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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2 Jan 2008 to 31 Jan 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report Date:
2008

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Tritolyl Phosphite (BU), tri(methylphenyl) phosphite
- Description: amber liquid
- Stability under test conditions: Stable under storage conditions
- Storage condition of test material: Room temperature (range of 20 ± 5 °C), light
protected.

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd Laboratory Animal Services, Füllinsdorf, Switzerland
- Age at study initiation: 11 weeks at start of exposure
- Fasting period before study: 17 -18 h (free access to water)
- Housing: groups of 3 animals in Makrolon cages
- Diet (ad libitum): Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 65/07 (Provimi Kliba AG, Kaiseraugst, Switzerland)
- Water (ad libitum): Community tap water from Füllinsdorf

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 /12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle:0.2 g/mL or 0.03g/mL
- Justification for choice of vehicle: The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date. This formulation trial is excluded from the statement of compliance.
- Lot/batch no. (if required): 27572782, Roth GmbH & Co., Karlsruhe, Germany

MAXIMUM DOSE VOLUME APPLIED: dosing volume 10 mL/kg bw
Doses:
0, 300 and 2000 mg/ kg bw
No. of animals per sex per dose:
3 females per group
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing:
Mortality / Viability: Daily during the acclimatization period, during the first 30
minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.
Clinical Signs: Daily during the acclimatization period, during the first 30
minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. All abnormalities were recorded.
Body Weights: On test days 1 (prior to administration), 8 and 15.
- Necropsy of survivors performed: yes
All animals which had to be sacrificed for ethical reasons were necropsied as soon as they were killed by an intraperitoneal injection of Pentobarbitone at a dose of at least 2.0 mL/kg body weight (324 mg sodium pentobarbitone/kg body weight).
All surviving animals were killed at the end of the observation period by carbon dioxide asphyxiation and discarded after macroscopic examinations were performed. No organs or tissues were retained.
Statistics:
No statistical analysis was used

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
The three females of the group treated at 2000 mg/kg had to be killed for ethical reasons 1.5 or 3 hours after dosing. The animals treated at 300 mg/kg survived until the end of observation time.
Clinical signs:
The females of the first group treated at 2000 mg/kg were found slightly to moderately sedated 1 hour after dosing. Additionally, one female (No. 1) showed slightly ruffled fur, moderate to marked tremor and lateral recumbency before it had to be humanely sacrificed for ethical reasons approximately 1.5 hours post treatment. Two hours after treatment the remaining two females were observed moderately sedated, with a hunched posture, moderately ruffled fur and slight tremor. The severity of tremor increased to marked at the 3-hour observation and additionally lateral recumbency was noted. Both animals had to be killed in extremis at this last observation.
One or two hours after treatment, the females of the second group treated at 300 mg/kg were found to express a slightly ruffled fur as well as a slight sedation. These symptoms persisted up to the 3- or 5-hour reading. All animals were free of clinical signs from test day 2 up to test day 15, the end of observation time.
No clinical signs were observed in the females of the third group treated at 300 mg/kg.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
The three females treated at 2000 mg/kg were found with a distended stomach and liquid contents in the duodenum, jejunum and ileum. Female nos. 2 and 3 were additionally found with discolorated kidneys (tan) at necropsy. Otherwise, no macroscopic findings were recorded at necropsy.

Applicant's summary and conclusion

Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The median lethal dose of the test item after single oral administration to female rats, observed over a period of 14 days is:
LD50 (female rat): 300 mg/kg bw < LD50 < 2000 mg/kg bw
Executive summary:

Three groups, each of three female Wistar rats, were treated with the test item by oral gavage administration at a dosage of 2000 mg/kg or 300 mg/kg bw. The test item was diluted in vehicle (com oil) at a concentration of 0.2 g/mL or 0.03 g/mL and administered at a dosing volume of 10 mL/kg.

The three females of the first group treated at 2000 mg/kg had to be killed for ethical reasons 1.5 or 3 hours after dosing. The animals of the second and third groups treated at 300 mg/kg bw survived until the end of the study period. The females of the first group treated at 2000 mg/kg were found slightly to moderately sedated 1 hour after dosing. Additionally, one female showed slightly ruffled fur, moderate to marked tremor and lateral recumbency before it had to be humanely sacrificed for ethical reasons approximately 1.5 hours post tretament. Two hours after treatment the remaining two females were observed moderately sedated, with a hunched posture, moderately ruffled fur and slight tremor. The severity of tremor increased to marked at the 3-hour observation and additionally lateral recumbency was noted. Both animals had to be killed in extremis at this last observation.One or two hours after treatment, the females of the second group treated at 300 mg/kg were found to express a slightly ruffled fur as well as a slight sedation. These symptoms persisted up to the 3- or 5-hour reading. All animals were free of clinical signs from test day 2 up to test day 15, the end of observation time.

No clinical signs were observed in the females of the third treated group treated at 300 mg/kg.The body weight of the animals was within the range commonly recorded for this strain and age. The three females treated at 2000 mg/kg were found with a distended stomach and liquid contents in the duodenum, jejunum and ileum. Female nos. 2 and 3 were additionally found with discolorated kidneys (tan) at necropsy. Otherwise, no macroscopic findings were recorded at necropsy.

The median lethal dose of the test item after single oral administration to female rats,observed over a period of 14 days is:

LD50 (female rat): 300 mg/kg bw < LD50 > 2000 mg/kg bw