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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 November 2018 to 15 December 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
2001
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
no

Test material

1
Chemical structure
Reference substance name:
Dibutyltin oxide
EC Number:
212-449-1
EC Name:
Dibutyltin oxide
Cas Number:
818-08-6
Molecular formula:
C8H18OSn
IUPAC Name:
dibutylstannanone
Test material form:
solid: particulate/powder
Details on test material:
- Appearance: white powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: In-house bred animals
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 9 weeks
- Weight at study initiation: 162.1 g to 177.89 g
- Fasting period before study: Three animals per step were fasted overnight (16 to 18 hours) prior to dosing. Water was provided ad libitum during the fasting period. Feed was offered 3 to 4 hours after dosing.
- Housing: Three animals were housed in standard polypropylene cage with stainless steel mesh top grill. Clean sterilised paddy husk was provided as bedding material.
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: Healthy young animas used for Step-I, Step-I confirmation, Step-II and Step-II confirmation were acclimatised for five, eight, eleven and thirteen days respectively to laboratory conditions prior to treatment and were observed for clinical signs once daily. Veterinary examination of all animals was performed on the day of receipt and on the 5th day of acclimatisation.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.3 - 22.9 °C
- Humidity (%): 47 % - 67 % relative humidity
- Air changes (per hr): 12 to 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours fluorescent light and 12 hours dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 30 and 200 mg/mL
- Justification for choice of vehicle: The test material formed uniform suspension in corn oil as evidenced by in-house solubility/suspensibility test. Hence, corn oil was selected for the test material formulation preparation. Corn oil is a universally accepted and routinely used vehicle in oral toxicity studies.
- Lot/batch no.: A1712001

MAXIMUM DOSE VOLUME APPLIED
- The dose volume administered to individual rats was adjusted according to its bodyweight recorded on the day of dosing. The dose volume was 10 mL/kg body weight.

DOSAGE PREPARATION
- The required quantity of test material was weighed, ground well using a pestle and mortar by adding a little volume of vehicle and transferred to a measuring cylinder. A small quantity of vehicle was added, rinsed and transferred into the measuring cylinder. Rinsing procedure was repeated until the complete transfer of contents to the measuring cylinder. Finally the volume was made up to the required quantity with vehicle to get the desired concentration.
- The freshly prepared test material formulation was used for administration. The homogeneity of the test material formulation was maintained by continuous stirring on a magnetic stirrer during dosing.

METHOD
- The freshly prepared test formulation was administered by oral gavage to each rat as a single dose using intubation cannula.
- The animals were dosed in a stepwise procedure with three female animals per step. A starting dose of 300 mg/kg body weight was selected from the fixed dose levels of 5, 50, 300 and 2000 mg/kg body weight as the LD50 of the test material was not available.
- The test material was administered by oral gavage as a single dose of 300 mg/kg body weight to three female rats in step-I. Clinical signs of toxicity and no mortality was observed at 300 mg/kg body weight in Step-I. Hence, as per the decision rules governing the sequential procedure presented in the OECD 423 guideline, Step-I confirmation was conducted using three more female rats after approximately 48 hours observation by administering a single dose of 300 mg/kg body weight of the test material. Clinical signs of toxicity and no mortality was observed at 300 mg/kg body weight in Step-I confirmation. Step-II was conducted using three more female rats after approximately 48 hours of observation by administering a single dose of 2000 mg/kg body weight. Clinical signs of toxicity and mortality were observed at 2000 mg/kg body weight in Step-II. Step-II confirmation was conducted using three more female rats after approximately 24 hours of observation by administering a single dose at 2000 mg/kg body weight. Clinical signs of toxicity and mortality were observed at 2000 mg/kg body weight in Step-II confirmation.
- Dose levels higher than 2000 mg/kg body weight were not tested.
Doses:
300 and 2000 mg/kg body weight
No. of animals per sex per dose:
Three females per step
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All surviving animals were observed for clinical signs of toxicity and mortality at 30 to 40 min, 1 hour (± 10 mins), 2 hours (± 10 mins), 3 hours (± 10 mins), and 4 hours (± 10 mins) post-dosing on day 1 and once daily thereafter for clinical signs of toxicity and twice daily for mortality during the 14 day observation period. Individual animal body weight was recorded on day 2 before test material administration and on day 8 and day 15 during the observation period. The body weight of dead animals was also recorded.
- Necropsy of survivors performed: Yes. At the end of the observation period, all surviving animals were humanely sacrificed under carbon dioxide asphyxiation, subjected to necropsy and a complete gross pathological examination and observations were recorded. In dead animals external gross changes were observed, hence tissues (stomach) were collected and preserved in 10 % neutral buffered formalin. Histopathological examination was not carried out on the collected tissues as per the sponsor’s request.
- Other examinations performed: Observations included changes in skin, fur, eyes and mucous membranes and also respiratory, circulatory, autonomic and central nervous system and somatomotor activity and behaviour pattern.

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
500 mg/kg bw
Based on:
test mat.
Mortality:
- In Step-I and Step-I confirmation, no mortality was observed.
- In Step-II on day 4 one animal was found dead; one animal revealed clinical signs and was found dead by afternoon observation. The surviving animal was found dead on day 6 observation.
- In Step-II confirmation all animals were found dead on Day 5 observation.
Clinical signs:
other: - In Step-I and Step-I confirmation, the animals were dosed at 300 mg/kg body weight. No clinical signs of toxicity and mortality were observed at 30 to 40 minutes; diarrhoea was observed at 1st, 2nd, 3rd and 4th hour observations. On day 2 clinical sig
Gross pathology:
- No gross pathological changes were observed in any of the surviving animals at 300 mg/kg body weight. However, in dead animals external gross change like wet perineum (6/6) and internal gross change like stomach haemorrhage (5/6) and autolysis (1/6) was observed.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
Under the conditions of the study it was concluded that the LD50 cut off value for the test material was 500 mg/kg bodyweight.
Executive summary:

The test material was evaluated for acute oral toxicity in Sprague Dawley rats according to the standardised method OECD Guideline 423, under GLP conditions.

A starting dose of 300 mg/kg body weight was selected from the fixed dose levels of 5, 50, 300 and 2000 mg/kg body weight as the LD50 of the test material was not available.

A total of 12 females (3 females for each Step-I, Step-I confirmation, Step-II and Step-II confirmation) were used for the experiment. All animals of Step-I and Step-I confirmation were administered 300 mg/kg body weight of the test material formulation and Step-II and Step-II confirmation were administered with 2000 mg/kg body weight of the test material formulation through the oral route.

All surviving animals were observed for clinical signs of toxicity and mortality at 30 to 40 min, 1 h (± 10 mins), 2 h (± 10 mins), 3 h (± 10 mins) and 4 hours (± 10 mins) post dosing on day 1 and once daily thereafter for clinical signs of toxicity and twice daily for mortality during the 14 day observation period. Body weight was recorded on day 1 before test material administration and on day 8 and day 15 during the observation period. At the end of the observation period, all surviving animals were sacrificed under carbon dioxide asphyxiation, subjected to necropsy and gross pathological examination.

In Step-I and Step-I confirmation the animals were dosed with 300 mg/kg body weight. Animals revealed clinical signs like diarrhoea and wet perineum. Clinical signs reversed back to normal by day 4 observation.

In Step-II and Step-II confirmation, the animals were dosed with 2000 mg/kg body weight. Animals revealed clinical signs like lethargy, diarrhoea, wet perineum and nasal discharge followed by death.

No changes were observed in body weight and percent change in body weight with respect to day 1 at 300 mg/kg body weight. All surviving animals revealed physiologically normal increase in the body weight.

No gross pathological changes were observed in any of the surviving animals at 300 mg/kg body weight. However, in dead animals external gross change like wet perineum (6/6) and internal gross change like stomach haemorrhage (5/6) and autolysis (1/6) was observed.

Under the conditions of the study it was concluded that the LD50 cut off value for the test material was 500 mg/kg bodyweight.