Dimethyl phosphonate

Endpoint summary

Description of key information

-In a primary skin irritation study (no guideline followed, application on rabbit ear) dimethyl phosphonate caused only very slight erythema at 24-hour observation time after 4-hour exposure and only very slight erythema at 24, 48, and 72 hours after 8-hour exposure. No further skin reactions were observed. Skin reactions were assessed using the Draize scheme. Dimethyl phosphonate was assessed to be not irritating to the skin.
-A primary skin irritation study in rabbits was conducted with the analogue substance diethyl phosphonate (4 hour-exposure, according to OECD 404, Draize scheme): dimethyl phosphonate is not a skin irritant.
-In an eye irritation study (equivalent to OECD 405): dimethyl phoshonate is not irritating to eye.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented study report which meets basic scientific principles. Adopted according to OECD SIDS (public available peer reviewed source). The original source is available and has been reviewed.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Dimethyl phosphonate was applied undiluted to the ears of rabbits for 1-4 hours.

GLP compliance:

no

Remarks:

GLP was not mandatory at the time of the study.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 3-4 kg
- Housing: the animals were individually caged.

Type of coverage:

other: plastic tape

Preparation of test site:

not specified

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

500 µL

Duration of treatment / exposure:

1-4 hour(s)

Observation period:

7 days

Number of animals:

2

Details on study design:

TEST SITE
- Area of exposure: ear
- Type of wrap if used: plaster tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the test substance was washed away with water and soap/vegetable oil
- Time after start of exposure: after the exposure

SCORING SYSTEM: Draize

Irritation parameter:

erythema score

Remarks:

(4-hour exposure)

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

erythema score

Remarks:

(2-hour exposure)

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

erythema score

Remarks:

(1-hour exposure)

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 5 days

Irritation parameter:

edema score

Remarks:

(4-hour exposure)

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

edema score

Remarks:

(2-hour exposure)

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

edema score

Remarks:

(1-hour score)

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritant / corrosive response data:

No further data.

Other effects:

No further data.

Table 1. Individual skin examination scores after 1 -4 hour exposure to dimethyl phosphhonate (scoring according to Draize scheme)

Skin effect	Erythema				Edema
Scoring^a	24h	48h	72h	Mean^b	24h	48h	72h	Mean^b
Animal No.10  (4 -hour exposure)	1	0	0*	0.3	0	0	0*	0
Animal No.35 (2 -hour exposure)	2	2	2	2	0	0	0	0
Animal No.77 (1 -hour exposure)	1	1	1	1	0	0	0	0

^aTimepoint of reading after substance removal subsequent to 1-4 hour dermal exposure

^bMean of 24, 48, and 72 hours in intact skin

Individual data were reported for only one animal per time point.

* Reading at 72 hours was not observed. The same scores assumed as for 48h time point (worst case).

On the basis of the results of the present study it can be concluded that dimethyl phosphonate is not a skin irritant, according to DSD and CLP criteria.

Interpretation of results:

other: not irritating.

Executive summary:

In a primary dermal irritation study, the skin irritation/corrosion potential of dimethyl phosphonate was tested. 500 µL of dimethyl phosphonate was applied undiluted to the ears of 2 New Zealand White rabbits for a period of time of 1 to 4 hours. The rabbits were observed for 7 days. Skin reactions were assessed using the Draize scheme approx. 24, 48, 72 hours after removal of the test substance. The exposure period of 4 hours caused only very slight erythema at 24 hours observation time. No further skin reactions were observed. On the basis of the results of the present study can be concluded that dimethyl phosphonate is not a skin irritant.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented study report which meets basic scientific principles. Adopted according to OECD SIDS (public available peer reviewed source). The original source is available and has been reviewed.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

Dimethyl phosphonate was applied undiluted to the ears of rabbits for 8 hours.

GLP compliance:

no

Remarks:

GLP was not mandatory at the time of the study

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

- Weight at study initiation: 3-4 kg
- Housing: the animals were individually caged.

Type of coverage:

other: plastic tape

Preparation of test site:

not specified

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied: 500 µL of undiluted test substance/animal.

Duration of treatment / exposure:

8 hour(s)

Observation period:

7 days

Number of animals:

2

Details on study design:

TEST SITE
- Area of exposure: ear.
- Type of wrap if used: plaster tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the test substance was washed away with water and soap/vegetable oil.
- Time after start of exposure: after the exposure.

SCORING SYSTEM: Draize.

Irritation parameter:

erythema score

Remarks:

(8-hour exposure)

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

edema score

Remarks:

(8-hour exposure)

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Table 1. Individual skin examination scores after 8-hour exposure to dimethyl phosphhonate (scoring according to Draize scheme)

Skin effect	Erythema				Edema
Scoring^a	24h	48h	72h	Mean ^b	24h	48h	72h	Mean ^b
Animal No.24	1	1	1	1	0	0	0	0

^a Timepoint of reading after substance removal subsequent to 8h-dermal exposure.

^b Mean of 24, 48, and 72 hours in intact skin.

Individual data were reported for only one animal

On the basis of the results of the present study it can be concluded that dimethyl phosphonate is not a skin irritant, according to DSD and CLP criteria.

Interpretation of results:

other: not irritating.

Executive summary:

In a primary dermal irritation study, the skin irritation/corrosion potential of dimethyl phosphonate was tested. 500 µL of dimethyl phosphonate was applied undiluted to the ears of 2 New Zealand White rabbits for a period of time of 8 hours. The rabbits were observed for 7 days. Skin reactions were assessed using the Draize scheme approx. 24, 48, and 72 hours after removal of the test substance. The exposure period of 8 hours caused only very slight erythema at 24, 48, and 72 hours after exposure. No further skin reactions were observed. On the basis of the results of the present study can be concluded that dimethyl phosphonate is not a skin irritant.

Reference 3

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Guideline study with acceptable restriction (No analytical purity reported). A primary skin irritation study in rabbits was conducted with the analogue substance diethyl phosphonate. The two compounds have similar chemical structure and have similar properties. Therefore, findings for diethyl phosphonate will be read across to the analogue substance, dimethyl phosphonate.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

No analytical purity reported.

GLP compliance:

not specified

Species:

rabbit

Strain:

other: HC:NZW

Details on test animals or test system and environmental conditions:

- Weight at study initiation: 3.5 kg (average).
- Housing: The animals were maintained conventionally under standardized conditions in individual cages.
- Diet (e.g. ad libitum): ad libitum.
- Water (e.g. ad libitum): ad libitum.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12 / 12

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

other: the untreated skin area of each animal served as control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL.

Duration of treatment / exposure:

4 hours

Observation period:

7-14 days

Number of animals:

6

Details on study design:

TEST SITE
The day before the application of the test substance the flank skin of each animal was shaved (on both sides) on an area of about 6x6 cm with an electric hair clipper. Only animals with intact skin were used in the experiment.
For the treatment of each animal 0.5 mL of undiluted test substance was applied to a gauze patch (about 2.5x2.5 cm).
The gauze patch was placed on the flanks of each animal and secured with elastic, permeable to air, adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water.
- Time after start of exposure: 4 hours.

SCORING SYSTEM: Draize

Irritation parameter:

erythema score

Basis:

mean

Remarks:

of 6 animals

Time point:

24/48/72 h

Score:

0.67

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

edema score

Basis:

mean

Remarks:

of 6 animals

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritant / corrosive response data:

5 of 6 animals showed erythema at the application sites. No edema was observed. No corrosive effect was noted. One animal showed no skin reaction. At the 9th day of the experiment all skin reactions were completely gone.

Table: Evaluation results of skin reactions after diethyl phosphite administration to rabbits

Animal No.	Symptoms	Time points for skin evaluation
		24 hours	48 hours	72 hours	7 days	14 days
62	Erythema	1	1	0	0	--
62	Oedema	0	0	0	0	--
92	Erythema	1	0	0	0	--
92	Oedema	0	0	0	0	0
93	Erythema	1	0	0	0	0
93	Oedema	0	0	0	0	0
82	Erythema	1	1	1	1	0
82	Oedema	0	0	0	0	0
84	Erythema	0	0	0	0	0
84	Oedema	0	0	0	0	0
94	Erythema	1	2	2	1	0
94	Oedema	0	0	0	0	0
Average (24h,48h,72h)	Erythema	0.67			--	--
Average (24h,48h,72h)	Oedema	0			--	--

On the basis of the results of the present study it can be concluded that diethyl phosphonate is not a skin irritant, according to DSD and CLP criteria. On the basis of the read across approach presented here it is assumed that dimethyl phosphonate is not a skin irritant. Thus, the data for this endpoint can be read across from the analogous substance diethyl phosphonate, and dimethyl phosphonate is not to be classified as skin irritant.

Interpretation of results:

GHS criteria not met

Executive summary:

A primary skin irritation study in rabbits was conducted with the analogue substance diethyl phosphonate. The two compounds have similar chemical structure and have similar properties. Therefore, findings for diethyl phosphonate will be read across to the analogue substance, dimethyl phosphonate. The skin irritation/corrosion potential of diethyl phosphonate was tested according to OECD guideline 404. The shaved dorso-lateral skin of the trunk of six male rabbits was exposed to 0.5 mL test material for 4 hours under semiocclusive conditions. The rabbits were observed for 14 days. Skin reactions were assessed using the Draize scheme approx. 1, 24, 48 and 72 hours after removal of the test substance.

The exposure period of 4 hours caused the following symptoms: 5 of 6 animals showed erythema at the application sites. A corrosive effect was not noted; one animal showed no skin reaction. At the 9th day of the experiment all skin reactions were completely gone.

On the basis of the results of the present study can be concluded that diethyl phosphonate is not a skin irritant.

On the basis of the read across approach presented here it is assumed that dimethyl phosphonate is not a skin irritant. Thus, the data for this endpoint can be read across from the analogous substance diethyl phosphonate, and dimethyl phosphonate is not to be classified as skin irritant.

Reference 4

Endpoint:

skin irritation: in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

ANALOGUE APPROACH JUSTIFICATION
[see attached justification]

Reason / purpose for cross-reference:

read-across source

Irritation parameter:

erythema score

Basis:

mean

Remarks:

of 6 animals

Time point:

24/48/72 h

Score:

0.67

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

edema score

Basis:

mean

Remarks:

of 6 animals

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritant / corrosive response data:

5 of 6 animals showed erythema at the application sites. No edema was observed. No corrosive effect was noted. One animal showed no skin reaction. At the 9th day of the experiment all skin reactions were completely gone.

Table: Evaluation results of skin reactions after diethyl phosphite administration to rabbits

Animal No.	Symptoms	Time points for skin evaluation
		24 hours	48 hours	72 hours	7 days	14 days
62	Erythema	1	1	0	0	--
62	Oedema	0	0	0	0	--
92	Erythema	1	0	0	0	--
92	Oedema	0	0	0	0	0
93	Erythema	1	0	0	0	0
93	Oedema	0	0	0	0	0
82	Erythema	1	1	1	1	0
82	Oedema	0	0	0	0	0
84	Erythema	0	0	0	0	0
84	Oedema	0	0	0	0	0
94	Erythema	1	2	2	1	0
94	Oedema	0	0	0	0	0
Average (24h,48h,72h)	Erythema	0.67			--	--
Average (24h,48h,72h)	Oedema	0			--	--

On the basis of the results of the present study it can be concluded that diethyl phosphonate is not a skin irritant, according to DSD and CLP criteria. On the basis of the read across approach presented here it is assumed that dimethyl phosphonate is not a skin irritant. Thus, the data for this endpoint can be read across from the analogous substance diethyl phosphonate, and dimethyl phosphonate is not to be classified as skin irritant.

Interpretation of results:

GHS criteria not met

Executive summary:

A primary skin irritation study in rabbits was conducted with the analogue substance diethyl phosphonate. The two compounds have similar chemical structure and have similar properties. Therefore, findings for diethyl phosphonate will be read across to the analogue substance, dimethyl phosphonate. The skin irritation/corrosion potential of diethyl phosphonate was tested according to OECD guideline 404. The shaved dorso-lateral skin of the trunk of six male rabbits was exposed to 0.5 mL test material for 4 hours under semiocclusive conditions. The rabbits were observed for 14 days. Skin reactions were assessed using the Draize scheme approx. 1, 24, 48 and 72 hours after removal of the test substance.

The exposure period of 4 hours caused the following symptoms: 5 of 6 animals showed erythema at the application sites. A corrosive effect was not noted; one animal showed no skin reaction. At the 9th day of the experiment all skin reactions were completely gone.

On the basis of the results of the present study can be concluded that diethyl phosphonate is not a skin irritant.

On the basis of the read across approach presented here it is assumed that dimethyl phosphonate is not a skin irritant. Thus, the data for this endpoint can be read across from the analogous substance diethyl phosphonate, and dimethyl phosphonate is not to be classified as skin irritant.

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Comparable to guideline study with restrictions (No GLP study. Only 2 animals used. Reading at 72 hours was not performed. No information about environmental and housing conditions). Adopted according to OECD SIDS (public available peer reviewed source). The original source is available and has been reviewed.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

No GLP study. Only 2 animals used. Reading at 72 hours was not performed. No information about environmental and housing conditions

GLP compliance:

no

Remarks:

GLP was not mandatory at the time of the study

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 3-4 kg
- Housing: individual housing

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

Amount applied: 0.1 mL

Observation period (in vivo):

up to 7 days

Number of animals or in vitro replicates:

2

Details on study design:

SCORING SYSTEM: Draize score

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

3

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

3

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

Reddening of the conjunctiva (grade 2) was observed 1h after treatment; no other  effects. Effects reversible in 5 days.

Reading at 72 hours was not performed. The same scores assumed as for 48h time point (worst case).

Interpretation of results:

GHS criteria not met

Executive summary:

In an eye irritation study, 0.1 mL of test substance was instilled into the conjunctival sac of one eye of two male young adult New Zealand White rabbits, with a method similar to OECD guideline 405 with deviations (No GLP study. Only 2 animals used. Reading at 72 hours was not performed. No information about environmental and housing conditions). Animals were observed for 7 days. Irritation was scored according to the method of Draize. Reddening of the conjunctiva (grade 2) was observed 1h after treatment; no other effects were observed. Effects were reversible within 5 days. Based on the study results, it can be concluded that dimethyl phosphonate is not irritating to eyes according to DSD and CLP criteria.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In order to assess the skin irritation potential of dimethyl phosphonate a weight of evidence approach is used. For skin irritation one reliable report exists. In a primary dermal irritation study, the skin irritation/corrosion potential of dimethyl phosphonate was tested. 500 µL of dimethyl phosphonate was applied undiluted to the ears of 2 New Zealand White rabbits for a period of time of 1 to 4 hours, and 8 hours. The rabbits were observed for 7 days. Skin reactions were assessed using the Draize scheme approx. 24, 48 and 72 hours after removal of the test substance. The exposure period of 4 hours caused only very slight erythema at 24 hours observation time. No further skin reactions were observed. The exposure period of 8 hours caused only very slight erythema at 24, 48 and 72 hours after exposure. No further skin reactions were observed. On the basis of the results of the present study it can be concluded that dimethyl phosphonate is not a skin irritant. Futhermore, a reliable primary skin irritation study in rabbits was conducted with the analogue substance diethyl phosphonate. The two compounds have similar chemical structure and have similar properties. Therefore, findings for diethyl phosphonate can be read across to the analogue substance, dimethyl phosphonate. The skin irritation/corrosion potential of diethyl phosphonate was tested according to OECD guideline 404. The shaved dorso-lateral skin of the trunk of six male rabbits was exposed to 0.5 mL test material for 4 hours under semiocclusive conditions. The rabbits were observed for 14 days. Skin reactions were assessed using the Draize scheme approx. 1, 24, 48 and 72 hours after removal of the test substance. The exposure period of 4 hours caused the following symptoms: 5 of 6 animals showed erythema at the application sites. A corrosive effect was not noted; one animal showed no skin reaction. At the 9th day of the experiment all skin reactions were completely gone. On the basis of the results of the present study it can be concluded that diethyl phosphonate is not a skin irritant. On the basis of the read across approach presented here it is assumed that dimethyl phosphonate is not a skin irritant as well. All together the above described results show that dimethyl phophonate is not a skin irritant.

For eye irritation one reliable study exists. 0.1 mL of dimethyl phosphonate was instilled into the conjunctival sac of one eye of two male young adult New Zealand White rabbits, with a method similar to OECD guideline 405 with deviations (No GLP study. Only 2 animals used. No information about environmental and housing conditions). Animals were observed for 7 days. Irritation was scored according to the method of Draize. Reddening of the conjunctiva (grade 2) was observed 1h after treatment; no other effects were observed. Effects were reversible within 5 days. Additionally, in another study it was found that dimethyl phosphonate is moderately irritating to the eyes of rabbits (Occidental Chemical Corporation, 1992). However this study is considered not reliable because of relevant methodological deficiencies (method shortly described; individual readings not reported, Draize Score system was not used to assess the eye effects; amount of test substance applied too little) and therefore is not used for hazard assessment of dimethyl phosphonate.

Based on the reliable data available, it can be concluded that dimethyl phosphonate is not irritating to eyes.

Justification for classification or non-classification

According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is not justified.