Registration Dossier

Administrative data

Description of key information

Skin irritation/corrosion: not corrosive and not irritating in vitro (OECD 431 and 439, GLP)
Eye irritation: irritating Category 2 (OECD 405, GLP)
Respiratory irritation: no study available

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:
30 Jul - 28 Aug 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study
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)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Leicestershire, UK.
- Age at study initiation: 12-20 weeks
- Weight at study initiation: 2.26 or 2.86 kg
- Housing: The animals were individually housed in suspended cages. The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
- Diet: 2930 Teklad Global Rabbit diet supplied by Harlan Laboratories UK Ltd., Oxon, UK, ad libitum
- Water: mains drinking water, ad libitum.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23
- Humidity (%): 30-70
- Air changes (per hr): At least 15
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml (approx. 98 mg)
Duration of treatment / exposure:
single instillation without rinsing
Observation period (in vivo):
14 days
Reading time points: 1, 24, 48 and 72 h and 7 and 14 days
Number of animals or in vitro replicates:
2 males
Details on study design:
SCORING SYSTEM: Draize scoring system

TOOL USED TO ASSESS SCORE: standard ophthalmoscope
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: mean after 24-72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
other: mean after 24-72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: mean after 24-72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 14 days
Irritation parameter:
iris score
Basis:
animal #2
Time point:
other: mean after 24-72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: Mean 24, 48 and 72 hours
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: small area of petechial haemorrhage on the nictitating membrane observed at 24 and 48 h
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: mean after 24-72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: mean after 24-72 h
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: mean after 24-72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritant / corrosive response data:
Individua scores for ocular irritation are given in Table 1.
Scattered or diffuse corneal opacity was noted in one treated eye one hour after treatment, in both treated eyes at the 24 and 48 h observations and in one treated eye at the 72 h observation.
Iridial inflammation was noted in both treated eyes one hour after treatment and at the 24, 48 and 72 h observations and in one treated eye at the 7-Day observation.
Moderate conjunctival irritation was noted in both treated eyes one hour after treatment and at the 24, 48 and 72 h observations with minimal conjunctival irritation noted at the 7-Day observation.
A small area of petechial haemorrhage on the nictitating membrane was noted in one treated eye at the 24 and 48 h observations.
Both treated eyes appeared normal at the 14-Day observation.
Other effects:
Both animals showed expected gain in bodyweight during the study.
No further local or systemic effects were noted.

Table 1. Individual eye irritation scores

Animal No. Time point Irritation parameter
Cornea score (opacity) Iris score Conjunctivae score (redness) Chemosis score
1 1 h 1 1 2 2
24 h 1 1 2 Pt 2
48 h 1 1 2 Pt 2
72 h 1 1 2 1
7 days 0 1 1 1
14 days 0 0 0 0
Mean after 24-72 h 1 1 2 1.67
2 1 h 0 1 2 2
24 h 1 1 2 2
48 h 1 1 2 2
72 h 0 1 2 2
7 days 0 0 2 1
14 days 0 0 0 0
Mean after 24-72 h 0.67 1 2 2

Pt = Small area of petechial haemorrhage on the nictitating membrane

Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test item produced individual scores of 1/0.67 for corneal opacity, 1/1 for iritis, 2/2 for conjunctival redness and 1.67/2 for chemosis, calculated as the mean scores following gradings at 24, 48 and 72 hour after instillation. Observed effects were fully reversible within the observation period.
Therefore, the test item meets the classification criteria for Eye Irritation Category 2 according to Regulation (EC) No 1272/2008 (CLP) and for Eye Irritation Category 2A accoridng to the Globally Harmonised System of Classification and Labelling of Chemicals (GHS).
The test item is thus considered to be eye irritating.

CLP: Eye Irrit. 2 (H319: Causes serious eye irritation.)
GHS: Eye Irrit. 2A (H319: Causes serious eye irritation.)
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation/corrosion

Skin corrosion (in vitro)

The corrosivity potential of aluminium dihydrogen triphosphate was tested using the EPISKIN™ in vitro Reconstituted Human Epidermis (RHE) Model following OECD Guideline 431 and complying with GLP (Warren, 2012). Duplicate tissues were treated with 20 mg of the test material for 3, 60 and 240 min. Duplicate tissues treated for 240 min with 50 µL 0.9% w/v sodium chloride or glacial acetic acid served as negative and positive controls, respectively. At the end of the exposure period, tissues were rinsed prior to MTT loading. Formazan crystals were extracted from the MTT loaded tissues by acidic isopropanol extraction. The optical density of the extracts was measured at 540 nm. The relative mean viability (MTT reduction to formazan in treated vs. negative control tissues) was calculated as percent mean optical density of the isopropanol extracts from treated tissues relative to the negative control.

The relative mean viability of tissues treated with the test material was 105.0, 93.3 and 106.1% after 3, 60 and 240 min, respectively. The relative mean viability of the positive control treated tissues was 16.1% after 240 min.

Therefore, based on the study results, the test material does not meet the criteria for classification for Skin corrosion Category 1 according to Regulation (EC) No 1272/2008 (CLP) or the Globally Harmonized System (GHS), and is thus considered to be not skin corrosive in vitro.

Skin irritation (in vitro)

In another GLP-compliant in vitro study, the skin irritation potential of aluminium dihydrogen triphosphate was evaluated using the EPISKIN™ RHE Model according to OECD Guideline 439 and EU Method B.46 (Warren, 2012). Triplicate tissues were treated with 10 mg of the test substance for 15 min, followed by rinsing and a 42 h post-exposure incubation period. Triplicate tissues concurrently treated with 10 µL of Dulbecco’s Phosphate Buffered Saline (DPBS) with Ca++ and Mg++ or Sodium Dodecyl Sulphate (SDS) 5% w/v served as negative and positive controls, respectively. Following the post-exposure period, MTT tissue loading and determination of relative mean viability was performed as described above under ‘Skin corrosion (in vitro)’.

The relative mean viability of the test substance-treated tissues was 128.1% of the negative control value, while the relative mean tissue viability of the positive control was 8.6%.

Therefore, based on the study results, the test item does not meet the criteria for classification according to Regulation (EC) No 1272/2008 (CLP) or the Globally Harmonized System (GHS), and is thus considered to be not skin irritating in vitro.

In support of this notion, no skin irritation was observed in mice topically treated with aluminium dihydrogen triphosphate in a skin sensitisation study (Bradshaw, 2012). This suggests that the substance is likely to be not skin irritating in vivo.

Based on the negative results of the above results from valid in vitro skin corrosion and irritation studies, along with supporting evidence from an in vivo skin sensitisation study, the test material does not fulfil the criteria for classification according to Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System of Classification and Labelling of Chemicals (GHS), and is thus considered to be not skin irritating.

Eye irritation/corrosion

Eye corrosion (in vitro)

A Bovine Corneal Opacity and Permeability (BCOP) Assay was conducted with aluminium dihydrogen triphosphate following OECD Guideline 437 and in accordance with GLP (Warren, 2012). Three corneas were treated with the test substance at 20% w/v in 0.9% w/v sodium chloride solution for 240 min at 32 °C. Two groups of three corneas each treated with 0.9% w/v sodium chloride and 20% w/v imidazole in 0.9% w/v sodium chloride served as negative and positive controls, respectively. Following opacity and permeability measurements, the in vitro irritancy score was calculated.

The corneas treated with the negative control item were clear post-treatment. The corneas treated with the positive control item were cloudy post-treatment. The corneas treated with the test item were slightly cloudy post-treatment. The in vitro irritancy scores of the test substance-treated, negative and positive control corneas were 19.7, 3.9 and 87.7.

Therefore, the test material does not meet the criteria for classification for Severe Eye Damage Category 1 according to Regulation (EC) No 1272/2008 (CLP) or the Globally Harmonized System (GHS), and is thus considered not to be an ocular corrosive or severe irritant in vitro.

Eye irritation (in vivo)

Aluminium dihydrogen triphosphate was tested for its irritancy potential to the rabbit eye in a GLP-compliant study conducted according to OECD Guideline 405 (Bradshaw, 2012). Two New Zealand White rabbits were sequentially tested. In each case, 0.1 mL (ca. 98) mg of the test material was placed into the conjunctival sac of one eye, the untreated eye serving as control. The treated eyes were not rinsed after exposure, and ocular effects were assessed at 1, 24, 48 and 72 h as well as 7 and 14 days post-instillation. Scattered or diffuse corneal opacity was noted in one treated eye one hour after treatment, in both treated eyes at the 24 and 48 h observations and in one treated eye at the 72 h observation. Iridial inflammation was noted in both treated eyes one hour after treatment and at the 24, 48 and 72 h observations and in one treated eye at the 7-Day observation. Moderate conjunctival irritation was noted in both treated eyes one hour after treatment and at the 24, 48 and 72 h observations with minimal conjunctival irritation noted at the 7-Day observation. A small area of petechial haemorrhage on the nictitating membrane was noted in one treated eye at the 24 and 48 h observations. Both treated eyes appeared normal at the 14-Day observation.

The test item produced individual scores of 1/0.67 for corneal opacity, 1/1 for iritis, 2/2 for conjunctival redness and 1.67/2 for chemosis, calculated as the mean scores following gradings at 24, 48 and 72 hour after instillation. Observed effects were fully reversible within the observation period.

Therefore, the test item meets the classification criteria for Eye Irritation Category 2 according to Regulation (EC) No 1272/2008 (CLP) and for Eye Irritation Category 2A accoridng to the Globally Harmonised System of Classification and Labelling of Chemicals (GHS).

The test item is thus considered to be eye irritating.


Justification for selection of skin irritation / corrosion endpoint:
No study was selected, since endpoint conclusions are based on the results of two in vitro studies (OECD guideline and GLP), which shall be considered jointly for the purpose of hazard assessment and in accordance with Annex XI, Section 1.4, of Regulation (EC) No. 1907/2006 (REACH).

Justification for selection of eye irritation endpoint:
Only one in vivo study available

Effects on eye irritation: irritating

Justification for classification or non-classification

The available data indicates that the substance meets/does not meet the classification criteria in accordance with Regulation (EC) No 1272/2008 (CLP) and Directive 67/548/EEC (DSD) as follows:

CLP

Skin irritation/corrosion: not classified

Eye irritation/corrosion: Eye Irrit. 2 (H319: Causes serious eye irritation.)

GHS

Skin irritation/corrosion: not classified

Eye irritation/corrosion: Eye Irrit. 2A (H319: Causes serious eye irritation.)