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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:
Not stated
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Restrictions: The dose volumes were excessive for dose levels greater than 2.0 g/kg. The 2.8 g/kg dose level was administered at a volume of 2.8 mL/100 g and the 4.0 g/kg dose level was administered at a volume of 4.0 mL/100 g. The maximum acceptable volume of a water carrier is 2.0 mL/kg. The high dose volumes may have contributed to observed effects and mortality. All dose volumes below the limit dose (2.0 g/kg) are acceptable. The LD50 should then be expressed as >2000 mg/kg bw, not as reported in the study (2.2 g/kg bw; 95% confidence limits 1.9-2.7 g/kg bw).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1969
Report Date:
1969

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Single oral dose administered to the test animals which were then observed for 12 days.
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): n-butyltin trichloride
- Analytical purity: not stated

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
- Initial body weight: 80-115 g
- Room temp./rel. humidity: 21-23 °C / 55-65 %
- Animals housed in: Type II macrolide cage, grated bottom, 1 animal/cage
- Feed: Altromin R, ad libitum
- Water: Tap water, ad libitum
- Acclimation: for 10  days

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
water
Details on oral exposure:
- Formulation: Emulsion
- Concentration: 10 g in 100 mL
- Denial of feed before application: 22 h
- Time of application: 10:30 am
- Period of observation after administration: 12 days
Doses:
6 doses - 0.5, 1.0, 1.4, 2.0, 2.8, and 4.0 g/kg
No. of animals per sex per dose:
5 animals per sex per dose group
total = 60 rats (30 M, 30 F)
Control animals:
no
Details on study design:
-Groups of 10 rats (Wistar SPF; 5 males/5 females) were acclimated for 10  days, then exposed to six nominal dose levels of the test material: 0.5, 1.0, 1.4, 2.0, 2.8, and 4.0 g/kg bw. 
-The test material was delivered orally as a volume/volume emulsion in  distilled water. Dose volumes ranged from 0.5 mL to 4.0 mL/100 g bw. Rats were fasted for ~22 hours prior to dosing. Following dosage, rats were provided commercial feed (e.g., Altromin R) and water ad libitum. 
-Animals were individually caged and maintained at a temperature of 21-23 °C and relative humidity of 55-65%. Animals were observed daily for signs of systemic toxicity and mortality over a 12-day observation  period, and were necropsied following death or the end of the observation period (whichever was longer).
Statistics:
LD50 values calculated using the Litchfield and Wilcoxon method (1949)

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
- There was no mortality at the following doses: 0.5, 1.0, and 2.0 g/kg bw.
- 10% mortality was observed at the 1.4 g/kg dose, 70% at 2.8 g/kg, and 100% at the highest dose of 4.0 g/kg bw. Animals died 1-10 days after dose administration.

MORTALITY (number of dead/number of animals tested):
0.5 g/kg bw: Males, 0/5; Females, 0/5
1.0 g/kg bw: Males, 0/5; Females, 0/5
1.4 g/kg bw: Males, 0/5; Females, 1/5 (@ Day 10)
2.0 g/kg bw: Males, 0/5; Females, 0/5
2.8 g/kg bw: Males, 3/5; Females, 4/5
4.0 g/kg bw: Males, 5/5; Females, 5/5
Animals in the 2.8 and 4.0 g/kg bw dose groups died 24-48 hours following dosing.
Clinical signs:
Apathy was reported as a typical clinical sign after administration.
Signs of systemic toxicity were observed at >= the 1.4 g/kg bw dose level  and included apathy, cachexia, and mortality.  
Body weight:
No data on body weight changes.
Gross pathology:
- Animals that died: Bleeding and erosion in the gastrointestinal tract, bleeding in the pancreas, focal necrosis in the liver, kidneys, and pancreas, bloody infiltration of the mesenteric lymph nodes.
- Observations on gross necropsy included hyperemia, emphysema and lung lesions, hemorrhagic  erosion/high grade bleeding of the mucosal (stomach) glands, swelling and bloody infiltration of mesenteric lymph nodes, extensive intestinal and pancreatic bleeding, and necrosis in liver and kidneys. No abnormalities were recorded for males in the 1.0, 1.4, and 2.0 g/kg bw dose levels and only one abnormality (medium grade testicular atrophy) in  the 0.5 g/kg dose. No abnormalities were recorded for females in the 0.5, 1.0, and 2.0 g/kg bw dose levels and only one abnormality (wine-red  mucus in stomach/small intestine) in the 1.4 g/kg dose.
- Animals that were sacrificed at the end of the observation period: Unremarkable findings

Applicant's summary and conclusion

Interpretation of results:
other: Not classified in accordance with EU criteria
Conclusions:
The oral LD50 for the test material in rats is reported as 2.2 g/kg bw, confidence limits (1.9-2.7 g/kg bw). However, the volumes of dosage administration were large (up to 4 mL/100 g). Hence, LD50 should be reported as >2 g/kg bw (>2000 mg/kg bw).
Executive summary:

A study was conducted in male and female Wistar rats to investigate the oral LD50 for the test material.

The animals were administered the test material orally as a 10 % emulsion in distilled water. Six doses were used: 0.5, 1.0, 1.4, 2.0, 2.8, and 4.0 g/kg body weight. After treatment the animals were observed for 12 days for clinical signs and mortality. Necropsy of all animals were performed at death or at the end of the observation period.

The method of Litchfield and Wilcoxon was used to calculate the LD50 which was reported as 2.2 g/kg body weight. The confidence limits were reported as 1.9 -2.7 g/kg body weight. Necropsy findings in animals that died were reported as bleeding and erosion in the gastrointestinal tract, bleeding in the pancreas, focal necrosis in the liver, kidney, and pancreas, and bloody infiltration of the mesenteric lymph nodes. Lethality appears to be the result of portal-of-entry corrosive effects rather than intrisic acute toxicity. The necropsy findings in the animals that survived the 12-day observation period were reported as unremarkable.

The oral LD50 for the test material in rats is reported as 2.2 g/kg bw, confidence limits (1.9-2.7 g/kg bw). However, the volumes of dosage administration were large (up to 4 mL/100 g). Hence, LD50 should be reported as >2 g/kg bw (>2000 mg/kg bw).