Tetrasodium pyrophosphate

Endpoint summary

Description of key information

Tetrasodium pyrophosphate has an oral LD50 of ca. 1624 mg/kg bw  when tested in accordance with an appropriate method and under the conditions of GLP. 
Tetrasodium pyrophosphate has an estimated inhalation LC50 of > 01.1 mg/L based on the results of studies performed on analogous substances.
Tetrasodium pyrophosphate has a dermal LD50 of > 2,000 mg/kg bw  when tested in accordance with an appropriate method and under the conditions of GLP. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

The study was performed between 14 October 2009 and 17 November 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Date of GLP inspection: 15 September 2009 Date of Signature on GLP certificate: 26 November 2009

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
Harlan Laboratories UK Limited, Bicester, Oxon, UK

- Age at study initiation:
At the start of the study the animals were eight to twelve weeks of age.

- Weight at study initiation:
The bodyweight variation did not exceed ± 20% of the initial/mean bodyweight of any previously dosed animal(s).

- Fasting period before study:
overnight fast immediately before dosing

- Housing:
The animals were housed in groups of up to four in suspended solid floor polypropylene cages furnished with woodflakes.

- Diet (e.g. ad libitum):
(2014 Teklad Global Rodent diet supplied by Harlan Laboratories UK Limited, Bicester, Oxon, UK was allowed ad libitum throughout the study.

- Water (e.g. ad libitum):free access to mains drinking water

- Acclimation period:acclimatisation period of at least five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C):
19 to 25°C

- Humidity (%):
30 to 70%

- Air changes (per hr):
The rate of air exchange was at least fifteen changes per hour.

- Photoperiod (hrs dark / hrs light):
lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.


IN-LIFE DATES: From: Day 1 To: Day 14

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle:
For the purpose of the study the test material was freshly prepared, as required, as a suspension in distilled water to give a dose levels of 300mg/kg and 2000mg/kg bodyweight.

- Amount of vehicle:
Not stated

- Justification for choice of vehicle:
Distilled water was the preferred vehicle of the test method.

- Lot/batch no.:
Not stated

- Purity:
Not stated


MAXIMUM DOSE VOLUME APPLIED:
10ml/kg


DOSAGE PREPARATION:
Not applicable

CLASS METHOD:
Not applicable

- Rationale for the selection of the starting dose:
Using available information on the toxicity of the test material, 2000 mg/kg was chosen as the starting dose.

Doses:

Following a sighting test at a dose level of 2000 mg/kg, an additional four fasted female animals were given a single oral dose of test material, as a suspension in distilled water, at a dose level of 2000 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.
Due to mortality and signs of systemic toxicity at a dose level of 2000 mg/kg, a sighting animal was treated at a dose level of 300 mg/kg, an additional four fasted female animals were given a single oral dose of test material, as a suspension in distilled water, at a dose level of 300 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

No. of animals per sex per dose:

1 female at 2000 mg/kg
4 females at 2000 mg/kg
1 female at 300 mg/kg
4 females at 300 mg/kg

Control animals:

no

Details on study design:

- Duration of observation period following administration:
14 days

- Frequency of observations and weighing:
Clinical observations were made ½, 1, 2, and 4 hours after dosing and then daily for fourteen days. Morbidity and mortality checks were made twice daily. Individual bodyweights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.

- Necropsy of survivors performed:
Yes

- Other examinations performed:
Clinical signs, body weight.

Preliminary study:

A sighting test at a dose level of 2000 mg/kg was performed.
A sighting test at a dose level of 300 mg/kg was performed.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - < 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 95% confidence limits not given in study report.

Mortality:

Dose Level - 2000 mg/kg:
One animal was humanely killed two days after dosing. Two animals were found dead three or seven days after dosing.

Dose Level - 300 mg/kg:
There were no deaths.

Clinical signs:

other: Dose level - 2000mg/kg: Signs of systemic toxicity noted were hunched posture, ataxia, lethargy, pilo erection, tiptoe gait and dehydration. Surviving animals appeared normal one or two days after dosing. Dose level - 300mg/kg No signs of systemic toxi

Gross pathology:

Dose level - 2000mg/kg:
Abnormalities noted at necropsy of the animal that was humanely killed or animals that died during the study were abnormally red lungs, dark liver or patchy pallor of the liver, dark kidneys, gaseous stomach and slight haemorrhage of the gastric mucosa. No abnormalities were noted at necropsy of animals that were killed at the end of the study

Dose level - 300mg/kg:
No abnormalities were noted at necropsy

Other findings:

- Organ weights:
Not recorded

- Histopathology:
EXAMPLE: Not recorded

- Potential target organs:
EXAMPLE: Not recorded

- Other observations:
EXAMPLE: None

Table1              Individual Clinical Observations and Mortality Data -2000mg/kg

Dose Level mg/kg	Animal Number and Sex	Effects Noted After Dosing (Hours)				Effects Noted During Period After Dosing (Days)
		½	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
2000	1-0 Female	0	0	0	0	H	0	Ä	0	0	0	0	0	0	0	0	0	0	0
	2-0 Female	0	HA	HAP	HAPWt	HAPLWt	HAPL WtDhX*
	2-1 Female	0	HAL	HALP	HALP	A	A	H	H	0	0	X
	2-2 Female	0	HA	HA	HA	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-3 Female	0	HAL	HAL	HALP	HA	HA	X

0= No signs of systemic toxicity

H = Hunched posture

A = Ataxia

L = Lethargy

P = Pilo‑erection

Wt = Tiptoe gait

Dh = Dehydration

X = Animal dead

X* = Animal humanely killed

Ä= Due to a technician error, observation not performed

Table2              Individual Bodyweights and Bodyweight Changes -2000mg/kg

Dose Level mg/kg	Animal Number and Sex	Bodyweight (g) at Day			Bodyweight (g) at Death	Bodyweight Gain (g) During Week
		0	7	14		1	2
2000	1-0 Female	182	184	199		2	15
	2-0 Female	171	-	-	158	-	-
	2-1 Female	186	-	-	162	-	-
	2-2 Female	165	174	189		9	15
	2-3 Female	174	-	-	150	-	-

Table3              Individual Necropsy Findings -2000 mg/kg

Dose Level mg/kg		Animal Number and Sex		Time of Death		Macroscopic Observations
2000		1-0 Female		Killed Day 14		No abnormalities detected
		2-0 Female		Humanely Killed Day 2		Liver: patchy pallor Stomach: gaseous Gastric mucosa: haemorrhagic, slight
		2-1 Female		Animal found dead Day 7		Lungs: abnormally red Liver: dark Kidneys: dark
		2-2 Female		Killed Day 14		No abnormalities detected
		2-3 Female		Animal found dead Day 3		Lungs: abnormally red Liver: patchy pallor Stomach: gaseous Gastric mucosa: haemorrhagic, slight

 

Table4              Individual Clinical Observations and Mortality Data -300mg/kg

Dose Level mg/kg	Animal Number and Sex	Effects Noted After Dosing (Hours)				Effects Noted During Period After Dosing (Days)
		½	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
300	3-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-1 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-2 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-3 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

 

0= No signs of systemic toxicity

Table5              Individual Bodyweights and Bodyweight Changes-300mg/kg

Dose Level mg/kg	Animal Number and Sex	Bodyweight (g) at Day			Bodyweight Gain (g) During Week
		0	7	14	1	2
300	3-0 Female	169	171	182	2	11
	4-0 Female	180	188	195	8	7
	4-1 Female	177	182	187	5	5
	4-2 Female	184	195	203	11	8
	4-3 Female	160	166	173	6	7

 

Table6              Individual Necropsy Findings-300mg/kg

Dose Level mg/kg	Animal Number and Sex	Time of Death	Macroscopic Observations
300	3-0 Female	Killed Day 14	No abnormalities detected
	4-0 Female	Killed Day 14	No abnormalities detected
	4-1 Female	Killed Day 14	No abnormalities detected
	4-2 Female	Killed Day 14	No abnormalities detected
	4-3 Female	Killed Day 14	No abnormalities detected

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute oral median lethal dose (LD50) of the test material in the female Wistar strain rat was estimated to be in the range of 300 - 2000 mg/kg bodyweight (EU CLP - Category 4).

Executive summary:

Introduction. The study was performed to assess the acute oral toxicity of the test material in the Wistar strain rat. The method was designed to meet the requirements of the following:

OECD Guidelines for Testing of Chemicals No 420 “Acute Oral Toxicity - Fixed Dose Method” (2001)

Method B1bisAcute Toxicity (Oral) of CommissionRegulation (EC) No. 440/2008

Method. Following a sighting test at dose levels of 2000 mg/kg and 300 mg/kg, further groups of four fasted females were given a single oral dose of test material, as a suspension in distilled water, at dose levels of 2000 mg/kg and 300 mg/kg bodyweight. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. Three animals treated at a dose level of 2000 mg/kg were humanely killed or found dead during the study. There were no deaths noted at a dose level of 300 mg/kg.

Clinical Observations. Signs of systemic toxicity noted in animals treated at a dose level of 2000 mg/kg were hunched posture, ataxia, lethargy, pilo-erection, tiptoe gait and dehydration. There were no signs of systemic toxicity noted at a dose level of 300 mg/kg.

Bodyweight. Surviving animals showed expected gains in bodyweight.

Necropsy. Abnormalities noted at necropsy of animals treated at a dose level of 2000 mg/kg that died during the study or was humanely killed were abnormally red lungs, dark liver or patchy pallor of the liver, dark kidneys, gaseous stomach and slight haemorrhage of the gastric mucosa. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Conclusion. The acute oral median lethal dose (LD₅₀) of the test material in the female Wistar strain rat was estimated to be in the range of 300 ‑ 2000 mg/kg bodyweight (EU CLP - Category 4).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 624 mg/kg bw

Quality of whole database:

Five studies are available to assess the acute toxicity of tetrasodium pyrophosphate via the oral route. The key study (Bradshaw J, 2010) has been conducted to a current guideline (OECD Method 420) and under the conditions of GLP. The acute oral median dose (LD50) of tetrasodium pyrophosphate in the female Wistar strain rats was estimated to be >300 < 2000 mg/kg bw. This conclusion is supported by an additional GLP study which was performed outside of the EU and provided to the Inorganic Phosphates Consortium after the key study had been performed. This study (Villagran A) uses the OECD 425 method to determine the LD50 to be ca. 1624 mg/kg bw. The additional data provided give LD50 values in the range 1825 - 3770 mg/kg bw, these studies were not considered to meet the requirements as key studies and were assigned Klimisch 4 or 2 ratings.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

No data

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
See read-across justification report under Section 13 ‘Assessment Reports’.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.

The similarities may be based on:
(1) a common functional group
(2) the common precursors and/or the likelihood of common breakdown products via physical or biological processes, which result in structurally similar chemicals; or
(3) a constant pattern in the changing of the potency of the properties across the category

(1) The source and target substances are both inorganic salts of a monovalent cation from Group 1A of the periodic table, sodium or potassium, and pyrophosphoric acid. Thus, they all share the Na+ or K+ cation and the P2O74- anion as common functional groups.
(2) All members of the group will ultimately dissociate into the common breakdown products of the Na+ or K+ cations and the P2O74- anion.
(3) The pyrophosphate ion is the simplest form of a condensed phosphate group. A condensed phosphate anion has one or several P-O-P bonds. As the group contains only two phosphate groups, both of the phosphorus ions are classified as “terminal phosphorus”. The pyrophosphate can undergo ionisation with loss of H+ from each of the two –OH groups on each P and therefore can occur in the -1, -2 -3 or -4 state. The degree of ionisation is dependent upon the associated cations and the ambient pH (if in solution). Therefore the above substances have a pyrophosphate anion that is likely to behave in a similar way. In addition, the sodium and potassium cations are key elements in various cellular processes their import and export over cell membranes is regulated via pore systems and usually tightly regulated. As such, the presence of varying quantities of such cations is not expected to have an impact on the toxicity of the substances detailed above therefore as the both ionic components of the substance are common the results of toxicity studies can be reliably read-across within the group. .


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report under Section 13 ‘Assessment Reports’.

3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report under Section 13 ‘Assessment Reports’.

4. DATA MATRIX
See read-across justification report under Section 13 ‘Assessment Reports’.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

according to guideline

Guideline:

EPA OPP 81-3 (Acute inhalation toxicity)

Deviations:

yes

Remarks:

- minor deviations: the chamber and room humidity was slightly higher than recommended in the guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Remarks:

- minor deviations: the chamber and room humidity was slightly higher than recommended in the guideline

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

yes

Remarks:

- minor deviations: the chamber and room humidity was slightly higher than recommended in the guideline

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Kingston, NY
- Age at study initiation: The actual age of the rats was not specified, only that they were young adults.
- Weight at study initiation (± SD): Males: 318 ± 11.4 g; Females: 249 ± 12.6 g
- Fasting period before study: No data
- Housing: Animals were housed individually in stainless steel suspended rat cages. Deosorb bedding was used in the litter pans.
- Diet: Purina Laboratory Rodent Chow 5001 available ad libitum
- Water: Tap water available ad libitum
- Acclimation period: Minimum of 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 23 °C (quoted in the study as 69 - 74 °F)
- Humidity (%): 42 - 77%
- Air changes (per hr): 14.2 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 h fluorescent light and 12 h dark cycle

Route of administration:

inhalation: dust

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The Rochester type exposure chamber was made of stainless steel and glass and was operated dynamically. The calculated 99% equilibrium time for the chamber at a flow rate of 35.6 L per minute was 19.4 minutes (equivalent to 14.2 "air changes per hour").
- Exposure chamber volume: 150 L
- Method of holding animals in test chamber: The test animals were assigned to and housed in individual compartments of a wire mesh cage bank (all on the same horizontal level) during the exposure.
- Source and rate of air: Breathing grade compressed air was used and the total chamber air flow rate was 35.6 L/minute.
- Method of conditioning air: No data
- System of generating particulates/aerosols: The test material was generated using a BGI Wright Dust Feeder II. The test material was desiccated and packed into large dust cups. Breathing Grade compressed air was metered to the Wright dust feeder through teflon tubing by a Matheson® 605 rotameter with a metal float. Rotameter back pressure was controlled using a Matheson® 3104C regulator. The dust feeder back pressure was monitored using a Marshalltown® back pressure gauge. The test material was made airborne by the compressed air dispersing the material into the exposure chamber. The concentration of the test atmosphere was controlled by the delivery rate setting of the Wright dust feeder.
- Method of particle size determination: The samples were drawn through a Sierra 218 cascade impactor at 2.78 liters per minute. The aerodynamic particle size distribution was determined by gravimetric analysis of the amount of test material collected on the impactor stages and subsequent determination of the mass median aerodynamic diameter (MMAD), geometric standard deviation and other particle size parameters by logarithmic-probability plotting.
- Treatment of exhaust air: The chamber air was exhausted from the bottom of the chamber and passed through an orifice tube system which continuously monitored airflow and then through a commercial filter box. The filter box was connected to a line leading to additional filters and an exhaust fan on the roof. The exhaust operated at a flow rate of 35.6 liters per minute, creating a slight negative pressure in the chamber, which was considered to be the total chamber air flow rate. The entire exposure system and primary exhaust filter were contained in a fume hood.
- Temperature, humidity, pressure in air chamber: The mean temperature and relative humidity in the chamber were 22 °C (71 °F) and 66%, respectively. The pressure in the air chamber was not measured.


TEST ATMOSPHERE
- Brief description of analytical method used: The airborne concentration of the test material was determined gravimetrically.
- Samples taken from breathing zone: Yes - Chamber air samples were taken on glass fiber filters held in cassettes at approximately one hour intervals during the exposure to determine the airborne concentration of test material. The airborne concentration of the test material was determined gravimetrically by drawing a known amount of chamber air through the filter. The samples were taken from the center of the chamber directly over the animal exposure caging.
The difference between gravimetric and nominal concentration was attributed to sedimentation of larger particles and/or adhesion of the test material to surfaces in the exposure chamber.


VEHICLE
- Not applicable: The test material was administered as received and a vehicle was not used.


TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: The fraction of particles less than or equal to 1 µm in mass aerodynamic diameter, based on the log-probability graphs, ranged from 7.6 to 9.4%. The fraction of particles less than or equal to 10 µm in mass aerodynamic diameter, based on the log probability graphs, ranged from 72.3 to 76.1%. These results indicated the test material was respirable in size to the rat.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): The MMADs ranged from 4.61 to 4.87 micrometers (µm) with geometric standard deviations ranging from 2.98 to 3.39. The MMAD represents the smallest size that could be achieved in this study. The material is hygroscopic causing the particles to agglomerate and/or adhere to surfaces inside the chamber. Several trials were initially performed with various generation schemes and the system which was ultimately chosen provided the best performance.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

Nominal concentration: 35.14 mg/L (maximum attainable concentration)
Gravimetric concentration: 0.58 ± 0.103 mg/L

No. of animals per sex per dose:

5 animals/sex

Control animals:

no

Details on study design:

- Duration of observation period following administration: 28 days
- Frequency of observations and weighing: Animals were observed for signs of toxicity and mortality every 15 mins during the first hour of exposure, hourly for the remainder of the exposure, upon removal from the chamber, at 1 h post-exposure, twice daily thereafter for 27 days and once on day 28. Individual body weights were recorded on days 0, 1, 2, 4, 7, 14, 21 and 28.
- Necropsy of survivors performed: Yes
- Other examinations performed: No data

Statistics:

No data

Preliminary study:

Not applicable

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 0.58 mg/L air (analytical)

Exp. duration:

4 h

Mortality:

See Table 1.
One female died on day 1 and one male died on day 14 post-exposure.

Clinical signs:

other: See Table 1. Clinical signs noted during the exposure included lacrimation, material on fur, oral discharge and squinting eyes. Incidence of clinical signs was highest at the removal from chamber observation. Signs gradually resolved during the study, how

Body weight:

See Table 2.
Most animals lost weight through day 4 of the study, then began to gain weight in a normal pattern. At termination all surviving animals exhibited increases in body weight over their day 0 values.

Gross pathology:

See table 3.
There were no gross internal lesions observed in any animal which survived to study termination. One male which died on day 14 had discoloured lungs with many light red nodules. This animal was also observed to have a corneal opacity in one eye.

Other findings:

No data

See attached file for Tables 1, 2 and 3.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study, the test material caused mortality in one male and one female Sprague Dawley rat when administered for four hours at a mean, maximum attainable chamber concentration of 0.58 mg/L. Based on this, the LC50 for sodium acid pyrophosphate is considered to be greater than 0.58 mg/L.
This study is considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement as a part of a weight of evidence for this endpoint. In addition the study is considered to be acceptable for classification and labelling in accordance with Regulation (EC) No 1272/2008 (EU CLP) and as such sodium acid pyrophosphate is not considered to be acutely toxic via the inhalation route (EU CLP).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

LC50 >580 mg/m3
Two studies are available to assess the acute inhalation toxicity of tetrasodium pyrophosphate. Studies were conducted on the analogous substances disodium dihydrogenpyrophosphate and tetrapotassium pyrophosphate. Both studies were conducted up to a mean, maximum attainable chamber concentration of 0.58 mg/L and 1.1 mg/L respectively. THe LC50 values have been determined to be greater than these concentrations.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

20-11-1979 to 4-12-1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

.

Qualifier:

according to guideline

Guideline:

other: EPA proposed guidelines for registering pesticides in the U.S; Fed. Reg. 43:163, 37336-37402

Deviations:

not specified

Principles of method if other than guideline:

not applicable

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Phillips Rabbitry, Soquel, CA
- Housing: 2 animals per cage , in suspended steel cages (24" x 16.5" x 14")
- Fasting period before study: overnight
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 65-70°F

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Type of wrap if used: non-absorbant binder, held in place with gauze.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): at the end of the 24 hour exposure period, wrappings were removed and the skin wiped (not washed) to remove any remaining test substance.
- Time after start of exposure: 24 hrs

Duration of exposure:

24 hrs

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 males and 5 females per dose

Control animals:

other: sham treated

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily
- Necropsy of survivors performed: yes
- Other examinations performed: body weight; animals were weighed on days 0, 7, 14 0r at death.

Statistics:

LD50 values were calcualted according to the Litchfield-Wilcoxon method.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No animals died during treatment or observation periods.

Clinical signs:

other: Local effects: mild erythema and dedema. Sins of toxcity: all animals appeared normal throughout.

Gross pathology:

No gross abnormalities were noted.

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 of tetrasodium pyrophosphate was determined to be >2000 mg/kg bw. In accordance with Regulation (EC) No. 1272/2008 (EU CLP) tetrasodium pyrophosphate is not considered to be acutely toxic via the dermal route.

Study is conducted to an appropriate guideline, raw data is provided and therefore the study is considered to be acceptable for assessment and use as a key study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

LD50 >2,000 mg/kg bw
The key study (Jones B, 1988) is considered to be reliable for use as a key study and is assigned a Klimisch 2 rating. In addition, a number of supporting studies on the analogous substances tetrapotassium pyrophosphate and disodium dihydrogenpyrophosphate are provided to support the conclusion that sodium and potassium pyrophosphates exhibit low systemic toxicity.

Additional information

A data gap was identified for the acute inhalation toxicity of tetrasodium pyrophosphate. This was addressed using the principles of read-across based on available data for analogous substances. The justification is as follows:

Read across between the following sodium and potassium pyrophosphates;

 

-         disodium dihydrogenpyrophosphate

-         trisodium hydrogen pyrophosphate

-         tetrasodium pyrophosphate

-         tetrapotassium pyrophosphate

 

Can be justified on the following basis; All substance contain a pyrophosphate anion and either a sodium or a potassium cation.

 

The pyrophosphate ion is the simplest form of a condensed phosphate group. A condensed phosphate anion has one or several P-O-P bonds. As the group contains only two phosphate groups, both of the phosphorus ions are classified as “terminal phosphorus”. The pyrophosphate can undergo ionisation with loss of H+ from each of the two –OH groups on each P and therefore can occur in the -1, -2 -3 or -4 state. The degree of ionisation is dependent upon the associated cations and the ambient pH (if in solution). Therefore the above substances have a pyrophosphate anion that is likely to behave in a similar way.

 

 In addition, the sodium and potassium cations are key elements in various cellular processes their import and export over cell membranes is regulated via pore systems and usually tightly regulated. As such, the presence of such cations is not expected to have an impact on the toxicity of the substances detailed above therefore as the pyrophosphate anion is common the results of toxicity studies can be reliably read-across within the group.

Justification for classification or non-classification

Acute oral toxicity: The weight of evidence indicates that the oral LD₅₀is within the range 300 - 2000 mg/kg bw and therefore in accordance with Regulation (EC) No. 1272/2008 (EU CLP) tetrasodium pyrophosphate is classified as acutely toxic via the oral route category 4.

Acute inhalation toxicity: The LC₅₀values for the inhalation of the analogous substances disodium dihydrogenpyrophosphate and tetrapotassium pyrophosphate were not classified at the greatest attainable concentration and therefore tetrasodium pyrophosphate is not considered to be classified in accordance with Regulation (EC) No. 1272/2008 and no further testing is recommended.

Acute dermal toxicity: The dermal LD50 of tetrasodium pyrophosphate in the rat was found to be > 2000 mg/kg bw and is therefore not classified according to Regulation (EC) No. 1272/2008 (EU CLP).