Registration Dossier

Administrative data

Description of key information

 Skin irritation: In accordance with the testing strategy detailed in Annex VIII, column 1 of Regulation (EC) No. 1907/2006 the assessment of the endpoint ‘skin irritation or skin corrosion’ has been performed following the consecutive steps detailed in the Regulation. As such an in vitro skin corrosion study has been performed. This study is not considered as the key study because it is not sufficient for classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP) and is therefore submitted as supporting data. The key study (Lowe C, 2013) is conducted according to an appropriate validated in vivo guideline and under the conditions of GLP and therefore the study is considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement as a key study for this endpoint and supersedes the study performed in vitro (warren 2012). In addition, the data is considered to be adequate and reliable for classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP).
    
    

Eye irritation: In accordance with the original testing strategy detailed in Annex VIII, column 1 of Regulation (EC) No. 1907/2006 (REACH) an ex vivo study was performed prior to conducting an in vivo study. This study was not considered as the key study because at the time of performing the study it was not considered to be suitable for classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP). The key study (Bradshaw J, 2010) is conducted according to an appropriate guideline and under the conditions of GLP and therefore the study is considered to be acceptable and to adequately satisfy the regulatory requirement as a key study for this endpoint.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Remarks:
Study was performed prior to the update of the REACH Regulation and prior to the validation of in vitro test methods.
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Received from Robinson Services, Inc on October 3, 2012
- Age at study initiation: Young adult
- Weight at study initiation:
- Housing: The animals were signly housed in suspended stainless steel caging with mesh floors, which conform to the size recommendations in the most recent 'Guide for the care and use of laboratory animals'. Litter paper was placed beneath the cage and was changed at least 3 times a week.
- Diet (e.g. ad libitum): Harlan Teklad Global High Fiber Rabbit Diet # 2031. A designated amount of the diet was available to each rabbit (150 g/day)
- Water (e.g. ad libitum): Filtered tap water was available ad libitum.

There were no known contaminants reasonable expected to be found in the food or water at levels which would interfere with the results of this study. Analysis of food and water were conducted regularly.

- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-21°C
- Humidity (%): 41-69%
- Air changes (per hr): 12
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
water
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.77 g of the test mixture.
- Concentration (if solution): 65% w/w in water
Duration of treatment / exposure:
4 hours
Observation period:
Up to 72 hours
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: 6cm2 intact dose site
- Type of wrap if used: semi-occlusive

The test item was placed on a 1 inch by 1 inch 4-ply gauze pad. The pad and entire trunk of each animal was then wrapped with semi-occlusive 3 inch micropore tape to avoid dislocation of the pad.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The test site was gently clensed with a 3% soap solution followed by tap water and a clean paper towel to remove any residual test substance.
- Time after start of exposure: 4 hours

SCORING SYSTEM: Draize scoring system.
Irritation parameter:
erythema score
Basis:
other: All 3 animals
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: no effects noted
Irritation parameter:
edema score
Basis:
other: all 3 animals
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: no effects noted
Other effects:
All animals appeared active and healthy during the study. There were no signs of gross toxicity, dermal irritation and adverse pharmacologic effects or abnormal behaviour.

Table 1: Erythema/Edema

Animal No.

Sex

Time after patch removal

30-60 mins

24 hrs

48 hrs

72 hrs

3501

F

0/0

0/0

0/0

0/0

3502

F

0/0

0/0

0/0

0/0

3503

F

0/0

0/0

0/0

0/0

Total

0/0

0/0

0/0

0/0

Mean

0/0

0/0

0/0

0/0

 

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, trisodium hydrogen diphosphate is classified as non-irritating to the skin.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation, other
Remarks:
In vivo: Study was performed prior to the update of the REACH Regulation and prior to the validation of in vitro test methods.
Type of information:
experimental study
Adequacy of study:
key study
Study period:
The study was performed between 30 July 2012 and 04 September 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Date of GLP inspection: Date of Signature on GLP certificate: 26/11/2009
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Harlan UK Limited, Bicester, Oxon, UK

- Age at study initiation: Twelve to twenty weeks old

- Weight at study initiation: 2.37 or 2.69 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 (e.g. ad libitum): ad libitum (2030C Teklad Global Rabbit diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK)

- Water (e.g. ad libitum): 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): Twelve hours continuous light (06:00 to 18:00) and twelve hours darkness


IN-LIFE DATES:
From: day 1 To:day 3
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): A volume of 0.1 ml (96 mg) of the test material was placed into the conjunctival sac of the right eye, formed by gently pulling the lower lid away from the eyeball.

- Concentration (if solution): Undiluted and used as supplied

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:
Up to 21 days (test item was not removed from the eyes).
Observation period (in vivo):
Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment. Additional observations were made on Days 7, 14 and 21 to assess the reversibility of the ocular effects.
Number of animals or in vitro replicates:
2 animals were tested in total. (After consideration of the ocular responses produced in the first treated animal, one additional animals was treated).

Details on study design:
REMOVAL OF TEST SUBSTANCE

- Washing (if done): Not applicable

- Time after start of exposure: Not applicable


SCORING SYSTEM:
Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment, according to the numerical evaluation given in Appendix 2, (from 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).


TOOL USED TO ASSESS SCORE:

Examination of the eye was facilitated by the use of the light source from a standard ophthalmoscope.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Remarks:
72293 Male
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: No effects observed
Irritation parameter:
cornea opacity score
Basis:
animal #2
Remarks:
72394 Male
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
iris score
Basis:
animal #1
Remarks:
72293 Male
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: No effect observed
Irritation parameter:
iris score
Basis:
animal #2
Remarks:
72394 Male
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 14 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #1
Remarks:
72293 Male
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #2
Remarks:
72394 Male
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not reversible
Remarks on result:
other: Haemorrhage on the lower and nictating conjunctival membranes was observed
Irritation parameter:
chemosis score
Basis:
animal #1
Remarks:
72293 Male
Time point:
24/48/72 h
Score:
1.66
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
animal #2
Remarks:
72394 Male
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 21 days
Irritant / corrosive response data:
Individual scores for ocular irritation are given in Table 1.

Scattered or diffuse corneal opacity was noted in one treated eye one hour after treatment and at the 24, 48, 72-Hour, 7, 14 and 21-Day observations.
Iridial inflammation was noted in one treated eye one hour after treatment and at the 24, 48, 72-Hour and 7-Day observations.
Moderate conjunctival irritation was noted in both treated eyes one hour after treatment. Severe conjunctival irritation was noted in one treated eye and moderate conjunctival irritation was noted in the other treated eye at the 24-Hour observation. Moderate conjunctival irritation was noted in both treated eyes at the 48 and 72-Hour observations. Moderate conjunctival irritation was noted in one treated eye and minimal conjunctival irritation was noted in the other treated eye at the 7-day observation. Minimal conjuctival irritation was noted in one treated eye at the 14-day observation.
Petechial haemorrhage of the nictitating and lower conjunctival membranes was noted in one treated eye one hour after treatment and at the 24, 48 and 72-Hour observations. A small area of haemorrhage, approximately 3 mm x 3 mm in size, on the lower eyelid was noted in this treated eye at the 7-Day observation. A small dark brown/black coloured scab, possibly due to rabbit scratching, was noted on the lower eyelid of this animal at the 14-Day observation. One treated eye appeared normal at the 14-Day observation.

The persistence of reactions in one treated eye at the 21-Day observation was considered to be indicative of irreversible ocular damage.
Other effects:
BODYWEIGHT: Individual bodyweights and bodyweight changes are given in Table 2.
Both animals showed expected gain in bodyweight during the study.

Table 1. Individual Score and Individual Total Scores for Ocular Irritation

 

Rabbit Number and Sex

72293 Male

72394 Male

IPR= 3

IPR = 0+

Time After Treatment

1
Hour

24
Hours

48
Hours

72
Hours

7
Days

14

Days   

1
Hour

24
Hours

48
Hours

72
Hours

1

Day

14

Days

21

Days

CORNEA

 

 

 

 

 

 

 

 

 

 

 

 

 

Degree of Opacity

0

0

0

0

0

0

1

1

1

1

1

1

1

Area of Cornea Involved

0

0

0

0

0

0

1

4

4

3

2

1

1

IRIS

0

0

0

0

0

0

1

1

1

1

1

0

0

CONJUNCTIVAE

 

 

 

 

 

 

 

 

Redness

2

2

2

2

1

0

3Pt

3Pt

3Pt

3Pt

2H

1

Chemosis

2

2

2

1

1

0

2

2

2

2

2

1

0

Discharge

2

1

1

1

0

0

2

3

2

2

1

0

0

 

IPR=  Initial pain reaction

+ = One drop of local anaesthetic instilled into both eyes 1 to 2 minutes before treatment

Pt = Petechial haemorrhage on the nictitating and lower conjunctival membranes

H = Small area of haemorrhage, approximately 3 mm x 3 mm in size, on lower eyelid

¤ = Small dark brown/black coloured scab on lower eyelid , possibly due to rabbit scratching

Table 2. Individual bodyweights and bodyweight changes

Rabbit number and sex

Individual bodyweight (kg)

Bodyweight change (kg)

72293 Male

Day 0

Day 14

0.24

2.69

2.93

72394 Male

Day 0

Day 21

0.43

2.37

2.80

 

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
The test item produced irreversible ocular damage and was considered to be corrosive to the rabbit eye and classified as Irreversible effects on the eye (Category 1) according to Regulation (EC) No. 1272/2008 (EU CLP).

This study is conducted according to the appropriate guidelines (OECD 405) and under the conditions of GLP and therefore the study is considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement for REACH (Regulation (EC) No.1907/2006) as a key study for this endpoint. Study is sufficient for classification and labelling purposes, in accordance with Regulation (EC) No. 1272/2008 (EU CLP).
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

Justification for selection of skin irritation / corrosion endpoint:
One key study available. This study is conducted according to the appropriate guidelines (OECD 404) and under the conditions of GLP and therefore the study is considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement for REACH (Regulation (EC) No.1907/2006) as a key study for this endpoint. Study is sufficient for classification and labelling purposes, in accordance with Regulation (EC) No. 1272/2008 (EU CLP) and contradictory in vitro data are disregarded on the basis that in vivo data supercedes in vitro data.

Justification for selection of eye irritation endpoint:
One key study available. This study is conducted according to the appropriate guidelines (OECD 405) and under the conditions of GLP and therefore the study is considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement for REACH (Regulation (EC) No.1907/2006) as a key study for this endpoint. Study is sufficient for classification and labelling purposes, in accordance with Regulation (EC) No. 1272/2008 (EU CLP).

Justification for classification or non-classification

Skin irritation: The data available to assess the skin irritation potential of trisodium hydrogen diphosphate concludes that the substance is not classified as skin irritant in accordance with Regulation (EC) No. 1272/2008 (EU CLP) and on the basis of the in vivo data. Contradictory in vitro data has been disregarded.

Eye irritation: The data available to assess the eye irritation potential of trisodium hydrogen diphosphate concludes that the substance is classified as Category 1 corrosive to eyes on the basis of irreversible damage noted at the end of the study. Classification is derived in accordance with Regulation (EC) No. 1272/2008 (EU CLP). It is not considered scientifically justified on ethical grounds to repeat in vivo studies for this endpoint as the data provided is sufficient.

Respiratory irritation: There are no data available (workplace observations or studies) to suggest that trisodium hydrogen diphosphate is a respiratory irritant.