual score were calculated within 3 scoring times (24, 48 and 72 hrs).

The mean individual scores were for 1.67/2.33/2.0/1.67/2.0/2.0 chemosis, 0.33/1.0/1.0/0.33/0.33/0.33 for iris lesion, 2.0/2.0/2.33/1.67/2.33/2.0 for conjunctival erythema, and 0.67/2.33/2.0/ 2.0/1.33/2.0 for corneal opacity. Effects on the iris and the conjunctivae (redness and chemosis) were fully reversible in all animals within 14 days. However, corneal opacity persisted in one animal until day 21 whereas in all other animals (5/6) the effect fully reversed within 7 days.

 

Under the test conditions,Triethyl phosphonoacetate is considered as irritating to the eye rabbit and is therefore classified as Eye Irr. 2 (H319)according to the Regulation (EC) 1272/2008 (CLP) and as Xi, R36 according to the Directive 67/548/EEC.

This study is considered as acceptable and satisfies the requirement for eye irritation endpoint.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation:

In a GLP study (Kieffer, 1992) following a protocol equivalent to the OECD guideline 404, Triethyl phosphonoacetate was applied on the skin (abraded or intact) of 6 rabbits for 24 hours under occlusive dressing conditions. The Primary Irritation Index was 0.54.The mean individual scores calculated within 2 scoring times (24 and 72 hrs) for the unabraded skin were 0.5/0.5/0.5/0.5/0.5/0.0 for erythema and 0.0/0.5/0.5/0.0/0.0/0.0 for edema. Therefore Triethyl phosphonoacetate is considered as slightly irritating to the rabbit skin but does not require any classification for the skin irritation under the current criteria for classification.

 

Eye irritation:

In a GLP study (Cerven, 1992) following a protocol equivalent to the OECD guideline 405, Triethyl phosphonoacetate was administered to one eye of 6 rabbits. Corneal opacity, iritis and moderate conjunctival irritation (redness and chemosis) were noted in all treated eyes. Most effects had cleared by day 14. Although corneal opacity persisted to day21 in a limited area of one eye, the degree had decreased and it was concluded that it would eventually have resolved. It was therefore concluded that Triethyl phosphonoacetate is irritating to the eye.

 

Respiratory Irritation:

No data available


Justification for selection of skin irritation / corrosion endpoint:
Only one study available

Justification for selection of eye irritation endpoint:
Only one study available

Effects on eye irritation: irritating

Justification for classification or non-classification

Self-classification:

Skin:

The threshold for classification of a substance as irritating to the skin according to the criteria of Annex VI of Directive 67/548/EEC (Xi, R38) based on 4-hour exposure is overall mean score for erythema or oedema at 24/48/72 hours ≥ 2 or mean score for 2/3 animals for 24/48/72 hours ≥ 2. According to the criteria of EU/GHS the threshold for Skin Irr. 2 is mean score for 2/3 animals for 24/48/72 hours ≥ 2.3.

In the study on Triethyl phosphonoacetate with 24-hour exposure, there were no scores >1 for intact skin at 24 and 72 hours. Triethyl phosphonoacetate is therefore not classified for skin irritation according to the criteria of the Regulation (EC) 1272/2008 (CLP) and the Directive 67/548/EEC.

Eye:

The threshold for classification of a substance as irritating to the eye according to the criteria of Annex VI Directive 67/548/EEC(Xi, R36) is mean score 24/48/72 hours ≥ 2 for corneal opacity, ≥ 1 for iritis, ≥ 2.5 for conjunctival redness and ≥ 2 for conjunctival chemosis. According to the criteria of EU/GHS the threshold for Eye Irr. 2 is mean score for 2/3 animals for 24/48/72 hours ≥ 1 for corneal opacity or iritis, or ≥ 2 for conjunctival redness or chemosis.

The ocular irritation scores for Triethyl phosphonoacetate were above the irritation classification thresholds for corneal opacity and conjunctival effects. Although corneal opacity was not fully resolved at the end of the observation period for one animal, it was considered potentially reversible. Triethyl phosphonoacetate is therefore classified as Eye Irr. 2 (H319) according to the Regulation (EC) 1272/2008 (CLP) and as Xi, R36 according to the Directive 67/548/EEC.

Respiratory System:

Triethyl phosphonoacetate cannot be classified for respiratory irritation due to a lack of data.