Phosphorous acid, mixed 2,4-bis(1,1-dimethylpropyl)phenyl and 4-(1,1-dimethylpropyl)phenyl triesters

Endpoint summary

Description of key information

The substance was found to be non-irritating to the skin and eyes during two separate studies on the New Zealand White Rabbit.

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:

16th December 2009 and 15th January 2010.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Date of GLP inspection: 15/09/09 Date of Signature on GLP certificate: 26/11/09

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Ltd, Hillcrest, Belton, Loughborough, UK.
- Age at study initiation: Twelve to twenty weeks old.
- Weight at study initiation: 2.18 to 2.63 kg.
- Housing: The animals were individually housed in suspended cages.
- Diet: Certified Rabbit Diet. ad libitum.
- Water: mains drinking water ad libitum
- Acclimation period: At least five days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 to 23°C
- Humidity (%): 30 to 70%
- Air changes (per hr): at least fifteen changes per hour.
- Photoperiod (hrs dark / hrs light): The lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

N-LIFE DATES: From: Day 0 To: 72 hours

Type of coverage:

semiocclusive

Preparation of test site:

other: clipped

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml
- Concentration (if solution): not applicable

VEHICLE
- Amount(s) applied (volume or weight with unit): not applicable
- Concentration (if solution): not applicable
- Lot/batch no. (if required): not applicable
- Purity: not applicable

Duration of treatment / exposure:

One patch was removed after 3 minutes, the second patch was removed after 1 hour and the final patch was removed after 4 hours.

Observation period:

72 hours

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure:three areas each of 2.5 cm x 2.5 cm.
- % coverage: 100% under patch
- Type of wrap if used: cotton gauze patch secured in position with a strip of surgical adhesive tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Distilled water
- Time after start of exposure: One patch was removed at each of three time points: 3 minutes, 1 hour and 4 hours after application. Any residual test material was removed by gentle swabbing with cotton wool soaked in distilled water.

SCORING SYSTEM: Draize J H (1959) "Dermal Toxicity" In: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics. Association of Food and Drug Officials of the United States, Austin, Texas, p.46 59

Irritation parameter:

erythema score

Basis:

animal: 68790 Male

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Remarks on result:

other: mean

Irritation parameter:

erythema score

Basis:

animal: 68796 Male

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 24 hours

Remarks on result:

other: mean

Irritation parameter:

erythema score

Basis:

animal: 68797 Male

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 24 hours

Remarks on result:

other: mean

Irritation parameter:

edema score

Basis:

animal: 68790 Male

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 48 hours

Remarks on result:

other: mean

Irritation parameter:

edema score

Basis:

animal: 68796 Male

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no effects observed

Remarks on result:

other: mean

Irritation parameter:

edema score

Basis:

animal: 68797 Male

Time point:

other: Mean of 24, 48 and 72 hrs

Score:

0

Max. score:

4

Reversibility:

other: No effects observed

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Score:

0.8

Irritant / corrosive response data:

3 minute exposure period: Well-defined erythema and very slight oedema were noted at the treated skin site 1 hour after patch removal and at the 24 hour observation with very slight erythema noted at the 48 hour observation.

1 hour exposure period: Very slight erythema was noted at the treated skin site 1 hour after patch removal and at the 48 hour observation with well-defined erythema and very slight oedema noted at the 24 hour observation.

4 hour exposure period: Well-defined erythema and very slight oedema was noted at one treated skin site immediately after patch removal and at the 1 and 24 hour observations with very slight erythema noted at the two remaining treated skin sites at the 24 hour observation. Very slight erythema was noted at one treated skin site at the 48 hour observation. Two treated skin sites appeared normal at the 48 hour observation and the remaining treated skin site appeared normal at the 72 hour observation.

Other effects:

All animals showed expected gain in bodyweight during the study.

Result of TER. Determination of the electrical resistance was not possible due to the presence of adhered residual test material, despite repeated attempts to remove it. Visual inspection of the skin discs showed no obvious evidence of damage or discolouration.

Conclusion. Following assessment of the data the test material was considered unlikely to have the potential to cause corrosion in vivo.

Interpretation of results:

not irritating

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The test material produced a primary irritation index of 0.8 and was classified as a mild irritant to rabbit skin according to the Draize classification scheme. No corrosive effects were noted. The test material did not meet the criteria for classification as irritant or corrosive according to EU or GHS labelling regulations. No symbol or risk phrase are required.

Executive summary:

Introduction. The study was performed to assess the irritancy potential of the test material to the skin of the New Zealand White rabbit. The method was designed to meet the requirements of the following:

-  OECD Guidelines for the Testing of Chemicals No. 404 “Acute Dermal Irritation/Corrosion” (adopted)

-   Method B4 Acute Toxicity (Skin Irritation) of Commission Regulation (EC) No. 440/2008

Initial considerations. In the absence of data suggesting that the test material was unlikely to produce severe irritation/corrosion, an ex vivo pre‑screen test, the Transcutaneous Electrical Resistance (TER) Assay, was performed. The results of the pre-screen test indicated that the test material was considered not to be corrosive to the skin and the in vivo study was performed.

Results. 3-minute and 1 hour semi-occluded applications of the test material to the intact skin of one rabbit produced no corrosive effects. A single 4 hour, semi-occluded application of the test material to the intact skin of three rabbits produced very slight to well-defined erythema and very slight oedema. No corrosive effects were noted.

Conclusion. The test material did not meet the criteria for classification as irritant or corrosive.

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:

19th January 2010 to 4th February 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Date of GLP inspection: 15/09/09 Date of Signature on GLP certificate: 26/11/09

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Ltd, Hillcrest, Belton, Loughborough, UK.
- Age at study initiation: twelve to twenty weeks old
- Weight at study initiation: 2.26 to 2.92 kg
- Housing: The animals were individually housed in suspended cages.
- Diet: ad libitum - 2030 Teklad Global Rabbit diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK
- Water: ad libitum - mains drinking water
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 to 23°C
- Humidity (%): 30 to 70%
- Air changes (per hr): at least fifteen changes per hour
- Photoperiod (hrs dark / hrs light): lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness

IN-LIFE DATES: From: Day of dosing (Day 0) To: Day of sacrifice - Day 7 :

Vehicle:

unchanged (no vehicle)

Controls:

other: The left eye remained untreated and was used for control purposes.

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml
- Concentration (if solution): not applicable

VEHICLE
- Amount(s) applied (volume or weight with unit): not applicable
- Concentration (if solution): not applicable
- Lot/batch no. (if required): not applicable
- Purity: not applicable

Duration of treatment / exposure:

Single exposure

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

One animal treated initially, then after consideration of the first animal's ocular response, two additional animals were treated.

Details on study design:

PRE-TESTING OBSERVATIONS
- Prior to testing, both eyes of the selected test animals were examined for evidence of ocular irritation or defect. Animals free from ocular damage were used.

METHOD
Initially one animal was treated according to the following procedure, in order to assess the initial pain reaction.
- 0.1ml of the test material was placed into the conjunctival sac of the right eye, formed by gently pulling the lower lid away from the eye ball.
- The eye lids were held closed for 1 second before the animal was released.
- The left eye remained untreated and was used as the control.
- Immediately after application of the test material an assessment of the initial pain reaction was made according to the six point pain scale.
- Two additional animals were treated, following the same procedure, after consideration of the ocular response produced in the first animal.
- Observations occurred at the following time points; 1, 24, 48 and 72 hours post application. One treated eye was also examined on day 7.
- Additional Observations: Any other ocular effects or clinical signs of toxicity were also noted.
- Bodyweight: Recorded on day 0 and the end of the observation period.
- Equipment: all examinations were aided by use of a standard opthalmoscope.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): not stated in report
- Time after start of exposure: not stated in report.

SCORING SYSTEM: Draize J H (1977) "Dermal and Eye Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of Household Substances, National Academy of Sciences, Washington DC, p 48 to 49) see Table 1.

INTERPRETATIONS OF RESULTS
- The data obtained from the Draize scoring system was subjected to a modified version of the system described by Kay and Calandra (1962) (see Table 2). This was used to classify the ocular irritancy potential of the test material. This was achieved by adding together the scores for the cornea, iris and conjunctivae for each time point for each rabbit. The group means of the total scores for each observation were calculated. The highest of these group means (the maximum group mean score) together with the persistence of the reactions enabled classification of the eye irritancy potential of the test material.
- If evidence of irreversible ocular damage is noted, the test material will be classified as corrosive to the eye.
- The results were evaluated according to Commission Directive 2001/59/EC.

Irritation parameter:

cornea opacity score

Remarks:

Degree of opacity

Basis:

animal: 68822 Male

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: mean

Irritation parameter:

cornea opacity score

Remarks:

Degree of opacity

Basis:

animal: 68842 Male

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: mean

Irritation parameter:

cornea opacity score

Remarks:

Degree of opacity

Basis:

animal: 68843 Male

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: mean

Irritation parameter:

iris score

Basis:

animal: 68822 Male

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

other: mean

Irritation parameter:

iris score

Basis:

animal: 68842 Male

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

other: mean

Irritation parameter:

iris score

Basis:

animal: 38843 Male

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

other: mean

Irritation parameter:

conjunctivae score

Remarks:

Redness

Basis:

animal: 68822 Male

Time point:

24/48/72 h

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 24hours

Remarks on result:

other: Score of 2 observed at 1 hour - mean value

Irritation parameter:

conjunctivae score

Remarks:

Redness

Basis:

animal: 68842 Male

Time point:

24/48/72 h

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 24 hours

Remarks on result:

other: Score of 2 observed at 1 hour - mean values

Irritation parameter:

conjunctivae score

Remarks:

Redness

Basis:

animal: 68843 Male

Time point:

24/48/72 h

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 24 hours

Remarks on result:

other: Score of 2 observed at 1 hour - mean values

Irritation parameter:

chemosis score

Basis:

animal: 68822 Male

Time point:

24/48/72 h

Score:

0.67

Max. score:

4

Reversibility:

fully reversible within: 24 hours

Remarks on result:

other: Score of 2 observed at 1 hour - mean values

Irritation parameter:

chemosis score

Basis:

animal: 68842 Male

Time point:

24/48/72 h

Score:

0.67

Max. score:

4

Reversibility:

fully reversible within: 24 hours

Remarks on result:

other: Score of 2 observed at 1 hour - mean values

Irritation parameter:

chemosis score

Basis:

animal: 68843 Male

Time point:

24/48/72 h

Score:

0.67

Max. score:

4

Reversibility:

fully reversible within: 24 hours

Remarks on result:

other: Score of 2 observed at 1 hour - mean values

Irritant / corrosive response data:

No corneal or iridial effects were noted during the study. Moderate conjunctival irritation was noted in all treated eyes one hour after treatment with minimal conjunctival irritation noted at the 24 and 48 hour observations. Minimal conjunctival irritation was noted in one treated eye at the 72 hour observation. Two treated eyes appeared normal at the 72 hour observation and the remaining treated eye appeared normal at the 7 day observation.

Other effects:

All animals showed expected gain in bodyweight during the study.

REET study: following assessment of the data for all endpoints the test material was considered unlikely to have the potential to cause severe ocular irritancy in vivo.

Interpretation of results:

not irritating

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The test material produced a maximum group mean score of 12.0 and was classified as a mild irritant to the rabbit eye according to a modified Kay and Calandra classification system. The test material did not meet the criteria for classification as an irritant.

Executive summary:

Introduction. The study was performed to assess the irritancy potential of the test material to the eye of the New Zealand White rabbit. The method was designed to meet the requirements of the following:

-  OECD Guidelines for the Testing of Chemicals No. 405 “Acute Eye Irritation/Corrosion” (adopted 24 April 2002)

-  Method B5 Acute Toxicity (Eye Irritation) of Commission Regulation (EC) No. 440/2008

Initial considerations. In the absence of available information indicating that the test material had the potential to produce severe effects in a rabbit eye, a Rabbit Enucleated Eye Test (REET) was performed prior to the in vivo test.

Result. A single application of the test material to the non-irrigated eye of three rabbits produced moderate conjunctival irritation. Two treated eyes appeared normal at the 72 hour observation and the remaining treated eye appeared normal at the 7 day observation.

Conclusion. The test material produced a maximum group mean score of 12.0 and was classified as a mild irritant (Class 4 on a 1 to 8 scale) to the rabbit eye according to a modified Kay and Calandra classification system. The test material did not meet the criteria for classification as irritant according to EU labelling regulations Commission Directive 2001/59/EC.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

A study was performed to assess the irritancy potential of the test material to the skin of the New Zealand White rabbit. The method used was OECD Guideline 404. A single 4 hour, semi-occluded application of the test material to the intact skin of three rabbits produced no irritation. All treated skin sites appeared normal at the 24 hour observation.

A study was performed to assess the irritancy potential of the test material to the eye of the New Zealand White rabbit following OECD Guideline 405. A single application of the test material to the non-irrigated eye of three rabbits produced moderate conjunctival irritation. All treated eyes appeared normal at the 48 hour observation.

The above studies have all been ranked reliability 1 according to the Klimisch system. This ranking was deemed appropriate because the studies were conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of relevant results.

Justification for selection of skin irritation / corrosion endpoint:

One key study available.

Justification for selection of eye irritation endpoint:

One key study available.

Justification for classification or non-classification

The test material did not meet the criteria for classification as an irritant or corrosive according to Regulation 1272/2008.

The test material did not meet the criteria for classification as an eye irritant (to the eye) according Regulation 1272/2008.