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Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
The study was performed between 25 June 2008 and 23 July 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Justification for type of information:
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 no effect the quality of the relevant results.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report date:
2008

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
UK GLP standards (Schedule 1, Good Laboratory Practice Regulations 1999 (SI 1999/3106 as amended by SI 2004/0994))
Test type:
fixed dose procedure
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
aluminium(3+) nickel(2+) λ²-cobalt(2+) lithium(1+) tetraoxidandiide
EC Number:
700-042-6
Cas Number:
177997-13-6
Molecular formula:
LiNiCoAlO2 where stoichiometry of Ni+Co+Al equals 1 and ranges are Li = 0.9 – 1.3, Co = 0.01 – 0.2, Ni = 0.75 – 0.99 and Al = 0.01 – 0.2
IUPAC Name:
aluminium(3+) nickel(2+) λ²-cobalt(2+) lithium(1+) tetraoxidandiide

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 (Hsd:Sprague Dawley (CD)) strain rats were supplied by Harlan UK Limited, Bicester, Oxon, UK
- Age at study initiation: At the start of the study the animals were 8 to 12 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): With the exception of an overnight fast immediately before dosing and for approximately three to four hours after dosing, free access to mains drinking water and food (Certified Rat and Mouse Diet) was allowed throughout the study.
- Water (e.g. ad libitum): As diet.
- Acclimation period: At least 5 days.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25°C
- Humidity (%): 30 to 70%
- Air changes (per hr): At lease 15 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.


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 mg/ml and 200 mg/ml
- Amount of vehicle (if gavage): All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted bodyweight at the time of dosing.
- Justification for choice of vehicle: Arachis oil BP was used because the test material did not dissolve/suspend in distilled water.
- Lot/batch no. (if required): Not stated.
- Purity: Not stated.


MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg


DOSAGE PREPARATION (if unusual):
For the purpose of the study the test material was freshly prepared, as required, as a suspension in arachis oil BP.
All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted bodyweight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each dose level to confirm the survival of the previously dosed animals.


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Not applicable.
Doses:
300 mg/kg chosen as starting dose and then 2000 mg/kg
No. of animals per sex per dose:
1 animal at 300 mg/kg.
5 animals 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. 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,organ weights, histopathology, other: Morbidity and mortality checks were made twice daily.

Statistics:
Data evaluations included the relationship, if any, between the animals' exposure to the test material and the incidence and severity of all abnormalities including behavioural and clinical observations, gross lesions, bodyweight changes, mortality and any other toxicological effects. If possible the signs of evident toxicity were also identified. Evident toxicity is defined as the toxic effects which are of a severity such that administration at the nexthighest level could result in mortality.
Using the mortality data obtained, an estimate of the acute oral median lethal dose (LD50) of the test material was made.

Results and discussion

Preliminary study:
A single animal was treated as a dose level of 300 mg/kg.
RESULTS
Dose Level - 300 mg/kg
Mortality: There was no mortality.
Clinical Observations: No signs of systemic toxicity were noted during the observation period.
Bodyweight: The animal showed expected gains in bodyweight over the observation period.

In the absence of toxicity at 300 mg/kg, an additional animal was treated at 2000 mg/kg
Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Remarks on result:
other: 95% CL not stated.
Mortality:
Dose level 2000 mg/kg:
There were no deaths.
Clinical signs:
other: Dose level 2000 mg/kg: No signs of systemic tocicity were noted during the observation period.
Gross pathology:
Dose level 2000 mg/kg.
No abnormalities were noted at necropsy.
Other findings:
None.

Any other information on results incl. tables

Dose Level -300mg/kg

Individual clinical observations and mortality data are given in Table 1.

Table1               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

1-0

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

Individual bodyweights and bodyweight changes are given in Table 2.

Table2               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

1-0 Female

158

173

192

15

19

 Dose Level -2000mg/kg

Individual clinical observations and mortality data are given in Table 3

Table3               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

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

Individual bodyweights and bodyweight changes are given in Table 4.

Table4               Individual Bodyweights and Bodyweight Changes-2000mg/kg

Dose Level mg/kg

Animal Number and Sex

Bodyweight (g) at Day

Bodyweight Gain (g) During Week

0

7

14

1

2

2000

2-0 Female

186

212

217

26

5

3-0 Female

160

189

224

29

35

3-1 Female

160

188

217

28

29

3-2 Female

161

180

197

19

17

3-3 Female

156

180

203

24

23

Individual necropsy findings are given in Table 5.

Dose Level
mg/kg

Animal Number
and Sex

Time of Death

Macroscopic Observations

2000

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

 

The acute oral median lethal dose (LD50) of the test material in the female Sprague‑Dawley CD strain rat was estimated to be greater than 2000mg/kg bodyweight.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
he acute oral median lethal dose (LD50) of the test material in the female Sprague‑Dawley CD strain rat was estimated to be greater than 2000mg/kg bodyweight.
Executive summary:

Introduction. The study was performed to assess the acute oral toxicity of the test material in the Sprague‑Dawley CD 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 B1 bis Acute Toxicity (Oral) of Commission Directive 2004/73/EC

Method. Following a sighting test at dose levels of 300 mg/kg and 2000 mg/kg, a further group of four fasted females was given a single oral dose of test material, as a suspension in arachis oil BP, 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 of animals treated at a dose level of 2000mg/kg bodyweight.

Conclusion. The acute oral median lethal dose (LD50) of the test material in the female Sprague‑Dawley CD strain rat was estimated to be greater than 2000 mg/kg bodyweight.