Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June - August 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
No reference is made to official Test Guidelines and no claim is made to GLP compliance. Furthermore, there is no reference to the purity of the substance. However, the species tested is relevant to the endpoint, the study report is well documented and its design appears to be in the spirit of the current guideline. The study is adequate for the purposes of hazard identification and classification.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
A preliminary range-finding test was performed to determine the approximate range in which the median lethal oral dose (LD50) fell. The subsequent main study involved testing of a larger number of animals to determine the LD50 value more precisely.
GLP compliance:
not specified
Remarks:
: older study, pre-dates GLP
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): DI-TMP

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS

- Weight at study initiation: 18 to 23 g.
- Fasting period before study: animals were fasted overnight before treatment.


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Aqueous methylcellulose 1%
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 40% (w/v)
- Amount of vehicle (if gavage): 40 mL/kg (control group, vehicle only); 10 to 40 mL/kg (treatment groups).


MAXIMUM DOSE VOLUME APPLIED: 40 mL/kg.
Doses:
0.4, 1.0, 4.0, 16 g/kg. (range finding screen)
0, 4.0, 6.4, 10, 16 g/kg. (main study)
No. of animals per sex per dose:
2 (range finding screen)
5 (main study)
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: wieghts recorded weekly
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, other: macrosopic examination of target organs.
Statistics:
The LD50 and its 95% confidence limits were calculated by the method of Litchfield J.T. and Wilcoxon F. (1949) J. Pharmac. Exp. Ther, 96, 99-113.

Results and discussion

Preliminary study:
The preliminary range finding tests indicated that the median lethal oral dose (LD50) was in the region of 4.0 to 16 g/kg.
Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
14 500 mg/kg bw
95% CL:
>= 11.2 - <= 18.7
Mortality:
One male and one female mouse died at 10 g/kg; three male and three female mice died at 16 g/kg. Deaths occurred within three hours to 23 hours
after dosing.
Clinical signs:
Signs of reaction to treatment, observed shortly after dosing included piloerection in all treated animals, abnormal body carriage (hunched posture)
and ptosis in animals treated at 6.4 g/kg and above and lethargy decreased respiratory rate and abnormal gait (waddling) in animals treated at 10 and 16 g/kg.
These signs were accompanied by fine body tremors and pallor of the extremities amongst mice at 10 and 16 g/kg, by ataxia in one mouse at 10 g/kg and intwo mice at 16 g/kg and, by coma with recovery in two female mice at 16 g/kg.
Body weight:
Bodyweight gains in surviving mice were normal
Gross pathology:
In the mice which died during the observation period, autopsy revealed haemorrhage and congestion of the lungs and pallor of the liver, kidneys and
spleen.
Other findings:
- Other observations: Prior to death loss of righting reflex was observed in threee mice at 16 g/kg. Piloerection only was observed in the control mice.

Any other information on results incl. tables

Mortality data for groups of mice dosed orally with DI-TMP

Range Finding Screen

Dosage (g/kg)

Mortality ratio (No. of deaths / No. dosed)

Time of death after dosing (Hours)

Concentration %

Male

Female

Combined

0.4

10

0/2

0/2

0/4

-

1.0

10

0/2

0/2

0/4

-

4.0

40

0/2

0/2

0/4

-

16

40

1/2

2/2

3/4

<20

Mortality ratio and group mean bodyweight (g) of mice dosed orally with DI-TMP

Main study

Sex

Dosage (g/kg)

Bodyweight (g) at

Mortality ratio (No. of deaths / No. dosed)

Time of death after dosing (Hours)

dosing

1 week

2 weeks

Male

0

21

30

34

0/5

-

4.0

20

30

36

0/5

-

6.4

21

29

32

0/5

-

10

20

30

33

1/5

<4

16

22

31

36

3/5

<4

Female

0

20

25

27

0/5

-

4.0

19

25

26

0/5

-

6.4

19

25

27

0/5

-

10

21

26

28

1/5

<23

16

19

23

36

3/5

<4

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute median lethal oral dose (LD50) and its 95% confidence limits to mice of DI-TMP were calculated to be 14.5 (11.2 to 18.7) g/kg bodyweight.
Executive summary:

A study was performed by Huntingdon Research Centre, England on behalf of Perstorp Chemicals, Sweden to determine the acute oral toxicity to CD-1 mice of the test substance DI-TMP. No official Test Guidelines were cited, however the study design and species used were relevant and broadly in line with modern test guidelines. The LD50 in mice of the test substance was found to be 14.5 g/kg bodyweight (95% confidence limits 11.2 to 18.7 g/kg bodyweight).