Barium, 1,4-bis (C13-rich C11-14-isoalkyl) 2-sulfobutanedioate phosphate complex

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 29 September 2005 and 20 October 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Date of inspection: 2nd December 2002 Date of signature: 13/2/03

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

dibarium(2+) bis(1,5-dioxo-1,5-bis(tridecyloxy)pentane-3-sulfonate) hydrogen phosphate

EC Number:

931-037-9

Molecular formula:

Molecular formula for each combination of chain length. C13,13: (C30H57O7S)2 Ba @ BaHOP4 C11,12: (C27H51O7S)2 Ba @ BaHOP4 C12,12: (C28H53O7S)2 Ba @ BaHOP4 C12,13: (C29H55O7S)2 Ba @ BaHOP4 C13,14: (C31H59O7S)2 Ba @ BaHOP4 C14,14: (C32H61O7S)2 Ba @ BaHOP4

IUPAC Name:

dibarium(2+) bis(1,5-dioxo-1,5-bis(tridecyloxy)pentane-3-sulfonate) hydrogen phosphate

Details on test material:

Identification : Barium di(bistridecylsulfosuccinate) in mixture with barium hydrogen phosphate
Description : Clolurless waxy solid block
Batch number : Y-T-1
Storage Conditions : room temperature in the dark.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Female Sprague-Dawley CD (Crl: CD (SD) IGS BR) strain rats were supplied by Charles River (UK) Ltd, Margate, Kent, UK.
- Age at study initiation: Eight to twelve weeks of age.
- Weight at study initiation: 193 - 224g. The bodyweights fell within an interval of ± 20% of the mean initial bodyweight of the first treated group.
- Fasting period before study: An overnight fast immediately before dosing and for approximately three to four hours after dosing.
- Housing: The animals were housed in groups of three in suspended solid-floor polypropylene cages furnished with woodflakes.
- Diet (e.g. ad libitum): Free access to food (Certified Rat and Mouse Diet (Code 5LF2) supplied by BCM IPS Limited, London, UK) was allowed throughout the study.
- Water (e.g. ad libitum): Free access to mains drinking water was allowed throughout the study.
The diet, drinking water and bedding were routinely analysed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.
- Acclimation period: At least five days.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): The temperature was set to achieve limits of 19 to 25°C.
- Humidity (%): Relative humidity was set to achieve limits of 30 to 70%.
- Air changes (per hr): At least fifteen changes per hour.
- Photoperiod (hrs dark / hrs light): The lighting was controlled by a time switch to give twelve hours continous light (06:00 to 18:00) and twelve hours darkness.


IN-LIFE DATES: From: Day 0 To: Day 14

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

DMSO

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/ml
- Amount of vehicle (if gavage): The volume administered to each animal was calculated according to the fasted bodyweight at the time of dosing.
- Justification for choice of vehicle: Dimethyl sulphoxide was used because the test material did not dissolve/suspend in distilled water.
- Lot/batch no. (if required): Not avaialable.
- Purity: Not available.


MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg

DOSAGE PREPARATION (if unusal): For the purpose of the study the test material was freshly prepared, as required, as a solution at the appropriate concentration in dimethyl sulphoxide. To aid preparation the test material formulation was heated to 80°C in a water bath. The formulation was allowed to cool before dosing.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Using all available information on the toxicity of the test material, 2000 mg/kg was chosen as the starting dose.

Doses:

Dose level of 2000 mg/kg.

No. of animals per sex per dose:

6 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: The animals were observed for deaths or overt signs of toxicity 1/2, 1, 2 and 4 hours after dosing and subsequently once daily for up to fourteen day.
- Necropsy of survivors performed: yes
- Other examinations performed: Individual bodyeights were recorded prior to dosing and seven and fourteen days after treatment or at death.

Statistics:

None reported.

Results and discussion

Preliminary study:

Not applicable.

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

ca. 2 500 mg/kg bw

Remarks on result:

other: LD50 estimated to be approximately 2500 mg/kg bodweight.

Mortality:

Individual mortality data are given in Table 1.
Two animals were found dead one day after dosing.

Clinical signs:

other: Individual clinical observations are given in Table 2. Signs of systemic toxicity noted during the study were hunched posture, lethargy, pilo-erection, decreased respiratory rate, laboured respiration, ataxia, pallor of the extremities, dehydration, diarr

Gross pathology:

Individual necropsy findings are given in Table 4.
Abnormalities noted at necropsy of animals that died during the study were haemorrhagic lungs, dark liver and dark kidneys. No abnormalities were noted at necropsy of animals that were killed at the end of the study.

Other findings:

None.

Any other information on results incl. tables

Table1               Mortality Data

Dose Level mg/kg	Sex	Number of Animals Treated	Deaths During Day of Dosing (Hours)				Deaths During Period After Dosing (Days)								Deaths
			½	1	2	4	1	2	3	4	5	6	7	8-14
2000	Female	3	0	0	0	0	1	0	0	0	0	0	0	0	1/3
	Female	3	0	0	0	0	1	0	0	0	0	0	0	0	1/3

Table2               Individual Clinical Observations

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	HLPRd	X
	1-1 Female	0	0	0	HP	HP	HLAPRdRlE Dh	HLPEDh	HPEDh	HP	H	H	H	H	0	0	0	0	0
	1-2 Female	0	0	0	H	HLPARdRl	HLPARdRl	HRdPRl	H	0	0	0	0	0	0	0	0	0	0
	2-0 Female	0	HD	HD	HD	H	H	0	0	0	0	0	0	0	0	0	0	0	0
	2-1 Female	0	HRdLRl	HRdLRlAWs	HRdLRlALiWs	HRdRl	0	0	0	0	0	0	0	0	0	0	0	0	0
	2-2 Female	0	0	0	H	X

 

0= No signs of systemic toxicity                     A = Ataxia                                                            D = Diarrhoea                                      Dh = Dehydration

E = Pallor of the extremities                               H = Hunched posture                                         L = Lethargy                                       Li = Increased lachrymation

P =                                                  Rd= Decreased respiratory rate                       Rl = Laboured respiration                  Ws = Splayed gait

X = Animal dead

Table3               Individual Bodyweights and Weekly Bodyweight Changes

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	222	-	-	205	-	-
	1-1 Female	222	218	280		-4	62
	1-2 Female	224	228	255		4	27
	2-0 Female	205	223	240		18	17
	2-1 Female	224	228	250		4	22
	2-2 Female	193	-	-	186	-	-

Table4               Individual Necropsy Findings

Dose Level mg/kg	Animal Number and Sex	Time of Death	Macroscopic Observations
2000	1-0 Female	Found dead Day 1	Lungs: haemorrhagic Liver: dark Kidneys: dark
	1-1 Female	Killed Day 14	No abnormalities detected
	1-2 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	Found dead Day 1	Lungs: haemorrhagic Liver: dark Kidneys: dark

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral median lethal dose (LD50) of the test material in the female Sprague-Dawley CD strain tat was estimated to be approximately 2500 mg/kg bodyweight (GHS Category 5 >2000 - 5000 mg/kg bodyweight).

Executive summary:

Introduction.

The study was performed to assess the acute oral toxicity of the test material following a single oral administration in the Sprague-Dawley CD strain rat. The method was designed to meet the requirements of the following:

• OECD Guidelines for the Testing of Chemicals No. 423 "Acute Oral Toxicity - Acute Toxic Class Method" (adopted 17 December 2001)
• Method B1 tris Acute Toxicity (Oral) of Commission Directive 2004/73/EC

Method.

A group of three fasted females was treated with the test material at a dose level of 2000 mg/kg bodyweight. This was followed by a further group of three fasted females at the same dose level.

The test material was administered orally as a solution in dimethyl sulphoxide. Clinical signs and bodyweight development were monitered during the study. All animals were subjected to gross necropsy.

Mortality.

Two animals were found dead one day after dosing.

Clinical Observations.

Signs of systemic toxicity noted during the study were hunched posture, lethargy, pilo-erection, decreased respiratory rate, laboured respiration, ataxia, pallor of the extremities, dehydration, diarrhoea, increased lachrymation and splayed gait. Surviving animals appeared normal two, three, five or ten days after dosing.

Bodyweight.

The surviving animals showed expected gains in bodyweight over the study period, except for one animal which showed a bodyweight loss during the first week but expected gain in bodyweight during the second week of the study.

Necropsy.

Abnormalities noted at necropsy of animals that died during the study were haemorrhagic lungs, dark liver and dark kidneys. 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 Sprague-Dawley CD strain rat was estimated to be approximately 2500 mg/kg bodyweight (GHS Category 5 >2000 - 5000 mg/kg bodyweight).