Phosphoric acid, isononyl ester

Endpoint summary

Description of key information

The substance is corrosive to skin and therefore assumed to cause serious damage to the eye.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

Experimental Start Date: 31 May 2011; Experimental Term Date: 16 jUN 2011

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study 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 effect the quality of the relevant results. Reliability downgraded from Klimisch 1 to 2 since study being used for read-across.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

The dermal score for the initial animal was not performed on Day 14, but was performed on Day 15. This deviation did not appear to have an impact on the outcome of the study since the scores had not resolved and the conclusion did not change.

GLP compliance:

yes

Remarks:

Report includes EPA GLP Compliance letter

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Animals were received from Millbrook Breeding Labs, Amherst, MA
- Age at study initiation: The animals were approximately 3 months old.
- Weight at study initiation: The pretest body weight range was 2.9 - 3.1 kg
- Housing: The animals were individually housed in suspended cages.
- Diet (e.g. ad libitum): Fresh Rabbit Chow (Diet #5321) was provided daily.
- Water (e.g. ad libitum): Water was available as libitum
- Acclimation period: At least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): The animal room was temperature controlled.
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

Type of coverage:

semiocclusive

Preparation of test site:

other: clipped free of hair

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): The test article was dosed by volume, 0.5 ml/site.

Duration of treatment / exposure:

Exposure periods of 3 minutes (for initial animal), 1 hour (for initial animal) and 4 hours (for all animals).

Observation period:

Up to 15 days.

Number of animals:

3 (1 initial animal then two additional animals).

Details on study design:

TEST SITE
- Area of exposure: Each dose site was approximately 6 cm2.
- Type of wrap if used:
Initially, one rabbit was dosed sequentially on sites #1, 2 and 3. The test article was placed under a 2 x 3 cm gauze patch. Gentle pressure was applied to aid in the distribution of the test article over the prepared site. The rabbit was gently held in place and a piece of porous dressing was secured with non-irritating tape over dose site #1 (semi-occlusive) for the 3 minute exposure period. The torso was covered with a piece of porous dressing large enough to cover dose sites 2 & 3 with at least 5 cm square to spare on all sides of the gauze patch. Porous, non-irritating tape was used to encircle the trunk of the animal.

REMOVAL OF TEST SUBSTANCE
The dressing and test article patch covering site #1 were removed at 3 minutes post dose, over site #2 at 1 hour post dose and the torso wrappings and patch covering site #3 at 4 hours post dose. All sites were gently washed with distilled water to remove residual test substance.

DOSING OF ADDITIONAL ANIMALS
Since no evidence of a corrosive or severely irritating effect was observed in the initial animal, two additional animals were added to the study. The animals were dosed at site #3 with 0.5 ml of test article. After an exposure period of 4 hours, the wrappings and patches were removed and the sites gently washed with distilled water.

SCORING SYSTEM:
Initial animal: Site #1 was scored for dermal irritation immediately and at 60 minutes following patches removal for the 3 minute exposure. Site #2 was scored at 60 minutes following the 1 hour exposure.

All animals: Site #3 was scored at 60 minutes and at 24, 48 and 72 hours and on Days 7 and 15 for the initial animal and at 24, 48 and 72 hours and on Days 7 and 14 for the two additional animals following the 4 hour exposure.

Erythema and edema were scored according to the numerical Draize technique. The skin was also evaluated for ulceration and necrosis or any evidence of tissue destruction. Any additional signs were described.

Draize scoring scheme:

Erythema & Eschar
No erythema: 0
Very slight erythema (barely perceptible): 1
Well defined erythema: 2
Moderate to severe erythema: 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth): 4

Edema
No edema: 0
Very slight edema (barely perceptible): 1
Slight edema (edges of area well-defined by definite raising): 2
Moderate edema (raised approximately 1.0 mm): 3
Severe edema (raised more than 1.0 mm, extending beyond the area of exposure): 4

Irritation parameter:

erythema score

Remarks:

(4 hour exposure)

Basis:

animal: 1 (initial animal)

Time point:

other: 7 days

Score:

4

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: Skin felt thickened and as though it had separated from the underlying tissue. Shiny areas were also observed.

Irritation parameter:

erythema score

Remarks:

(4 hour exposure)

Basis:

animal: 1 (initial animal)

Time point:

other: 15 days

Score:

4

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: Shiny areas observed.

Irritation parameter:

erythema score

Remarks:

(4 hour exposure)

Basis:

animal: 2 (additional animal)

Time point:

other: 7 days

Score:

4

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: Skin felt thickened and as though it had separated from the underlying tissue.

Irritation parameter:

erythema score

Basis:

animal: 2 (additional animal)

Time point:

other: 14 days

Score:

4

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: Shiny areas observed.

Irritation parameter:

erythema score

Remarks:

(4 hour exposure)

Basis:

animal: 3 (additional animal)

Time point:

other: 7 days

Score:

4

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: Skin felt thickened

Irritation parameter:

erythema score

Remarks:

(4 hour exposure)

Basis:

animal: 3 (additional animal)

Time point:

other: 14 days

Score:

4

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: Shiny areas observed

Irritant / corrosive response data:

Dermal Observations (Table 1 - attached background material).
Initial animal:
No erythema or edema was observed immediately following or at 60 minutes after patch removal following the 3 minute exposure. Slight erythema and no edema was observed at 60 minutes following the 1 hour exposure. Slight erythema and very slight edema was observed at 60 minutes, 24, 48 and 72 hours after patch removal following the 4 hour exposure. At 48 and 72 hours, the skin felt thickened. On Day 7, erythema was severe. The skin felt thickened and as though it had separated from the underlying tissue. Shiny areas were also observed. On Day 15, erythema was severe with shiny areas. No edema was observed on Days 7 or 15.

2 additional animals:
Erythema was slight to moderate at 1 hour post patch removal following the 4 hour exposure. Erythema was slight at 24 hours and 48 hours and very slight to slight at 72 hours. At 48 and 72 hours, the skin felt thickened and as though it had separated from the underlying tissue. Edema was slight at 1 hour and very slight at 24, 48 and 72 hours after patch removal following the 4 hour exposure. On Day 7, erythema was severe. The skin felt thickened for both animals and as though it had separated from the underlying tissue for one animal. On Day 14, erythema was severe with shiny areas. No edema was observed on Days 7 or 14.

Other effects:

Systemic Observations and Body Weights (Table 1 - attached background material).
There were no abnormal physical signs noted during the observation period.

See attached background material for Table 1: Dermal Observations, Body Weights and Systemic Observations.

Interpretation of results:

corrosive

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The substance is considered to be corrosive.

Executive summary:

Objective:

To determine the irritant or corrosive effects, if any, of a test article when applied to the skin of a rabbit. This study was designed to comply with standards set forth in OECD Guideline for Testing of Chemicals, Number 404 Acute Dermal Irritation/Corrosion, adopted April 24, 2002.

Method Synopsis:

Since the test article was suspected to be a dermal irritant/corrosive substance, one healthy male New Zealand White rabbit was dosed dermally with the test article. The test article (0.5 ml) was applied dermally to three intact sites for an exposure period of 3 minutes on site #1, 1 hour on site #2 and 4 hours on site #3. Erythema and edema were scored immediately after patch removal following the 3 minute exposure and at 60 minutes after each patch removal for the 1 and 4 hour exposure. Site #3 was scored again at 24, 48 and 72 hours. The skin was also evaluated for ulceration and necrosis or any evidence of tissue destruction at these time periods. Since the reaction of the initial animal did not produce a corrosive or severely irritating effect, two additional animals (males) were added to the study. The two animals were dosed at site #3 for a four hour exposure. Erythema and edema were scored at 60 minutes, and at 24, 48 and 72 hours and on Days 7 and 15 for the initial animal and at 24, 48 and 72 hours and on Days 7 and 14 for the two additional animals.

Animals were observed for toxicological and pharmacological effects at each dermal observation period and observed for mortality daily. Body weights of all animals were recorded pre-test, 72 hours and at termination

Summary:

Initial animal:

No erythema or edema was observed immediately following or at 60 minutes after patch removal following the 3 minute exposure. Slight erythema and no edema was observed at 60 minutes following the 1 hour exposure. Slight erythema and very slight edema was observed at 60 minutes, 24, 48 and 72 hours after patch removal following the 4 hour exposure. At 48 and 72 hours, the skin felt thickened. On Day 7, erythema was severe. The skin felt thickened and as though it had separated from the underlying tissue. Shiny areas were also observed. On Day 15, erythema was severe with shiny areas. No edema was observed on Days 7 or 15.

2 additional animals:

Erythema was slight to moderate at 1 hour post patch removal following the 4 hour exposure. Erythema was slight at 24 hours and 48 hours and very slight to slight at 72 hours. At 48 and 72 hours, the skin felt thickened and as though it had separated from the underlying tissue. Edema was slight at 1 hour and very slight at 24, 48 and 72 hours after patch removal following the 4 hour exposure. On Day 7, erythema was severe. The skin felt thickened for both animals and as though it had separated from the underlying tissue for one animal. On Day 14, erythema was severe with shiny areas. No edema was observed on Days 7 or 14.

Conclusion:

The substance is considered to be corrosive.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (corrosive)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

The irritation/corrosion assessment of isononyl phosphate is based on read-across data from the structurally related substance 2-ethylhexyl phosphate (CAS 12645-31-7).

Skin Irritation/Corrosion

The substance is considered to be corrosive based on the effects observed in a reliable in vivo skin irritation/corrosion study on a related substance, which produced irreversible damage to the skin following exposure to the test substance for up to 4 hours. Severe effects were still present after 14 days. A reliable in vitro study gave a non corrosive result however the in vivo result is considered more definitive.

Eye Irritation:

A reliable in vivo skin irritation/corrosion study showed the substance to be corrosive. In accordance with column 2 of REACH Annex VII (8.2) and Annex VIII (8.2.1), neither an in vitro or in vivo eye irritation study was conducted as the substance is classified as corrosive to the skin. The substance can therefore be considered to lead to serious eye damage.

Respiratory Irritation:

As the substance is a corrosive, it can be reasonably assumed that it may have the potential to cause respiratory irritation if inhaled.

Justification for selection of skin irritation / corrosion endpoint:
The most recent in vivo study indicating corrosivity of the skin is considered more reliable than the available in vitro study which indicates that the substance is not corrosive. Study is Klimisch 2 (due to read-across only).

Justification for selection of eye irritation endpoint:
The substance is classified as corrosive to the skin and is therefore assumed to be corrosive to the eye. In accordance with REACH Annex VII, 8.2, column 2 and Annex VIII, 8.2.1, column 2, neither an in vitro or in vivo eye irritation study has been conducted as the substance is classified as corrosive to the skin.

Effects on skin irritation/corrosion: corrosive

Effects on eye irritation: corrosive

Effects on respiratory irritation: irritating

Justification for classification or non-classification

The substance is considered to be corrosive based on the effects observed in an in vivo skin/irritation study on a related substance, which produced irreversible damage to the skin following exposure to the test substance for up to 4 hours. Severe effects were still present after 14 days. The substance is classified as Skin corrosion Category 1; subcategory 1B (exposure of ≥3 minutes to ≤1 hour to cause corrosive effects). This represents a worst case classification for corrosion as the effects observed at the 1 hour exposure site were only scored after 60 minutes and not up to 14 days. Therefore, although the corrosive effects observed in the study were observed for the 4 hour exposure sites, the substance is classified as corrosive subcategory 1B.

Based on the substances corrosive classification, it is considered to cause serious damage to the eye. Therefore, a classification of Eye Damage Category 1 (Irreversible effects on the eye) is assumed.

The substance shall be classified as Corrosive, H314.