Trisodium hydrogen diphosphate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

The study was performed between 26 June 2012 and 2 August 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Test guideline 2

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: 19-21 July 2011 Date of Signature on GLP certificate: 31 August 2011

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Trisodium hydrogen diphosphate

EC Number:

238-735-6

EC Name:

Trisodium hydrogen diphosphate

Cas Number:

14691-80-6

Molecular formula:

H1O7P2Na3

IUPAC Name:

trisodium hydrogen (phosphonooxy)phosphonate

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Sponsor's identification: trisodium hydrogen diphosphate
Description: white powder
Batch number: 147/12
Purity: 95%
Date received: 07 March 2012
Expiry date: 01 February 2014
Storage conditions: room temperature in the dark

Test animals

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: 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

Administration / exposure

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 300 mg/kg and 2000 mg/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 applicable

- Purity: Not applicable


MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg


DOSAGE PREPARATION: Not applicable

CLASS METHOD: Not applicable

- Rationale for the selection of the starting dose: In the absence of data regarding the toxicity of the test item, 300 mg/kg was chosen as the starting dose.

Doses:

Dosing regimen:
A single animal was treated with the starting dose of 300 mg/kg bw. In this absence of toxicity on this animal an additional animal was treated with 2000 mg/kg bw. As this animal exhibited no toxicity an additional 4 animals were treated with 2000 mg/kg be of the test material (a total of 5 animals were treated with 2000 mg/kg bw). Due to mortality and signs of systemic toxicity in the animals tested at 2000 mg/kg bw an additional group of 4 animals were treated with 300 mg/kg bw (a total of 5 animals were treated with 300 mg/kg bw).

No. of animals per sex per dose:

5 females at 2000 mg/kg
5 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.

Results and discussion

Preliminary study:

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

Effect levels

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: Two animals were found dead one or two 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, pilo-erection, ptosis, lethargy and ataxia. Surviving animals appeared normal one, five or six days after dosing. Dose level - 300mg/kg: No signs of systemic toxicity were not

Gross pathology:

Dose level - 2000mg/kg: Abnormalities noted at necropsy of animals that died during the study were dark liver, dark spleen, dark kidneys and haemorrhagic gastric mucosa. A raised limiting ridge of the stomach and pale gastric mucosa were noted at necropsy of one animal that was killed at the end of the study. No abnormalities were noted at necropsy of the remaining 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: Not recorded

- Potential target organs: Not recorded

- Other observations: None

Any other information on results incl. tables

Table 1. 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	2-0 Female	0	0	0	H	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-0 Female	0	0	0	0	0	0	H	H	0	0	0	0	0	0	0	0	0	0
	3-1 Female	0	0	0	0	HP	H	H	HP	H	0	0	0	0	0	0	0	0	0
	3-2 Female	0	0	0	HAPPtL	X
	3-3 Female	0	0	0	HLP	HAP	X

 

0 = No signs of systemic toxicity

H = Hunched posture

P = Pilo-erection

Pt = Ptosis

L = Lethargy

A = Ataxia

X = Animal dead 

Table 2. 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	2-0 Female	162	179	187		17	8
	3-0 Female	186	202	217		16	15
	3-1 Female	180	174	213		- 6	39
	3-2 Female	165	-	-	160	-	-
	3-3 Female	166	-	-	153	-	-

 

Table 3.  Individual Necropsy Findings -2000 mg/kg

 

Dose Level mg/kg		Animal Number and Sex		Time of Death		Macroscopic Observations
2000		2-0 Female		Killed Day 14		Stomach: raised limiting ridge Gastric mucosa: pale
		3-0 Female		Killed Day 14		No abnormalities detected
		3-1 Female		Killed Day 14		No abnormalities detected
		3-2 Female		Animal found dead Day 1		Liver: dark Spleen: dark Kidneys: dark Gastric mucosa: haemorrhagic
		3-3 Female		Animal found dead Day 2		Liver: dark Spleen: dark Kidneys: dark Gastric mucosa: haemorrhagic

 

 

 

 

 

Table 4. 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	2-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-1 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-2 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-3 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

Table 5. 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	2-0 Female	162	187	202	25	15
	3-0 Female	182	199	216	17	17
	3-1 Female	188	197	220	9	23
	3-2 Female	183	199	214	16	15
	3-3 Female	189	214	230	25	16

 

Table 6. Individual Necropsy Findings - 300mg/kg

 

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

Applicant's summary and conclusion

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).

This study is considered to be reliable and acceptable for use as a key study in accordance with Regulation (EC) No. 1907/2006 (REACH) and for the purposes of classification and labelling in accordance with Regulation (EC) No. 1272/2008 (EU CLP).

Executive summary:

.