Tetrasodium pyrophosphate

Endpoint summary

Description of key information

Skin irritation: Five in vivo studies are available for skin irritation. The study reported by Freeman C (1988) is selected as the key study as it is conducted according to modern guidelines and performed in a GLP accredited facility. The results of this study are sufficient for classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP). The additional studies are provided to support this conclusion.

Eye irritation: Two in vivo studies are available for eye irritation. The key study (Bradshaw, 2011) is conducted according to modern day guidelines and was performed in a GLP accredited facility. The results are deemed sufficient for classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP).

The additional studies are provided to support this conclusion.

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:

13/06/1988 to 17/06/1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

other: FMC Non-Definitive Primary Skin Irritation Protocol (Number 10)

Deviations:

no

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

see additional information on materials and methods

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton Research Animals, Inc., Denver, Pennsylvania on May 18, 1988
- Age at study initiation: Young
- Weight at study initiation: 2.37 - 2.50 kg
- Housing: individually housed in stainless steel cages. DAGB cageboard bedding was used in the litter pans.
- Diet (e.g. ad libitum): ad libitum; Purina High Fiber Rabbit Chow 5326
- Water (e.g. ad libitum): ad libitum; fresh tap water
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 67 - 73°F
- Humidity (%): 60 - 64 %
- Photoperiod (hrs dark / hrs light): 12 hour fluorescent light: 12 hour dark cycle.


IN-LIFE DATES: May 18, 1988 - 17/06/1988

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

other: the test material was moistened with physiological saline

Controls:

not specified

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 gram

Duration of treatment / exposure:

4 h

Observation period:

72 h

Number of animals:

3 animals each with 2 test sites per animal.
2 females and 1 male.

Details on study design:

TEST SITE
- Area of exposure: 2" by 2"
- % coverage: no data
- Type of wrap if used: The test material was moistened and applied to an 8-ply, 2x2" gauze pad. The entire trunk of the animal was wrapped with a semi-occlusive cheesecloth bandage. The animals were fitted with Elizabethan collars to prevent disturbance of the test sites.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The test sites were wiped clean with a gauze moistened with methanol, then rinsed with tap water.
- Time after start of exposure: 4 h

SCORING SYSTEM: Draize J. H.,G. Woodard and H. O. Calvery, J. Pharmacol. Exp. Ther., 83, 384 (1944).

Irritation parameter:

erythema score

Basis:

other: all 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:

No erythema and no edema were recorded at 4.5, 24, 48 or 72 h. Zero scores were recorded at all timepoints for all animals.

Other effects:

All animals remained healthy during the study.

Three animals, each with two test sites did not display any sign of erythema formation or edema. Zero scores were recorded at all timepoints for all six test sites.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study and in accordance with Regulation (,EC) No. 1272/2008, tetrasodium pyrophosphate is non-irritating to intact skin when applied topically to New Zealand White rabbits.

This study is considered to be scientifically justified for use as a key study.

Executive summary:

no data

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

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:

16 June 2010 - 5 Ocotober 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

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 U.K. Ltd., Loughborough, UK
- Weight at study initiation: 2.02 kg
- Housing:Suspended cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 to 23°C
- Humidity (%): 30 to 70%
- Air changes (per hr): at least 15 changes per hour
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 95 mg (as measured by gently compacting the required volume into an adapted syringe)

Duration of treatment / exposure:

Once

Observation period (in vivo):

4 hours - after which the animal was euthanized.

Number of animals or in vitro replicates:

1

Details on study design:

SCORING SYSTEM:
Assessment of ocular damage/irritation was made approximately 1 hour following treatment, according to the numerical evaluation (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).
Any other ocular effects were also noted.



TOOL USED TO ASSESS SCORE: Examination of the eye was facilitated by the use of the light source from a standard ophthalmoscope.
Any clinical signs of toxicity, if present, were also recorded.

The animal’s bodyweight was recorded on Day 0 (the day of dosing).

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

other: 1 hr

Score:

1

Max. score:

4

Remarks on result:

other: Exposure to the test material for 1 hour only due to severe reactions

Irritation parameter:

iris score

Basis:

animal #1

Time point:

other: 1 hr

Score:

1

Max. score:

2

Remarks on result:

other: Exposure to the test material for 1 hour only due to severe reactions

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #1

Time point:

other: 1 hr

Score:

3

Max. score:

3

Remarks on result:

other: Haemorrhage of the nictitating membrane and upper and lower conjunctival membrane observed. Exposure to the test material for 1 hour only due to severe reactions

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

other: 1hr

Score:

2

Max. score:

4

Remarks on result:

other: Exposure to the test material for 1 hour only due to severe reactions

Irritant / corrosive response data:

Scattered or diffuse corneal opacity, iridial inflammation and moderate conjunctival irritation were noted in the treated eye one hour after treatment. Haemorrhage of the nictitating membrane and upper and lower conjunctival membrane were also noted in the treated eye at this observation. Blood stained discharge was also observed on the day of dosing.
Due to severe bleeding of the eye the animal was killed for humane reasons, on the day of dosing, in accordance with Company policy and current UK Home Office guidelines.

Individual and Total Scoresfor Ocular Irritation

Rabbit Number and Sex	69566Male K*
	IPR= 3
Time After Treatment	1 Hour
CORNEA
E = Degree of Opacity	1
F = Area of Cornea Involved	4
Score (E x F) x 5	20
IRIS
D	1
Score (D x 5)	5
CONJUNCTIVA
A = Redness	3H
B = Chemosis	2
C = Discharge	2
Score (A + B + C) x 2	14
Total Score	39

 

IPR=  Initial pain reaction

H =      Haemorrhage of the nictitating membrane and upper and lower conjunctival membrane

K =     Animal killed for humane reasons in accordance with Company policy and current UK Home Office guidelines due to severe bleeding of the eye

*=       Blood stained discharge observed prior to death

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

Substance was considered to cause irreversible effects on the eye of 1 rabbit. The reaction was so severe that the test animal had to be euthanized 4 hours post-administration. Therefore in accordance with Regulation (EC) No. 1272/2008 (EU CLP) tetrasodium pyrophosphate is considered to cause serious and irreversible effects on the eye.
This study has been selected as the key study because the results are sufficient in order to derive a reliable conclusion on classification and labelling in accordance with Regulation EC (No.) 1272/2008 (EU CLP).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

A data gap was identified for eye irritation in that the available data was not adequate in order to assess the classification of tetrasodium pyrophosphate. As such additional testing was performed. The justification for the additional in vivo testing is as follows:

A review of the existing data (four studies, reliability 3 or 4) gave contradictory results. As no data was sufficient for classification and labelling as stand-alone key data or as part of a weight of evidence and given that the results were contradictory (ranging from mild irritant to corrosive) it was necessary to further investigate the effects of tetrasodium pyrophosphate in the eye. In accordance with the testing strategy detailed in Annex VIII, section 8.2, column 2 of Regulation (EC) No. 1907/2006 (REACH) an ex-vivo BCOP assay (OECD Method 437) was first conducted to determine whether the substance is corrosive to the eyes (as no in vitro methods are validated for classification and labelling and given the data already available it was justified to first perform the BCOP) as this came back negative it was necessary to proceed to in vivo testing.

Justification for selection of skin irritation / corrosion endpoint:
All studies except one conclude that tetrasodium pyrophosphate is not a skin irritant. The one study that is not in agreement with this (Younger F, 1962) is the oldest study available and assesses the skin irritation in accordance with the "Federal hazardous substances labelling act" which pools the results from abraded and unabraded skin. This report lacks the raw data required to convert the results for use under current classification systems and therefore cannot be used for classification purposes. As there are great differences between the criteria for classification under Regulation (EC) No. 1272/2008 and the Federal hazardous substances labelling act this classification cannot be considered to cast doubt on the conclusions made in the key study (and supporting data). The key study is selected on the basis that this is considered to be the most reliable for the purpose of classification and labelling.

Justification for selection of eye irritation endpoint:
Five studies are available to assess the eye irritancy of tetrasodium pyrophosphate. The available data was contradictory and as such an intelligent testing approach was utilised to determine the eye irritancy of tetrasodium pyrophosphate. In accordance with the testing strategy detailed in Annex VIII, section 8.2, column 2 of Regulation (EC) No. 1907/2006 (REACH) an ex-vivo BCOP assay (OECD Method 437) was first conducted to determine whether the substance is corrosive to the eyes (as no in vitro methods are validated for classification and labelling and given the data already available it was justified to first perform the BCOP) as this came back negative it was necessary to proceed to in vivo testing. The key study (Bradshaw J, 2010) is a GLP, guideline in vivo study and the results is considered to be appropriate and adequate for classification and labelling.

Effects on eye irritation: corrosive

Justification for classification or non-classification

Skin Irritation: In accordance with Regulation (EC) No. 1272/2008 (EU CLP) tetrasodium pyrophosphate is not considered to be irritating to skin.

Eye Irritation: In accordance with Regulation (EC) No. 1272/2008 (EU CLP) tetrasodium pyrophosphate is considered to be corrosive to the eyes due to the severity of the effects noted in one animal at the 4 -hr observation point.

Respiratory irritation: No data (workplace or study) are available to suggest that tetrasodium pyrophosphate is a respiratory irritant.