Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
02 May 2017 - 25 July 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report Date:
2017

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Willing New Material Technology Co.,Ltd.; 23161211201
- Expiration date of the lot/batch: 10 December 2017
- Purity: 97%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Refrigerated (2-8 ºC)


Test animals

Species:
rat
Strain:
other: Crl:WI Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8 weeks
- Weight at study initiation: 180 - 202 g
- Fasting period before study: Yes, night before
- Housing: Type II polypropylene/polycarbonate cages; Lignocel 3/4-S Hygienic Animal Bedding produced by J. Rettenmaier & Söhne GmbH + CO.KG (D-73494 Rosenberg, Germany). Arbocel crinklets natural nesting produced by J. Rettenmaier & Söhne GmbH + CO.KG (D-73494 Rosenberg, Germany).
- Diet & water: Animals received ssniff® SM R/M "Autoclavable complete diet for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest, Germany (Batch number: 285 17890, expiry date: 31 August 2017), ad libitum, and tap water from the municipal supply, as for human consumption from a 500 ml bottle, ad libitum. The food is considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.
- Acclimation period: 6 and 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5 – 25.0 °C
- Humidity (%): 31 – 58 %
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.



Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 1 % methyl cellulose
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Lot/batch no. (if required): 5115851

The test item was freshly formulated at a concentration of 200 mg/mL in the 1 % methyl cellulose (dispensary code: S11129), in the Pharmacy of CiToxLAB Hungary Ltd. on the day of administration. The formulation container was magnetic stirred continuously up to the end of dose administration procedures
Doses:
Group 1: 2000 mg/kg bw
Group 2: 2000 mg/kg bw
No. of animals per sex per dose:
3 females
Control animals:
no
Details on study design:
Clinical Observations
Clinical observations were performed on all animals at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Individual observations were performed on the skin, fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

Body Weight Measurement
The body weight was recorded on the day before treatment (Day -1), on the day of the treatment (Day 0), weekly thereafter (Day 7) and at necropsy (Day 14).

Necropsy
Macroscopic examination was performed on all animals. The animals were sacrificed by exsanguination under pentobarbital anaesthesia (Release; Lot No.: 106 075, Expiry date: July 2018, produced by: Wirtschaftsgenossenschaft deutscher Tierärzte eG, Siemensstr. 14, 30827 Garbsen, Germany). After examination of the external appearance, the cranial, thoracic and the abdominal cavities were opened and the organs and the tissues were observed.
Statistics:
The method used was not intended to allow the calculation of a precise LD50 value.
The method used was not intended to allow the calculation of a precise LD50 value. The test item was ranked into categories of Globally Harmonized Classification System (GHS (rev. 6) 2015). Clinical signs, body weight, body weight gain and gross macroscopic data were tabulated.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
TiBTD did not cause mortality at a dose level of 2000 mg/kg bw in any animal.
Clinical signs:
All animals were symptom-free during the observation period at a dose level of 2000 mg/kg bw.
Body weight:
Body weight gains of TiBTD treated animals during the study showed no indication of a test item-related effect
Gross pathology:
There was no evidence of the macroscopic observations in animals dosed at 2000 mg/kg bw and subjected to the necropsy on Day 14.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, the acute oral LD50 value of the test item TiBTD was found to be above 2000 mg/kg bw in female Crl:WI Wistar rats.
Executive summary:

In an acute oral toxicity study (17/053-001P), Crl:WI Wistar female rats (3/dose) were given TiBTD (97%) in 1% methyl cellulose at doses of 2000 mg/kg bw and observed for 14 days.

LD50 (female): was >2000 mg/kg bw.

Initially, 3 females were treated at a dose level of 2000 mg/kg bw. As no mortality was observed, a confirmatory group of 3 females was treated at the same dose level. TiBTD did not cause mortality at a dose level of 2000 mg/kg bw in any animal. All animals were symptom-free during the observation period at a dose level of 2000 mg/kg bw. Body weight gains of TiBTD treated animals during the study showed no indication of a test item-related effect. There was no evidence of the macroscopic observations in animals dosed at 2000 mg/kg bw and subjected to the necropsy on Day 14.

This acute oral study is classified as acceptable. It does satisfy the guideline requirement for an acute oral study (OECD 423) in the rat.