Registration Dossier

Administrative data

Description of key information

Skin irritation: Four in vivo studies are available to assess the skin irritancy of disodium dihydrogenpyrophosphate. The study performed by Bullock (1971) is considered to be the key study as the methods used are comparable to modern-day guidelines and the results reported are sufficient for classification and labelling. The additional studies are not sufficient for the purpose of classification and labelling and therefore are submitted as supporting data only. 
Acute eye irritation: Four studies are available to assess the eye irritancy of disodium dihydrogenpyrophosphate. The key study (Bradshaw J, 2010) has been conducted according to current guidelines (OECD Method 405) and under the conditions of GLP and is therefore adequate for classification and labelling. The additional studies are not adequate for classification and labelling.

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
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
Animals were examined at 24 and 72 hours only. No data reported on reversibility of effects. Study uses intact and abraded skin. No controls were included in the study.
Qualifier:
equivalent or similar to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
Animals were examined at 24 and 72 hours only. No data reported on reversibility of effects. Study uses intact and abraded skin. No controls were included in the study.
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Details on test animals and environmental conditions:
No data
Type of coverage:
not specified
Preparation of test site:
other: Shaved, abraded and intact
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied : 0.5 g


VEHICLE
Used as received.
Duration of treatment / exposure:
24 hours
Observation period:
Up to 72 hours
Number of animals:
6, 3 males and 3 females.
Details on study design:
TEST SITE
- Type of wrap if used: Rubber (occlusive)


REMOVAL OF TEST SUBSTANCE
No data


SCORING SYSTEM:
The Draize dermal method of testing primary irritant substance as described in the Code of Federal Refulations under the Federal Hazardous Substances Labelling Act, Part 191.11, Chapter 1, Title 21.

Compounds producing combined averages (primary irritation indexes) of 2 or less are only mildly irritating; indexes from 2 to 5 are moderate irritants and those with scores above 5 are considered severe or primary irritants.
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.5
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
erythema score
Basis:
other: remaining 5 animals tested
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
other: all animals tested
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
The primary dermal irritation index is calculated by the following:

Total ÷ 4 = Primary dermal irritation index
Other effects:
No data

Table 1: Results for Sodium acid pyrophosphate

Exposure time Hours

Rabbit No.

Mean

 

8M

15M

16M

32F

33F

34F

 

Score

Score

Score

Score

Score

Score

Erythema

24

Intact

1

0

0

0

0

0

0.17

72

Intact

0

0

0

0

0

0

0.00

24

Abraded

4

4

4

2

4

2

3.33

72

Abraded

4

4

4

0

0

0

2.00

Subtotal

5.50

Oedema

24

Intact

0

0

0

0

0

0

0.00

72

Intact

0

0

0

0

0

0

0.00

24

Abraded

4

4

4

1

3

1

2.83

72

Abraded

4

4

4

0

0

0

2.00

Subtotal

4.83

Total score

10.33

(Total/4) Primary Irritation Index

2.58

Result

Mild Irritant

 

Interpretation of results:
GHS criteria not met
Conclusions:
Sodium acid pyrophosphate was determined to be a mild irritant to rabbit skin with a primary dermal irritation score of 2.58, mostly the reactions were noted in abraded skin.
This study is selected as the key study because the results are sufficient in order to derive a reliable conclusion on classification and labelling. The substance is not considered to be classified in accordance with Regulation (EC) No. 1272/2008 (EU CLP) as only mild effects are noted in 1 animal at the 24 hour time period and therefore due to the mild nature of the reaction and considering it was only observed in one animal for the parameter erythema the absence of 48 hr scores is not considered to have a detrimental effect on the reliability of the study for use in classification and labelling.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye 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
Study period:
The study was performed between 27 April 2010 and 26 May 2010.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
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
Principles of method if other than guideline:
.
GLP compliance:
yes (incl. certificate)
Remarks:
Date of GLP inspection: 15 September 2009 Date of Signature on GLP certificate: 26 November 2009
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source:
Harlan Laboratories U.K. Ltd., Loughborough, UK

- Age at study initiation:
Twelve to twenty weeks old

- Weight at study initiation:
2.0 to 3.5 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 (2030 Teklad Global Rabbit diet supplied by Harlan Laboratories U.K. Ltd., 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 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:
Used as supplied

VEHICLE

- Amount(s) applied:
Not applicable

- Concentration:
Not applicable

- Lot/batch no.:
Not applicable

- Purity:
Not reported
Duration of treatment / exposure:
up to 1 hour
Observation period (in vivo):
Approximately 1 hour and 24, 48 and 72 hours following treatment. Additional observations were made on Days 7 and 14 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 animal was treated. )
Details on study design:
REMOVAL OF TEST SUBSTANCE

- Washing:
No

- 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). Additional observations were made on Days 7 and 14 to assess the reversibility of the ocular effects.


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: 69148 Male
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible
Remarks:
7 days
Irritation parameter:
cornea opacity score
Basis:
animal: 69202 Male
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
iris score
Basis:
animal: 69148 Male
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal: 69202 Male
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal: 69148 Male
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 14 days
Remarks on result:
other: Small areas of haemorrhage scattered over the upper and lower conjunctival membrane and nictitating membrane
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal: 69202 Male
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
animal: 69148 Male
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
animal: 69202 Male
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritant / corrosive response data:
Ocular Reactions
Individual and group mean scores for ocular irritation are given in Table 1 and Table 2.
Scattered or diffuse corneal opacity was noted in both treated eyes at the 24, 48 and 72 Hour observations and in one treated eye at the 7-Day observation.
Iridial inflammation was noted in both treated eyes one hour after treatment and at the 24, 48 and 72-Hour observations.
Moderate conjunctival irritation was noted in both treated eyes one hour after treatment and at the 24, 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.
Small areas of haemorrhage scattered over the upper and lower conjunctival membrane and nictitating membrane were noted in one treated eye at the 24, 48 and 72 Hour observations.
Both treated eyes appeared normal at the 14-Day observation.
Other effects:
Body weight
Both animals showed expected gain in bodyweight during the study.

Interpretation of Results

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 cornea involved). 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 ( Modified Kay and Calandra Interpretation of Eye Irritation Test 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.

Table 1              Individua lScores and Individual Total Scores for Ocular Irritation

Rabbit Number and Sex

69148 Male

69202 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

7
Days

14
Days

CORNEA

 

 

 

 

 

 

 

 

 

 

 

 

E = Degree of Opacity

0

1

1

1

0

0

0

1

1

1

1

0

F = Area of Cornea Involved

0

4

4

4

0

0

0

4

4

4

2

0

Score (E x F) x 5

0

20

20

20

0

0

0

20

20

20

10

0

IRIS

 

 

 

 

 

 

 

 

 

 

 

 

D

1

1

1

1

0

0

1

1

1

1

0

0

Score (D x 5)

5

5

5

5

0

0

5

5

5

5

0

0

CONJUNCTIVAE

 

 

 

 

 

 

 

 

 

 

 

 

A = Redness

2

2H

2H

2H

1

0

2

2

2

2

2

0

B = Chemosis

2

2

2

2

1

0

2

2

2

3

1

0

C = Discharge

2

3

3

2

0

0

2

3

3

3

1

0

Score (A + B + C) x 2

12

14

14

12

4

0

12

14

14

16

8

0

Total Score

17

39

39

37

4

0

17

39

39

41

18

0

IPR=  Initial pain reaction

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

H =      Small areas of haemorrhage scattered over the upper and lower conjunctival membrane and nictitating membrane

Table 2              Individual Total Scores and Group Mean Scores for Ocular Irritation

Rabbit Number

and Sex

Individual Total Scores At:

1 Hour

24 Hours

48 Hours

72 Hours

7 Days

14 Days

69148Male

17

39

39

37

4

0

69202Male

17

39

39

41

18

0

Group Total

34

78

78

78

22

0

Group Mean Score

17.0

39.0

39.0

39.0

11.0

0

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
The test material produced a maximum group mean score of 39.0 and was classified as 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 data are sufficient to classify the material as irritating to eyes (category 2), in accordance with Regulation (EC) No. 1272/2008 (EU CLP).
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

Result. A single application of the test material to the non-irrigated eye of two rabbits produced scattered or diffuse corneal opacity, iridial inflammation and moderate conjunctival irritation. Both treated eyes appeared normal at the 14-Day observation.

Conclusion. The test material produced a maximum group mean score of 39.0 and was classified as a moderate irritant (Class 5 on a 1 to 8 scale) to the rabbit eye according to a modified Kay and Calandra classification system.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

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

Additional information

Justification for classification or non-classification

Skin irritation: sodium acid pyrophosphate is not considered to be irritating to skin in accordance with Regulation (EC) No. 1272/2008 (EU CLP). The key study is considered to be adequate and reliable for the purposes of classification and therefore further testing is not considered to be scientifically justified.

Eye irritation: Sodium acid pyrophosphate is considered to be classified as irritating to the eyes (category 2) in accordance with Regulation (EC) No. 1272/2008 as the key study shows that the following criteria for classification are met:

Two animals exhibited the following responses (Based on the mean scores at 24, 48 and 72 hours):

- Corneal opacity ≥1

- Irititis ≥ 1

- Conjunctival redness ≥2

- Chemosis ≥ 2

All effects were fully reversed by day 14 and therefore sodium acid pyrophosphate is classified as category 2 (Reversible effects on the eye) in accordance with Regulation (EC) No.1272/2008 (EU CLP). No further testing is deemed scientifically justified.

There are no data (study or workplace) to support a classification for respiratory irritation.