Registration Dossier

Administrative data

Description of key information

The oral LD50 value of TRANTOS in Wistar rats was established to exceed 2000 mg/kg body weight. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Purity/Composition 99.9%
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nohsan, Notification No. 8147, April 2011; including the most recent partial revisions.
GLP compliance:
yes
Test type:
acute toxic class method
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
Species Rat, Wistar strain Crl:WI (Han) (outbred, SPF-Quality). Recognized by international guidelines as the recommended test system (e.g. OECD,EC).
Source: Charles River Deutschland, Sulzfeld, Germany.

Number of animals 9 Females (nulliparous and non-pregnant). Each dose group consisted of 3 animals.
Age and body weight Young adult animals (approx. 8 weeks old) were selected.
Body weight variation did not exceed +/- 20% of the sex mean.
Identification Ear- and tailmark
Health inspection At least upon receipt of the animals and prior to dosing.

Conditions
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, approximately 15 room air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.

Accommodation
Group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Litalabo, S.P.P.S., Argenteuil, France) and paper as cageenrichment (Enviro-dri, Wm. Lillico & Son (Wonham Mill Ltd), Surrey, United Kingdom). Acclimatization period was at least 5 days before start of treatment under laboratory conditions.

Diet
Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).

Water
Free access to tap water.

Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study.
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
Vehicle: Propylene glycol (Merck, Darmstadt, Germany) (specific gravity 1.036)

Rationale: The vehicle was selected based on trial formulations performed at WIL Research Europe and on test substance data supplied by the sponsor.

Preparation: The formulations (w/w) were prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level. Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test substance. The concentration of the test substance in vehicle was varied to allow constant dosage volume in terms of mL/kg body weight.

Doses:
300 mg/kg (10 mL/kg) body weight.
2000 mg/kg (10 mL/kg) body weight.
No. of animals per sex per dose:
stepwise treatment of groups of 3 females
Control animals:
not specified
Details on study design:
The toxicity of the test substance was assessed by stepwise treatment of groups of 3 females. The
first group was treated at a dose level of 300 mg/kg. The absence or presence of mortality of animals
dosed at one step determined the next step, based on the test procedure defined in the guidelines.
The onset, duration and severity of the signs of toxicity were taken into account for determination of
the time interval between the dose groups.
Statistics:
No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Clinical signs observed during the study period were as follows:
Dose level Clinical signs
300 mg/kg The animals showed hunched posture, uncoordinated movements and/or
piloerection on Day 1.
2000 mg/kg The animals showed lethargy, hunched posture, uncoordinated movements
and/or piloerection on Day 1. Additionally hunched posture was noted
between 2 and 5.
Body weight:
The body weight gain shown by the animals over the study period was considered to be similar to that
expected of normal untreated animals of the same age and strain.
Gross pathology:
No toxicologically relevant abnormalities were found at macroscopic post mortem examination of the
animals.
In one animal at 300 mg/kg a diaphragmatic hernia in the left median lobe was noted. This finding is
incidentally seen in these animals of the same age and strain and was therefore considered not
toxicologically significant.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The oral LD50 value of TRANTOS in Wistar rats was established to exceed 2000 mg/kg body weight.
Executive summary:

The oral LD50 value of TRANTOS in Wistar rats was established to exceed 2000 mg/kg body weight. Based on these results: - according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures, TRANTOS does not have to be classified and has no obligatory labelling requirement for oral toxicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
One reliable, acute oral study, completed in 2013, was available.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for selection of acute toxicity – oral endpoint
Key, reliable study (Klimisch 1)

Justification for classification or non-classification

The oral LD50 value of TRANTOS in Wistar rats was established to exceed 2000 mg/kg body weight. Based on these results: - according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures, TRANTOS does not have to be classified and has no obligatory labelling requirement for oral toxicity.