5'-O-(p,p'-dimethoxytrityl)thymidine

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2017-12-12 to 2018-03-01

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

adopted 17 December 2001

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

5'-O-(p,p'-dimethoxytrityl)thymidine

EC Number:

255-003-1

EC Name:

5'-O-(p,p'-dimethoxytrityl)thymidine

Cas Number:

40615-39-2

Molecular formula:

C31H32N2O7

IUPAC Name:

5'-O-[bis(4-methoxyphenyl)(phenyl)methyl]thymidine

Test material form:

solid

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 8 – 9 weeks
- Weight at study initiation: Step 1: 145 – 159 g, Step 2: 152 – 166 g
- Fasting period before study: 16 - 19 h
- Housing: The animals were kept in groups in individually ventilated cages (IVC), type III H, polysulphone cages on Altromin saw fibre bedding
- Diet (e.g. ad libitum): ad libitum, Altromin 1324 maintenance diet for rats and mice
- Water (e.g. ad libitum): ad libitum, free access to tap water, sulphur acidified to a pH value of approximately 2.8
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 55 +/- 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Justification for choice of vehicle: the vehicle was chosen due to its non-toxic characteristics
- Lot/batch no. (if required): Aqua ad injectionem (sterile water, DeltaMedica, lot no. 705820, expiry date: 30 April 2020)

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3 females per step, 2 steps

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: Observed for 14 days after dosing for general clinical signs, morbidity and mortality
- Frequency of weighing: The animals were weighed on days 1 (prior to the administration) and on days 8 and 15
- Necropsy of survivors performed: Yes, all animals were subjected to gross necropsy and examined macroscopically for gross pathological changes. In the absence of gross pathological changes no tissues were preserved for a possible histopathological evaluation.
- Other examinations performed: clinical signs: A careful clinical examination was made several times on the day of dosing (at least once during the first 30 minutes and with special attention given during the first 4 hours post-dose). Thereafter, the animals were observed for clinical signs once daily until the end of the observation period. Cageside observations included changes in the skin and fur, eyes and mucous membranes. Also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern were examined. Particular attention was directed to observations of tremor, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

Statistics:

n.a.

Results and discussion

Preliminary study:

n.a.

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no mortality occurred at the limit dose of 2000 mg/kg bw

Mortality:

No mortality was observed for any of the test animals.

Clinical signs:

other: The clinical findings in the animals treated with the test item at a dose of 2000 mg/kg bw were reduced spontaneous activity and piloerection starting directly or at 30 minutes after dosing. However, all animals recovered within up to 2 days post-dose.

Gross pathology:

No macroscopic findings were observed in any animal of any step.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute oral toxicity study in rats conducted according to OECD 423 no mortality occurred at the limit dose of 2000 mg/kg bw. Hence, the LD50 value was determined to be greater than 2000 mg/kg bw.

Executive summary:

In an acute oral toxicity study (acute toxic class method, OECD 423), two groups of fasted, 8 -9 weeks old, female Wistar rats (3 rats/group) were given a single oral dose of the test item (100% purity) in water at the limit dose of 2000 mg/kg bw and were observed for 14 days. All animals survived until the end of the study showing only mild signs of toxicity. The clinical findings in the animals treated with the test item at a dose of 2000 mg/kg bw were reduced spontaneous activity and piloerection starting directly or 30 minutes after dosing. All symptoms were no longer detectable by day 2 after dosing.

Throughout the 14-day observation period, the body weight gain of the test animals was within the normal range of variation for this strain. At necropsy, no macroscopic findings were observed in any animal of any step. Based on the results from this study, the oral LD50 in rats is considered to exceed 2000 mg/kg bw.