Dimethyl octadecylphosphonate

Endpoint summary

Key value for chemical safety assessment

Skin irritation / corrosion

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:

72 hours

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-guideline study

Principles of method if other than guideline:

A volume of the test item (equivalent to 0.1 mL) was placed in the conjunctival sac of one eye in 6 New Zealand Albino Rabbits (6 ♀, approximately 9 weeks old) and the lid was held together briefly.

The ocular reactions of the cornea, iris, and conjunctiva were graded at 1, 2 and 3 days after dosing by the Draize scoring system. In addition, eyes were examined on day three using sodium fluorescein.

GLP compliance:

yes

Remarks:

FDA's GLP

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Nicholas Helf
- Age at study initiation: 9 weeks
- Weight at study initiation: Not reported
- Fasting period before study: Not reported
- Housing: Individually housed in suspended wire mesh cages
- Diet (e.g. ad libitum): Rabbits were fed Purina Rabbit Chow ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: approx. 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not specified (in accordance with the standards of AAALAC)
- Humidity (%): not specified (in accordance with the standards of AAALAC)
- Air changes (per hr): not specified (in accordance with the standards of AAALAC)
- Photoperiod (hrs dark / hrs light): not specified (in accordance with the standards of AAALAC)

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated eye acts as a control

Amount / concentration applied:

0.1 mL

Duration of treatment / exposure:

72h (the test item was not flushed from the eye after dosing)

Observation period (in vivo):

72h

Number of animals or in vitro replicates:

6 ♀, approximately 9 weeks old.

Details on study design:

The test item equivalent to 0.1 mL was placed in the conjunctival sac of one eye in 6 New Zealand Albino Rabbits (6 ♀, approximately 9 weeks old) and the lid was held together briefly.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): none
- Time after start of exposure: not applicable

SCORING SYSTEM: The ocular reactions of the cornea, iris, and conjunctiva were graded at 1, 2 and 3 days after dosing according to the method by Draize.

TOOL USED TO ASSESS SCORE: In addition, eyes were examined on day three using sodium fluorescein.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

other: Mean of 24, 48 and 72h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

mean

Time point:

other: Mean of 24, 48 and 72 h

Score:

0.06

Max. score:

2

Reversibility:

fully reversible

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

mean

Time point:

other: Mean of 24, 48 and 72 h

Score:

1.39

Max. score:

3

Reversibility:

not specified

Remarks:

last evaluation was at 72 hr

Irritation parameter:

chemosis score

Basis:

mean

Time point:

other: mean of 24, 48 and 72 h

Score:

0.89

Max. score:

4

Reversibility:

not specified

Remarks:

last evaluation was at 72 hr

Irritant / corrosive response data:

Based on the following mean scores for 24, 48 & 72 hours: Corneal opacity - 0, Iridial inflammation - 0.06, Conjunctival redness - 1.39,
Conjunctival chemosis - 0.89, the test item is not classified for irritation according to the criteria in Regulation (EC) 1272/2008.

Other effects:

UV Fluorescein scan at 3 days was scored 0 in all animals.

Individual and mean scores for cornea, iris & conjunctivae for EC labelling regulations

Animal number	Time after treatment	Corneal opacity	Iridial inflammation	Conjunctival redness	Conjunctival chemosis
5001	24 hr	0	0	2	1
	48 hr	0	0	1	1
	72 hr	0	0	1	0
Total		0	0	4	2
Mean		0	0	1.33	0.67
5002	24 hr	0	1	2	2
	48 hr	0	0	2	2
	72 hr	0	0	1	2
Total		0	1	5	6
Mean		0	0.33	1.67	2.00
4352	24 hr	0	0	2	1
	48 hr	0	0	1	1
	72 hr	0	0	1	0
Total		0	0	4	2
Mean		0	0	1.33	0.67
5006	24 hr	0	0	2	1
	48 hr	0	0	1	1
	72 hr	0	0	1	1
Total		0	0	4	1
Mean		0	0	1.33	0.67
5007	24 hr	0	0	2	1
	48 hr	0	0	1	1
	72 hr	0	0	1	1
Total		0	0	4	3
Mean		0	0	1.33	0.67
5008	24 hr	0	0	2	1
	48 hr	0	0	1	1
	72 hr	0	0	1	1
Total		0	0	4	3
Mean		0	0	1.33	0.67
Group mean		0	0.06	1.39	0.89

 

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: OECD GHS

Conclusions:

According to Regulation EC 1272/2008, dimethyl octadecylphosphonate is not classified as irritating to eyes.

Executive summary:

The test item (equivalent to 0.1 mL) was placed in the conjunctival sac of one eye in 6 New Zealand Albino Rabbits (6 ♀, approximately 9 weeks old) and the lid was held together briefly. The ocular reactions of the cornea, iris, and conjunctiva were graded at 1, 2 and 3 days after dosing according to the grading system of Draize. In addition, eyes were examined on day three using sodium fluorescein.

Based on the following mean scores for all animals for 24, 48 & 72 hours: Corneal opacity - 0, Iridial inflammation - 0.06, Conjunctival redness - 1.39 and Conjunctival chemosis - 0.89, dimethyl octadecylphosphonate is not classified for irritation to the eye according to the criteria in Regulation (EC) 1272/2008.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

Skin irritation:

One in-vitro and 3 in-vivo skin irritation studies are available.

In-vitro

Costin, GE. 2012: Dimethyl octadecylphosphonate (DMOP) was tested in this GLP, guideline compliant in vitro test. The MatTek Corporation’s EpiDerm reconstituted human epidermis model was used to assess the potential skin irritation of the test article, DMOP. The skin irritation potential of the test article was evaluated by measuring the relative cell viability in treated tissues at 42-hour post-exposure incubation after a 60-minute exposure to the test substance, following MatTek Corporation’s EpiDerm™ SOP, Version 7.0 (Revised March 2009). The protocol met the requirements of the OECD guideline, “In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method” (OECD 439).

One definitive test with DMOP was conducted in triplicate with ground test material applied to the EpiDerm skin undiluted. Prior to conducting the test it was confirmed that DMOP did not directly reduce MTT in the absence of viable cells. The results of the study determined a mean OD570 of the negative control, CMF-DPBS, of 2.208, the mean viability of the positive control, 5% SDS, was 5.0%. The standard deviation calculated from individual percent tissue viabilities of the 3 identically treated replicates was < 18% for the positive control and negative control. Since the acceptance criteria were met, the assay was considered valid. It was concluded that on the basis of a mean viability of 103.3% for DMOP, the skin irritation prediction is non-irritant.

In vivo

Unwin, SE. 1978: This non-guideline and non-GLP study was performed in 1976 in the United States prior to the issue of the OPPTS harmonized test guidelines. The objective of the study was to evaluate corrosive properties of the test item as defined in 49.CFR 173.1200, 1976. A patch test was performed where dimethyl octatdecylphosphonate (DMOP, 0.5 ml) was applied to the intact skin of 6 New Zealand Albino Rabbits (3♂, 3♀) and covered with impervious material. The skin was exposed to DMOP for 4 hours and then observations for corrosion of the skin were made. Following the initial reading the test site was washed with soap and water. At 48 hours further observations for corrosion were performed. The criteria for corrosion was "Corrosion will be considered to have resulted if the substance in contact with the rabbit skin has caused destruction or irreversible ulceration of the tissue.  Tissue destruction is considered to have occurred if, at any of the readings, there is ulceration or necrosis. Tissue destruction does not include merely sloughing of the epidermis or erythrema, edema or fissuring." It was concluded that DMOP was not corrosive to skin.

Weatherby, SE. 1980: The study makes a claim of GLP compliance (FDA) and includes a quality assurance evaluation, however some details are lacking from the report. This study was performed in 1980 in the United States prior to the issue of the OPPTS harmonized test guidelines. The objective of the study was to identify corrosive materials as defined in 49.CFR 173.240. It is not possible to use this study for the purposes of classification since individual Draize irritation scores were not reported.

Six female New Zealand Albino Rabbits (approximately 9 weeks old) were dosed once dermally at one intact site. 0.5 g of DMOP was applied beneath 2.5 cm × 2.5 cm gauze patches. The patches were secured with adhesive tape and the trunks were covered with impervious material. The test material was kept in contact with the skin for 4 hours after which time the patches were removed. Dermal reactions were scored at 4, 24 and 48 hours according to the Draize scoring method.  The modified primary irritation index was derived and since the value was <5, it was concluded that DMOP is non-corrosive/non-irritant.

Birch, MD. 1972: This non-guideline and non-GLP study was conducted in the United States prior to issue of the OPPTS harmonised Test Guidelines. The exposure period was 24 hours (rather than 4 hours as specified in OECD Guideline 404), the result is therefore not considered to be valid for the purposes of classification. DMOP was applied to the clipped intact skin of New Zealand White male and female rabbits under a one inch by one inch square patch which was held in place by an occlusive dressing for an exposure period of 24 hours. Observations were made over a period of seven days for irritation and scored according to the method of Draize, Woodard and Calvery.

It was concluded by the author that DMOP was a "corrosive irritant", however the test (conducted in 1972) was not performed to GLP or test guidelines and the exposure period was 24 hours rather than 4 hours as specified in OECD Test Guideline 404. The result is therefore not considered to be valid for the purposes of classification.

 

Conclusion for skin irritation

It may therefore be concluded that dimethyl octatdecylphosphonate is not a skin irritant based on the negative result from a GLP, guideline compliant in-vitro study supported by 2 further negative in-vivo studies in rabbits. 

Eye Irritation:

In the key GLP, non-guideline study (Weatherby, SE. 1980) 0.1 ml of the test item was instilled into one eye of 6 albino rabbits. The study was performed according to GLP (FDA’s GLP) but deviated from the current guideline in that no further observations were conducted after 3 days and therefore reversibility of the findings was not fully investigated. The ocular reactions in this study were graded according to the method of Draize and mean scores for all animals at 24, 48 and 72 hours were 0 for corneal opacity, 0.06 for iridial inflammation, 1.39 for conjunctival redness and 0.89 for conjunctival chemosis. According to the criteria for classification in Regulation (EC) 1272/2008 dimethyl octadecylphosphonate was not classified with respect to eye irritation.

 

In a second supporting study (Birch, MD. 1972, non-GLP, non-guideline) in 3 albino rabbits the observation period extended to 7 days and reversibility of the findings was observed within 5 days of instillation of the test item. In this study dimethyl octadecylphosphonate was classed as a mild irritant in male and female rabbits using the EPA eye irritation criteria valid at the time of the study. The average maximum score was 16.0 out of a possible 110 in 24 hours. However, scores for conjunctivae, iris and cornea are not reported and therefore the information reported in this study is not considered suitable for the classification of dimethyl octadecylphosphonate according to Regulation (EC) 1272/2008.

 

Conclusion for eye irritation

It may therefore be concluded that dimethyl octatdecylphosphonate is not an eye irritant based on the mean scores from a GLP, non-guideline in-vivo study in rabbits. Reversibility was found in a second non-GLP, non-guideline in vivo study in rabbits. 

Justification for selection of skin irritation / corrosion endpoint:
Weight of evidence conclusion based on negative outcomes from 1 in-vitro and 2 in-vivo studies

Justification for selection of eye irritation endpoint:
Key study

Justification for classification or non-classification

Skin irritation:

In accordance with EU CLP (Regulation (EC) No. 1272/2008), classification is not required for skin irritation based on the available data.

Eye irritation:

In accordance with EU CLP (Regulation (EC) No. 1272/2008), classification is not required for eye irritation based on the available data.