Polyphosphoric acids, ammonium salts

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 08 January 2015 to 11 February 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conclusive, performed to a valid guideline (OECD TG 420, adopted 17 December 2001) and was conducted under GLP conditions. No deviations from the test methods were noted.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Report date:

2015

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: 12 to 14 March 2014 Date of Signature on Certificate: 12 May 2014

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Polyphosphoric acids, ammonium salts

EC Number:

269-789-9

EC Name:

Polyphosphoric acids, ammonium salts

Cas Number:

68333-79-9

Molecular formula:

[NH4PO3]n

IUPAC Name:

undecaammonium bis(phosphonatooxy)phosphinate dihydrogen phosphate hydrogen (phosphonatooxy)phosphonate hydrogen phosphate

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): IP 65: POLYPHOSPHORIC ACIDS, AMMONIUM SALTS (SOLID)
- Physical state: white powder
- Analytical purity: 100%
- Lot/batch No.: MD141010
- Expiration date of the lot/batch: 14 October 2015
- Storage condition of test material: 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 Ltd., Oxon, UK
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: 145-168g
- Fasting period before study: Overnight
- Housing: In groups of up to four in suspended solid-floor polypropylene cages furnished with woodflakes
- Diet (e.g. ad libitum): 2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK provided ad libitum
- Water (e.g. ad libitum): Mains drinking water provided ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25
- Humidity (%): 30 to 70
- Air changes (per hr): At least fifteen
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on oral exposure:

VEHICLE
- Justification for choice of vehicle: The test item did not dissolve/suspend in distilled water

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION (if unusual):
No analysis was conducted to determine the homogeneity, concentration or stability of the test item formulation. This is an exception with regard to GLP and has been reflected in the GLP compliance statement.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The available information on the toxicity of the test item was used to select 2000 mg/kg as the starting dose

Doses:

300 mg/kg, 2000 mg/kg

No. of animals per sex per dose:

Five animals per dose.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations were made 30 minutes, 1, 2 and 4 hours after dosing and then daily for up to 14 days. Morbidity and mortality checks were made twice daily. Individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14 or at death.
- Necropsy of survivors performed: yes

Results and discussion

Preliminary study:

Individual clinical observations and mortality data are given in Table 1. One animal was killed for humane reasons, 30 minutes after dosing, due to the occurrence of clinical signs of toxicity that exceeded the severity limit set forth in the UK Home Office Project Licence. One other animal was found dead 2 days after dosing. increased respiratory rate, labored respiration, prostration and tiptoe gait.
Surviving animals appeared normal 1 or 2 days after dosing. Individual necropsy findings are given in Table 3.
Abnormalities noted at necropsy of the animals that died or was humanely killed during the study were dark liver or patchy pallor of the liver, dark kidneys, gaseous stomach and hemorrhagic non-glandular epithelium of the stomach and/or hemorrhagic gastric mucosa.
No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 300 - <= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Individual clinical observations and mortality data are given in Table 4. There were no deaths.

Clinical signs:

other: No signs of systemic toxicity were noted during the observation period.

Gross pathology:

Individual necropsy findings are given in Table 6.
No abnormalities were noted at necropsy.

Any other information on results incl. tables

Table 1:Individual Clinical Observations and Mortality Data - 2000 mg/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	H	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-0 Female	RlRdPrX*
	2-1 Female	HLa	HLPWt	HWt	HPRl	HWt	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-2 Female	HA	HA	HA	HP	HWt	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-3 Female	HA	HAWt	HWt	HPWt	HPPtRlRi	X

0 = No signs of systemic toxicity H = Hunched posture A = Ataxia L = Lethargy Pt = Ptosis P = Pilo-erection

Ri = Increased respiratory rate Rl = Labored respiration Pr = Prostration Wt = Tiptoe gait X = Animal dead

X* = One animal was killed for humane reasons due to the occurrence of clinical signs of toxicity that exceeded the severity limit set forth in the UK Home Office Project Licence 

Table 2:Individual Body Weights and Body Weight Changes - 2000 mg/kg

Dose Level mg/kg	Animal Number and Sex	Body Weight (g) at Day			Body Weight (g) at Death	Body Weight Gain (g) During Week
		0	7	14		1	2
2000	1-0 Female	160	189	195	-	29	6
	2-0 Female	165	-	-	162	-	-
	2-1 Female	168	184	207		16	23
	2-2 Female	161	180	196		19	16
	2-3 Female	153	-	-	137	-	-

- = Animal dead 

Table 3: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 0	Liver: patchy pallor Kidneys: dark Stomach: gaseous Gastric mucosa: hemorrhagic
	2-1 Female	Killed Day 14	No abnormalities detected
	2-2 Female	Killed Day 14	No abnormalities detected
	2-3 Female	Found dead Day 2	Liver: dark Kidneys: dark Stomach: gaseous Gastric mucosa: hemorrhagic Non-glandular epithelium of the stomach: hemorrhagic

 

Table 4:Individual Clinical Observations and Mortality Data - 300 mg/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	H	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-0 Female	0	0	0	H	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-1 Female	0	0	0	H	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-2 Female	0	0	0	H	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	4-3 Female	0	0	0	H	0	0	0	0	0	0	0	0	0	0	0	0	0	0

0 = No signs of systemic toxicity H = Hunched posture A = Ataxia L = Lethargy Pt = Ptosis P = Pilo-erection

Ri = Increased respiratory rate Rl = Labored respiration Pr = Prostration Wt = Tiptoe gait X = Animal dead

X* = One animal was killed for humane reasons due to the occurrence of clinical signs of toxicity that exceeded the severity limit set forth in the UK Home Office Project Licence 

 

Table 5:Individual Body Weights and Body Weight Changes - 300 mg/kg

Dose Level mg/kg	Animal Number and Sex	Body Weight (g) at Day			Body Weight Gain (g) During Week
		0	7	14	1	2
300	3-0 Female	167	182	193	15	11
	4-0 Female	187	205	212	18	7
	4-1 Female	189	211	222	22	11
	4-2 Female	181	199	204	18	5
	4-3 Female	190	211	221	21	10

- = Animal dead 

Table 6:Individual Necropsy Findings - 300 mg/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

Applicant's summary and conclusion

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be in the range of 300 - 2000 mg/kg body weight (Globally Harmonized Classification System - Category 4).

The test item was also classified as Category 4 according to Regulation (EC) No. 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures. It is reasonable to assume that the Signal Word “Warning” and the Hazard Statement “H302: Harmful if swallowed” are therefore required.

Executive summary:

Introduction

The study was performed to assess the acute oral toxicity of the test item in the Wistar strain rat.

Methods

Following a sighting test at a dose level of 2000 mg/kg, a group of four fasted animals was given a single oral dose of test item at the same dose level. Based on the results from this dose level an additional animal was treated with the test item at a dose level of 300 mg/kg body weight. Based on the results from this animal, a further group of four fasted animals was given a single oral dose of test item at a dose level of 300 mg/kg body weight.

The test item was administered orally as a suspension in arachis oil BP. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Results

Mortality. One animal treated at a dose level of 2000 mg/kg was killed for humane reasons, 30 minutes after dosing, due to the occurrence of clinical signs of toxicity that exceeded the severity limit set forth in the UK Home Office Project Licence. One other animal treated at a dose level of 2000 mg/kg was found dead 2 days after dosing. There were no deaths at a dose level of 300 mg/kg.

Clinical Observations. Signs of systemic toxicity noted at a dose level of 2000 mg/kg were hunched posture, ataxia, lethargy, pilo-erection, ptosis, increased respiratory rate, labored respiration, prostration and tiptoe gait. Surviving animals treated at a dose level of 2000 mg/kg appeared normal 1 or 2 days after dosing. There were no signs of systemic toxicity at a dose level of 300 mg/kg.

Body Weight. Surviving animals showed expected gains in body weight.

Necropsy. Abnormalities noted at necropsy of the animals that died or was humanely killed during the study were dark liver or patchy pallor of the liver, dark kidneys, gaseous stomach and hemorrhagic non-glandular epithelium of the stomach and/or hemorrhagic 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 item in the female Wistar strain rat was estimated to be in the range of 300 - 2000 mg/kg body weight (Globally Harmonized Classification System  Category 4). The test item was also classified as Category 4 according to Regulation (EC) No. 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures. It is reasonable to assume that the Signal Word “Warning” and the Hazard Statement “H302: Harmful if swallowed” are therefore required.