Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 07 November, 1986 to 10 December, 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report Date:
1987

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Test material form:
liquid
Specific details on test material used for the study:
- Physical state: Clear, yellow coloured liquid
- Composition: TMAC: 50%, water: 15%, isopropyl alcohol: 35%
- Storage condition of test material: Stored in plastic screw-top bottle at room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Interfauna (UK) Limited, Wyton, Huntingdon, Cambridgeshire
- Age at study initiation: 5-8 wks old
- Weight at study initiation: Males weighed: 130 - 162g and females weighed: 123 - 151g
- Fasting period before study: Overnight fast immediately before dosing and for approximately two hours after dosing.
- Housing: Solid-floor polypropylene cages with sawdust bedding
- Diet and water (e.g. ad libitum): Free access to mains drinking water and food (rat and mouse expanded diet No.1, special diet services limited, with am, Essex, U.K.) was allowed throughout the study.
- Acclimation period: 5 d

ENVIRONMENTAL CONDITIONS
- Temperature: 19-23°C
- Humidity: 45-65%
- Air changes: 15/h
- Photoperiod: 12 h light/12 h dark

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: Undiluted

MAIN STUDY:
Four groups of ten rats (five males and five females) were dosed at logarithmically spaced dose levels, selected using the results of the range-finding study. All animals were dosed once only at the appropriate dose level by gavage using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to its fasted bodyweight at the time of dosing.


Doses:
0, 1,000, 1,260, 1,587 and 2,000 mg/kg bw
No. of animals per sex per dose:
5/sex/dose
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 d
- Frequency of observations and weighing: Animals were observed 1 and 4 h after dosing and subsequently once daily for 14 d. Deaths and evidence of overt toxicity were recorded at each observation. Individual bodyweights were recorded on the day of treatment (day 0), Day 7 and 14, and at death.
- Necropsy of survivors performed: Yes, all animals were subjected to gross necropsy examination for any macroscopic abnormalities
- Other observations: Clinical signs
Statistics:
Method of Weil C.S. (1952) Biometrics 8, 249 was used to calculate the acute oral median lethal dose (LD50 )and 95% confidence limits of the test substance.

Results and discussion

Preliminary study:
The results of the range finding study based on mortality indicated an oral LD50 between 1,000 and 2,000 mg/kg bw.
Effect levelsopen allclose all
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
1 260 mg/kg bw
Based on:
test mat.
95% CL:
1 061 - 1 496
Remarks on result:
other: equivalent to 630 mg a.i./kg bw
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
1 289 mg/kg bw
Based on:
test mat.
95% CL:
1 151 - 1 444
Remarks on result:
other: equivalent to 644.5 mg a.i./kg bw
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
1 000 - 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: equivalent to be between 500 to 1000 mg a.i./kg bw
Mortality:
The number and percentage of mortality observed at different doses were:
- At 1,000 mg/kg bw: 0/5 (M); 2/5 (F); 2/10 (total), i.e., 20%
- At 1,260 mg/kg bw: 2/5 (M); 4/5 (F); 6/10 (total), i.e., 60%
- At 1,587 mg/kg bw: 5/5 (M); 2/5 (F); 7/10 (total), i.e., 70%
- At 2,000 mg/kg bw: 5/5 (M); 4/5 (F); 9/10 (total), i.e., 90%
Clinical signs:
Major signs of toxicity noted in decedent and survlvlng animals were hunched posture, lethargy, pilo-erection, decreased respiratory rate and diarrhoea. Animals treated with 1,260 mg/kg bw and above showed additional signs including: ataxia, tip-toe gait, ptosis, pallor of the extremities, increased lacrimation, chromodacryorrhoea, diuresis, occasional body tremors, emaciation and red/brown staining around the snout.
The single survivor in the 2,000 mg/kg bw dose group showed signs of toxicity until Day 12, but all other surviving animals appeared normal three to six days
after treatment.
Body weight:
Effects on bodyweight gain (reduction) were commonly noted in animals treated with 1,260 mg/kg bw and above at Day 7, but all survivors made expected bodyweight gains during the second week.
Gross pathology:
Necropsy of decedents revealed abnormally red lungs, dark livers, haemorrhage and ulceration of the gastric mucosa and congestion of the small intestines. Surviving animals necropsied at termination showed white raised areas on the non-glandular region of the stomach or general white thickening of this region. Isolated animals from the 1,260 and 2,000 mg/kg bw dose groups showed adhesion of the stomach to the abdominal wall and/or liver.

Applicant's summary and conclusion

Interpretation of results:
other: Acute Tox. 4 based on CLP criteria
Conclusions:
Under the test conditions, the LD50 of the test substance in the Sprague-Dawley CFY rats was determined to be 1,260 mg/kg bw for males/females (i.e., equivalent to 630 mg a.i./kg bw).
Executive summary:

An OECD guideline study was performed to assess the acute oral toxicity of C16-18 and C18-unsatd. TMAC in Sprague-Dawley rats. Four groups of 10 fasted animals (five males and five females) were administered an oral gavage dose of the test substance (i.e., 50% active ingredient) at doses of 1,000, 1,260, 1,587 and 2,000 mg/kg bw. The animals were observed for 14 days and were then sacrificed and subjected to gross pathological examination. Mortality was observed at all doses (females: 2/5, 4/5, 2/5, 4/5; males: 0/5, 2/5, 5/5, 5/5, at each respective dose) with percentages ranging from 60-90 at ≥1,260 mg/kg bw. Major signs of toxicity noted in decedent and surviving animals were hunched posture, lethargy, pilo-erection, decreased respiratory rate and diarrhoea. All animals showed expected body weight gain during the second week of the study. Necropsy of decedents revealed abnormally red lungs, dark livers, haemorrhage and ulceration of the gastric mucosa and congestion of the small intestines. Surviving animals necropsied at termination showed white raised areas on the non-glandular region of the stomach or general white thickening of this region. Under the test conditions, the LD50 was determined to be 1,260 mg/kg bw for males/females (i.e., equivalent to 630 mg a.i./kg bw).