Sodium metaphosphate

Endpoint summary

Description of key information

Acute oral toxicity: Three studies are available for the acute oral toxicity endpoint. All studies indicate that sodium hexametaphosphate has a low potential for systemic toxicity following acute administration via the oral route. 
The key study (Bradshaw, 2010) has been conducted to a current guideline (OECD 420) and according to GLP. The acute oral median dose (LD50) of sodium hexametaphosphate in the female Wistar strain rat was estimated to be greater that 2000 mg/kg bw and is therefore not classified according to Regulation (EC) No 1272/2008 (EU CLP). This conclusion is supported by the additional data provided for this endpoint.
Acute inhalation toxicity: One key study is available to assess the acute inhalation toxicity of sodium metaphosphate. Sodium metaphosphate was considered to exhibit a low potential toxicity via the inhalation route and is not expected to be of significant concern. 
The key study (Signorin J, 1993) has been conducted according to the relevant guidelines (EU and US) and according to the principles of GLP. The acute inhalation median concentration (LC50) of sodium metaphosphate in male and female rats was estimated to be > 3.69 mg/L (the maximum attainable concentration). 
Acute dermal toxicity: Testing was waived on the basis that further in vivo testing is considered to be scientifically unjustified.

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:

EThe study was performed between 11 March 2010 and 06 April 2010

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 inspection: 15 September 2009 Date of signature: 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 Teklad, Blackthorn, 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 level of 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.

No. of animals per sex per dose:

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

Statistics:

Not available

Preliminary study:

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

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

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

Mortality:

There were no deaths.

Clinical signs:

other: No signs of systemic toxicity were noted.

Gross pathology:

No abnormalities were noted at necropsy.

Other findings:

- Organ weights:
Not recorded

- Histopathology:
Not recorded

- Potential target organs:
Not recorded

- Other observations:
None

Table 1              Individual Clinical Observations and Mortality Data

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	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-1 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-2 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-3 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

Table2              Individual Bodyweights and Bodyweight Changes

Dose Level mg/kg	Animal Number and Sex	Bodyweight (g) at Day			Bodyweight Gain (g) During Week
		0	7	14	1	2
2000	1-0 Female	186	193	202	7	9
	2-0 Female	171	180	198	9	18
	2-1 Female	171	186	199	15	13
	2-2 Female	174	184	193	10	9
	2-3 Female	175	190	206	15	16

Table3              Individual Necropsy Findings

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	Killed Day 14	No abnormalities detected
	2-1 Female	Killed Day 14	No abnormalities detected
	2-2 Female	Killed Day 14	No abnormalities detected
	2-3 Female	Killed Day 14	No abnormalities detected

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral median lethal dose (LD50) of the test material in the female Wistar strain rat was estimated to be greater than 2000 mg/kg bodyweight (EU CLP - Unclassified).
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). Sodium metaphosphate is not considered to be classified according to Regulation (EC) No. 1272/2008 (EU CLP).

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” (adopted17 December 2001)

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

Method. 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 solution 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.

Mortality. There were no deaths.

Clinical Observations. There were no signs of systemic toxicity.

Bodyweight. All animals showed expected gains in bodyweight.

Necropsy. No abnormalities were noted at necropsy.

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

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

LD50 >2000 mg/kg bw
Key study is performed according to guideline and under GLP (Klimisch reliability 1).

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

No data

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OPP 81-3 (Acute inhalation toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

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
- Strain Reference: Sprague-Dawley (Crl:CDBR VAF Plus)
- 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: 281 ± 9.4 g; Females: 243 ± 15.7 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 - 73 °F)
- Humidity (%): 41 - 70%
- Air changes (per hr): 14.0 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 35.0 L per minute was 19.7 minutes (equivalent to 14.0 "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 35.0 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 35.0 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 19.44 °C (67±1.5 °F) and 63±3.8%, 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 0.8 to 12.2%. The fraction of particles less than or equal to 10 µm in mass aerodynamic diameter, based on the log probability graphs, ranged from 78.9 to 86.4%. 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 3.25 to 4.98 micrometers (µm) with geometric standard deviations ranging from 2.38 to 2.78. 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: 12.68 mg/L (maximum attainable concentration)
Gravimetric concentration: 3.698 ± 0.288 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: 14 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 13 days and once on day 14. Individual body weights were recorded on days 0, 1, 2, 4, 7 and 14.
- Necropsy of survivors performed: Yes
- Other examinations performed: See Table 1 for a list of recorded observations.

Statistics:

No data

Preliminary study:

Not applicable

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 3.69 mg/L air (analytical)

Exp. duration:

4 h

Mortality:

None of the animals died as a result of dosing.

Clinical signs:

other: See Table 1. Clinical signs noted during the exposure included lacrimation, oral discharge and squinting eyes. Clinical signs noted upon removal from the chamber and at one hour post exposure included abdominogenital staining, chromodacryorrhea, chromorhi

Body weight:

See Table 2 and 3.
All animals lost weight through day 1 of the study and then began to gain weight in a normal pattern. At termination all animals exhibited increased in body weight over their day 0 values.

Gross pathology:

See table 3.
There were no gross internal lesions observed in any animal.

Other findings:

No data

See attached tables.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute inhalation median lethal concentration (LC50) of the test material in male/female Sprague-Dawley rats was estimated to be greater than 3.69 mg/ L of air. The study was conducted up to a maximum attainable concentration and can therefore be considered to be equivalent to a limit test conducted at 5 mg/ L. As such, sodium metaphosphate is not classified for inhalation toxicity, in accordance with Regulation EC (No.) 1272/2008 (EU CLP). This study is considered to be acceptable and to adequately satisfy both the guideline requirement and the regulatory requirement for this endpoint.

Executive summary:

Introduction

The study was performed to assess the acute inhalation toxicity of the test material in the Sprague-Dawley rat. The method was designed to meet the requirements of the follwing:

OECD Guideline 403 (Acute Inhalation Toxicity)

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

EPA OPP 81-3 (Acute inhalation toxicity)

Method

Five male and five female animals were exposed for a period of 4 hours to the maximum attainable concentration of the dust (test material). The analytical dose of the test material was determined to be 3.69 ± 0.288 mg/ L air. Clinical signs, bodyweight and mortality were monitored during the study, after 14 days surviving animals were subjected to gross necropsy.

Mortality

There were no deaths.

Clinical Observations

Clinical signs noted during the 14 day post-exposure observation period included alopecia on head, chromodacryorrhea, chromorhinorrhea, decreased feces and exophthalmos.

Bodyweight

All animals lost weight through day 1 of the study and then began to gain weight in a normal pattern. At termination all animals exhibited increased in body weight over their day 0 values.

Necropsy

No abnormalities were noted

Conclusion

The study was conducted up to a maximum attainable concentration and can therefore be considered to be equivalent to a limit test conducted at 5 mg/ L [actual result LC50>3.96 mg/ L]. As such, sodium metaphosphate is not classified for inhalation toxicity (EU CLP - Unclassified).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

LC50 > 3690 mg/m3
Key study is performed according to guideline and under GLP (Klimisch reliability 1).

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The data available for oral and inhalation routes conclude that sodium metaphosphate should not be classified according to regulation (EC) No. 1272/2008 (EU CLP). For the reasons stated above it is also considered that sodium metaphospahte will not be classified for dermal acute toxicity.