Registration Dossier

Administrative data

Description of key information

- Skin irritation: OECD 404, 3 New Zealand White rabbits, well-defined to slight erythema, moderate to very slight oedema, fully reversible. Conclusion: not irritating.
- Eye irritation: OECD 405, 3 New Zealand White rabbits, corneal opacity, iridial inflammation and severe conjunctival irritation. Conclusion: damaging to eyes.

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:
1998-08-11 to 1998-08-25
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well documented guideline study in compliance with GLP (conducted with a read-across substance)
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Department of Health of the Government of the United Kingdom
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: David Percival Ltd, Moston, Sandbach, Cheshire, UK
- Age at study initiation: twelve to sixteen weeks
- Weight at study initiation: 2.75 to 2.90 kg
- Housing: individually housed in suspended metal cages
- Diet/Water (e.g. ad libitum): free access to mains drinking water and food (STANRAB SQC Rabbit Diet, Special Diets Services Ltd, Witham, Essex, UK)
- Acclimation period: five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 to 25
- Humidity (%): 65 to 74
- Air changes (per hr): approximately fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light and twelve hours darkness
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
Duration of treatment / exposure:
4 h
Observation period:
14 d
Number of animals:
2 males / 1 female
Details on study design:
TEST SITE
- Area of exposure: 2.5 cm x 2.5 cm
- Type of wrap if used: strip of surgical adhesive tape (BLENDERM: approximate size 2.5 cm x 4.0 cm); wrapped in an elasticated corset (TUBIGRIP)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Corset and patches were removed from each animal and any residual test material removed by gentle swabbing with cotton
wool soaked in distilled water.

SCORING SYSTEM:
-Method by Draize
Irritation parameter:
erythema score
Basis:
animal: 1
Time point:
other: 24 h, 48 h, 72 h
Score:
1.7
Max. score:
2
Reversibility:
fully reversible within: 14 d
Irritation parameter:
erythema score
Basis:
animal: 2
Time point:
other: 24 h, 48 h, 72 h
Score:
1.7
Max. score:
2
Reversibility:
fully reversible within: 14 d
Irritation parameter:
erythema score
Basis:
animal: 3
Time point:
other: 24 h, 48 h, 72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 14 d
Irritation parameter:
edema score
Basis:
animal: 1
Time point:
other: 24 h, 48 h, 72 h
Score:
1.7
Max. score:
2
Reversibility:
fully reversible within: 14 d
Irritation parameter:
edema score
Basis:
animal: 2
Time point:
other: 24 h, 48 h, 72 h
Score:
1.7
Max. score:
2
Reversibility:
fully reversible within: 14 d
Irritation parameter:
edema score
Basis:
animal: 3
Time point:
other: 24 h, 48 h, 72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 14 d
Irritant / corrosive response data:
- Well-defined erythema (24 and 48-hour observations);
- Well-defined erythema to very slight erythema (72-hour observation);
- Moderate oedema, slight oedema (1-hour observation);
- Slight oedema (24 and 48-hour observations);
- Slight oedema, very slight oedema (72-hour observation).
Other effects:
Loss of skin elasticity (48 and 72-hour observation), crust formation (7 days after treatment): fully reversible within 14 days.

Well defined erythema was noted at all treated skin sites one hour after patch removal and at the 24 and 48-hour observations. Well-defined erythema was noted at one treated skin site with very slight erythema at two treated skin sites at the 72-hour observation.

Moderate oedema was noted at one treated skin site with slight oedema at two treated skin sites one hour after patch removal. Slight oedema was noted at all treated skin sites at the 24 and 48-hour observations. Slight oedema persisted at one treated skin site with very slight oedema at two treated skin sites at the 72-hour observation.

Loss of skin elasticity was noted at one treated skin site at the 48-hour observation and at all treated skin sites at the 72-hour observation. Crust formation was noted at one treated skin site with slight desquamation at two treated skin sites at the 7-day observation. Treated skin sites appeared normal at the 14-day observation.

Table 1. Individual Skin Reactions

Skin Reaction Observation Time Individual Scores - Rabbit Number and Sex (Bodyweight kg) Total
10 Male (2.75) 36 Male (2.90) 78 Male (2.88)
Erythema/Eschar Formation 1 Hour 2 2 2 ( 6 )
24 Hours 2 2 2 6
48 Hours 2 2 2 Le (6)
72 Hours 1 Le 1 Le 2 Le 4
7 Days 0 D 0 D 0 Cf (0)
14 Days 0 0 0 (0)
Oedema Formation 1 Hour 2 3 2 ( 7 )
24 Hours 2 2 2 6
48 Hours 2 2 2 (6 )
72 Hours 1 1 2 4
7 Days 0 0 0 (0 )
14 Days 0 0 0 (0)
Sum of 24 and 72-hour Readings (S)   20      
Primary Irritation Index (S/6)   20/6 = 3.3      
Classification  MODERATE IRRITANT           

( ) = Total values not used for calculation of primary irritation index; Cf = crust formation; D = desquamation; Le = loss of skin elasticity

Table 2. Individual Daily and Mean Scores for Dermal Irritation following 4 -hour Exposure required for EU Labelling Regulations

Skin Reaction Skin ReactionReading (Hours) Individual Scores - Rabbit Number and Sex (Bodyweight kg)
10 Male
(2.75)
36 Male
(2.90)
78 Male
(2.88)
Erythema/Eschar Formation 24 2 2 2
48 2 2 2
72 1 1 2
Total   5 5 6
 Mean Score   1.7 1.7 2.0 +
Oedema Formation 24 2 2 2
48 2 2 2
72 1 1 2
Total   5 5 6
Mean Score   1.7 1.7 2.0 +

+ = positive criterion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: EU-GHS
Conclusions:
According to Regulation (EC) No 1272/2008, the test material is not classified as skin irritant or corrosive. Mean values for erythema/eschar or for oedema from gradings at 24, 48 and 72 hours after patch removal amount up to 2 (under the cut-off value of 2.3).
Executive summary:

An OECD Guideline 404 study was performed to assess the irritancy potential of phosphoric acid, mono- and di-(C8 -C10) ester, compds. with C12 -14 amine to the skin of the New Zealand White rabbit in compliance with GLP. A single 4-hour, semi-occluded application of 0.5 mL of the test material to the intact skin of three rabbits (2 males / 1 female) produced well-defined erythema and slight to moderate oedema. Observations were performed 1 h, 24 h, 48 h, 72 h, 7 d and 14 d after application. Loss of skin elasticity, crust formation and slight desquamation were also noted. Treated skin sites appeared normal at the 14-day observation. The test material produced a primary irritation index of 3.3 and was classified as a moderate 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 labelling regulations. No symbol and risk phrase are required.

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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1998-07-07 - 1998-12-30
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well documented study in compliance with GLP (conducted with a read-across substance)
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Department of Health of the Government of the United Kingdom
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: David Percival Ltd, Moston, Sandbach, Cheshire, UK
- Age at study initiation: twelve to sixteen weeks
- Weight at study initiation: 2.53 to 2.84 kg
- Housing: individually housed in suspended metal cages
- Diet/Water (e.g. ad libitum): free access to mains drinking water and food (STANRAB SQC Rabbit Diet, Special Diets Services Ltd, Witham, Essex, UK)
- Acclimation period: five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 to 21
- Humidity (%): 65 to 74
- Air changes (per hr): approximately fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light and twelve hours darkness
Vehicle:
unchanged (no vehicle)
Controls:
other: 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
Duration of treatment / exposure:
single application
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
3
Details on study design:
SCORING SYSTEM: Method by Draize, J.H. (1977)

TOOL USED TO ASSESS SCORE: standard ophthalmoscope
Irritation parameter:
cornea opacity score
Basis:
animal: 1
Time point:
other: 24h, 48h, 72h
Score:
ca. 0.67
Max. score:
1
Reversibility:
fully reversible within: 7 d
Irritation parameter:
cornea opacity score
Basis:
animal: 2
Time point:
other: 24h, 48h, 72h
Score:
ca. 1.33
Max. score:
2
Reversibility:
other: not applicable
Remarks on result:
other: animal killed after 72 h observation
Irritation parameter:
cornea opacity score
Basis:
animal: 3
Time point:
other: 24h, 48h, 72h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 d
Irritation parameter:
iris score
Basis:
animal: 1
Time point:
other: 24h, 48h, 72h
Score:
ca. 0.33
Max. score:
1
Reversibility:
fully reversible within: 7 d
Irritation parameter:
iris score
Basis:
animal: 2
Time point:
other: 24h, 48h, 72h
Score:
1
Max. score:
1
Reversibility:
other: not applicable
Remarks on result:
other: animal killed after 72 h observation
Irritation parameter:
iris score
Basis:
animal: 3
Time point:
other: 24h, 48h, 72h
Score:
ca. 0.67
Max. score:
1
Reversibility:
fully reversible within: 7 d
Irritation parameter:
conjunctivae score
Basis:
animal: 1
Time point:
other: 24h, 48h, 72h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 7 d
Irritation parameter:
conjunctivae score
Basis:
animal: 2
Time point:
other: 24h, 48h, 72h
Score:
3
Max. score:
3
Reversibility:
other: not applicable
Remarks on result:
other: animal killed after 72 h observation
Irritation parameter:
conjunctivae score
Basis:
animal: 3
Time point:
other: 24h, 48h, 72h
Score:
ca. 2.33
Max. score:
3
Reversibility:
fully reversible within: 7 d
Irritation parameter:
chemosis score
Basis:
animal: 1
Time point:
other: 24h, 48h, 72h
Score:
ca. 1.33
Max. score:
2
Reversibility:
fully reversible within: 7 d
Irritation parameter:
chemosis score
Basis:
animal: 2
Time point:
other: 24h, 48h, 72h
Score:
ca. 2.33
Max. score:
3
Reversibility:
other: not applicable
Remarks on result:
other: animal killed after 72 h observation
Irritation parameter:
chemosis score
Basis:
animal: 3
Time point:
other: 24h, 48h, 72h
Score:
ca. 1.67
Max. score:
2
Reversibility:
fully reversible within: 7 d
Irritant / corrosive response data:
Under the conditions of this test, the test item was considered to be irritating to the eye.

Interpretation of Results

Classification According to a Modified Version of the Kay and Calandra System

The numerical values corresponding to each animal, tissue and observation time were recorded. The data relating to the conjunctivae were designated by the letters A (redness), B (chemosis) and C (discharge), those relating to the iris designated by the letter D and those relating to the cornea by the letters E (degree of opacity) and F (area of opacity). For each tissue the score was calculated as follows:

Score for conjunctivae = ( A + B + C ) x 2

Score for iris = D x 5

Score for cornea = ( E x F ) x 5

Using the numerical data obtained a modified version of the system described by Kay J H and Calandra J C, 1. SOC. Cosmet. Chem., 1962 13

281-289 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 any rabbit shows irreversible ocular damage the test material will be classified as corrosive to the eye.

Results

Individual and group mean scores for ocular irritation are given. Dulling of the normal lustre of the cornea was noted in two treated eyes one hour after treatment. Diffuse corneal opacity was noted in all treated eyes at the 24 and 48-hour observations. Translucent corneal opacity was noted in one treated eye with diffuse corneal opacity in one other treated eye at the 72-hour observation.

Iridial inflammation was noted in all treated eyes one hour after treatment and at the 24-hour observation, in two treated eyes at the 48-hour observation and persisted in one treated eye at the 72-hour observation.

Moderate conjunctival irritation was noted in all treated eyes one hour after treatment with severe conjunctival irritation in all treated eyes at the 24-hour observation. Severe conjunctival irritation was noted in one treated eye with moderate conjunctiva irritation in two treated eyes at the 48 and 72-hour observations. One animal was killed for humane reasons, immediately after the 72-hour observation, due to the severity of the reactions noted, in accordance with Safepharm company policy and current UK Home Office guidelines. The two remaining treated eyes appeared normal at the 7-day observation.

Interpretation of results:
Category 1 (irreversible effects on the eye)
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Mean scores at the 24, 48 and 72 h readings for cornea opacity of the three tested animals amount to 0.67, 1.33 and 1, respectively, according to the method of Draize. Iritis mean scores of 0.33, 1.0 and 0.67 and conjunctivae mean scores of 2.0, 3.0 and 2.33 were yielded for the test animals, respectively. Chemosis mean scores of 1.33, 2.33 and 1.67 are reported for the three tested animals, respectively. However, one animal had very severe effects resulting in its termination at 72-h time point. The effects in this animal are considered to be irreversible and therefore the substance is classified as seriously damaging to eyes (Category 1) according to Regulation (EC) No 1272/2008.
Executive summary:

According to OECD Guideline 405, a study was performed to assess the irritancy potential of the test material to the eye of the New Zealand White rabbit in compliance with GLP. Local eye effects were observed 1 h, 24 h, 48 h, 72 h and 7 d after test material application and evaluated by the method of Draize (1977) and by the modified Kay and Calandra classification system. A single instillation (0.1 mL) of phosphoric acid, mono- and di-(C8 -C10) ester, compds. with C12 -14 amine to the non-irrigated eye of three rabbits produced diffuse to translucent corneal opacity, iridial inflammation and severe conjunctival irritation. One animal was killed for humane reasons, immediately after the 72-hour observation. The remaining treated eyes appeared normal at the 7-day observation. The test material produced a maximum group mean score of 35.0 and was classified as at least a moderate irritant (Class 5 on a 1 to 8 scale) to the rabbit eye according to a modified Kay and Calandra classification system. The test material was also considered to be irritant according to EU labelling regulations. It is reasonable to assume that the symbol "Xi", the indication of danger "irritant" and the highest risk phrase R 41 "RISK OF SERIOUS DAMAGE TO EYES" are therefore required.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin irritation

An OECD Guideline 404 study was performed to assess the irritancy potential of the read-across substance (Phosphoric acid, mono- and di-(C8 -C10) ester, compds. with C12 -14 amine) to the skin of the New Zealand White rabbit in compliance with GLP (Sanders, 1998c; Project No. 525/128). A single 4-hour, semi-occluded application of 0.5 mL of the test material to the intact skin of three rabbits (2 males / 1 female) produced well-defined erythema and slight to moderate oedema. Observations were performed 1 h, 24 h, 48 h, 72 h, 7 d and 14 d after application. Loss of skin elasticity, crust formation and slight desquamation were also noted. Treated skin sites appeared normal at the 14-day observation. The test material produced a primary irritation index of 3.3 and was classified as a moderate irritant to rabbit skin according to the Draize classification scheme. No corrosive effects were noted. The test material does not meet the criteria for classification as irritant or corrosive according to EU labelling regulations since all scores were under the cut-off value of 2.3. No symbol and risk phrase are required.

Eye irritation

According to OECD Guideline 405, a study was performed to assess the irritancy potential of the read-across substance (Phosphoric acid, mono- and di-(C8 -C10) ester, compds. with C12 -14 amine) to the eye of the New Zealand White rabbit in compliance with GLP (Sanders, 1998d, Project No. 525/129). Local eye effects were observed 1 h, 24 h, 48 h, 72 h and 7 d after test material application and evaluated by the method of Draize (1977) and by the modified Kay and Calandra classification system. A single instillation (0.1 mL) of phosphoric acid, mono- and di-(C8 -C10) ester, compds. with C12 -14 amine to the non-irrigated eye of three rabbits produced diffuse to translucent corneal opacity, iridial inflammation and severe conjunctival irritation. One animal was killed for humane reasons, immediately after the 72-hour observation. The remaining treated eyes appeared normal at the 7-day observation.The test material produced a maximum group mean score of 35.0 and was classified as at least a moderate irritant (Class 5 on a 1 to 8 scale) to the rabbit eye according to the modified Kay and Calandra classification system. The test material was also considered to be an irritant according to EU labelling regulations. It is reasonable to assume that the symbol "Xi", the indication of danger "irritant" and the highest risk phrase R 41 "RISK OF SERIOUS DAMAGE TO EYES" are therefore required.


Justification for selection of skin irritation / corrosion endpoint:
Only one study available (conducted with the read-across substance).

Justification for selection of eye irritation endpoint:
Only one study available (conducted with the read-across substance).

Effects on eye irritation: highly irritating

Justification for classification or non-classification

Skin irritation

According to the classification criteria outlined in the section 3.2.2.2. (Guidance on the Application of CLP criteria, 2012), if the mean value of ≥ 2.3 - ≤ 4.0 was reached for erythema/eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal, the classification as Skin Irritant would be assigned. The highest value for erythema/eschar and oedema was 2.0 in each of three animals at 24 -h, 48 -h or 72 -h reading points. The mean values of 1.7, 1.7 and 2.0 for erythema and oedema were measured in animal 1, 2 and 3, respectively. Therefore, the target substance (Reaction products of diphosphorus pentaoxide and alcohol C7-9-iso, C8 rich, salted with 2-ethylhexylamine) does not meet criteria under EU CLP Regulation (EC) No. 1272/2008) for classification and labelling as a skin irritant.

Eye irritation

According to the classification criteria outlined in the section 3.3.2.2. (Guidance on the Application of CLP criteria, 2012), if a substance cause positive but reversible reactions such as corneal opacity (score ≥ 1), iritis (score ≥ 1), conjunctival redness (score ≥ 2) or conjunctival oedema (chemosis) (score ≥ 2) in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after application, the classification as Eye Irritant (Category 2) is assigned. The average irritation scores over 24, 48, and 72 hours for corneal opacity were 0.67, 1.33 and 1.0 in animal 1, 2 and 3, respectively. Iritis mean scores of 0.33, 1.0 and 0.67 and conjunctivae mean scores of 2.0, 3.0 and 2.33 were yielded for each of the test animals, respectively. Furthermore, chemosis mean scores of 1.33, 2.33 and 1.67 are reported for the three tested animals, respectively. However, one animal had very severe effects resulting in its termination at 72-h time point. The effects in this animal are considered to be irreversible. According to the ECETOC Guidance (No. 37, EC Classification of Eye Irritancy, 1997), euthanasia of one animal in this study can be considered as "significant, severe and/or persistent" effect (section 4.4.2). Furthermore, there mentioned that "if instillation of a substance or preparation results in treatment-related effects, including severe and enduring signs of pain or distress or severe irritancy, which require an animal to be euthanised before assessment of irritancy has been completed, R41 should be assigned" (section 4.6). Based on this knowledge, the target substance (Reaction products of diphosphorus pentaoxide and alcohol C7-9-iso, C8 rich, salted with 2-ethylhexylamine) is classified as seriously damaging to eyes (Category 1, H318) according to Regulation (EC) No. 1272/2008.