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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:
January 2, 2008 through January 31, 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to test guidelines and in accordance with GLP.

Data source

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

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Tris(methylphenyl) phosphite
EC Number:
247-119-6
EC Name:
Tris(methylphenyl) phosphite
Cas Number:
25586-42-9
Molecular formula:
C21H21O3P
IUPAC Name:
tris(methylphenyl) phosphite
Details on test material:
- Name of test material (as cited in study report): Tritolyl Phosphite
- Physical state: Liquid; amber
- Analytical purity: 91.8% (GC)
- Impurities (identity and concentrations): 7.9-11.9% Bis(3-Tolyl)Phosphorochoridite CAS # 21719-86-8 and <0.5% Cresol CAS # 1319-77-3
- Lot/batch No.: 11237993-7079
- Expiration date of the lot/batch: Nov 23, 2008
- Storage condition of test material: Room temperature, light protected

Test animals

Species:
rat
Strain:
other: HanRcc:WIST (SPF)
Sex:
female
Details on test animals or test system and environmental conditions:
Animals were HanRcc:WIST (SPF) rats from RCC Ltd Laboratory Animal Services. There were 3 females per groups which were 11 weeks when treated. The animals were identified with a unique cage number and corresponding color-coded spots on the tail. The animals were maked at acclimatization start. Acclimatization was under laboratory conditions after health examination. Only animals without any visible signs of illness were used for the study. Animals were housed under standard laboratory conditions: air conditioned with 10-15 air changes per hour, and continuously monitored environment with ranges for room temperature 22 +/- 3C and for relative humidity between 30-70% (values above 70% during cleaning process), automatically controlled light cycle of 12 hours light and 12 hours dark, music during the daytime light period. Animals were in groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland). Fed pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 65/07 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad libitum. Animals drank commuity tap water from Fullinsdorf ad libitum.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Justification for choice of vehicle: vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date.
- Lot/batch no. (if required): 27572782
MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg body weight
DOSAGE PREPARATION (if unusual): Dose formulations were made shortly before each dosing occasion using a magnestic stirrer as homogenizer. The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume) Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.
CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: not given
Doses:
single dose of 300 mg/kg and 2000 mg/kg body weight after being fasted for approximately 17 to 18 hours (access to water was permitted).
No. of animals per sex per dose:
3 females per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality / viability observations were 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. Body weights recorded on test days 1 (prior to administration), 8 and 15. Clinical signs were observed 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.
- Necropsy of survivors performed: All animals which had to be sacrificed for ethical reasons were necropsied as sonn as they were killed. All surviving animals were killed at the end of the observation period by carbon dioxide asphyxiation abd discarded after macroscopic examinaitons 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
Mortality:
The three females of the first dosing 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 treatement the remianing 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 discolored kidneys (tan) at necropsy. Otherwise, no macroscopic findings were recorded at necropsy.

Any other information on results incl. tables

Table 1. Mortality / Clinical Signs

Dose

mg/kg bw

Animal No.

Sex

Signs

Test days

1

1

1

 

1

 

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0.5*

1*

2*

3*

5*

2000

1

F

No clinical signs

x

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Sedation

 

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Lateral recumbency

 

x

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tremor

 

2

3^K

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ruffled fur

 

1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2

F

No clinical signs

x

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Sedation

 

1

2

2K

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Lateral recumbency

 

 

 

x

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tremor

 

 

1

3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ruffled fur

 

1

2

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hunched posture

 

 

x

x

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

3

F

No clinical signs

x

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Sedation

 

1

2

2K

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Lateral recumbency

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Tremor

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ruffled fur

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Hunched posture

 

 

x

x

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

300

4

F

No clinical signs

x

x

 

 

 

x

x

x

x

x

x

x

x

x

x

x

x

x

x

Sedation

 

 

1

1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ruffled fur

 

 

1

1

1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

5

F

No clinical signs

x

 

 

 

 

x

x

x

x

x

x

x

x

x

x

x

x

x

x

Sedation

 

 

1

1

1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ruffled fur

 

 

1

1

1

1

 

 

 

 

 

 

 

 

 

 

 

 

 

6

F

No clinical signs

x

x

 

 

 

x

x

x

x

x

x

x

x

x

x

x

x

x

x

Sedation

 

 

1

1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Ruffled fur

 

 

1

1

1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

300

7

F

No clinical signs

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

8

F

No clinical signs

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

9

F

No clinical signs

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

Key: 1 slight, 2 moderate, 3 marked,Kkilled in extremis, x noted

* Examinations were performed within the first 30 minutes and 1, 2, 3 and 5 hours after treatment.

^The severity of tremor increased approx. 30 minutes after the 1 hour observation and the animal was killed.

 

 Table 2. Body Weights

  Dose mg/kg  Animal No.  Sex  Day 1 (treatment)  Day 8  Day 15 
  2000   F  194.1  -
  2000  F  183.0  -  -
  2000  F  185.6  -  -
  300  F  181.0  209.5  227.4
  300  F  195.4  223.6  236.6
  300  F 188.3   209.1  222.0
  300  F  195.9  207.5  220.2
  300  F  188.1  207.3  223.5
  300  9  F  190.5  215.7  227.9

Body weights are presented in grams.

 

Table 3. Macroscopic Findings

Dose mg/kg

Animal No.

Sex

Mode of death

Findings

2000

1

F

K

Stomach: distended

Duodenum: contents liquid

Jejunum: contents liquid

Ileum: contents liquid

2

F

K

Stomach: distended

Duodenum: contents liquid

Jejunum: contents liquid

Ileum: contents liquid

Kidneys: discoloration (tan)

3

F

K

Stomach: distended

Duodenum: contents liquid

Jejunum: contents liquid

Ileum: contents liquid

Kidneys: discoloration (tan)

300

4

F

S

No macroscopic findings

5

F

S

No macroscopic findings

6

F

S

No macroscopic findings

300

7

F

S

No macroscopic findings

8

F

S

No macroscopic findings

9

F

S

No macroscopic findings

S: scheduled necropsy, K: killed in extremis

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information
Conclusions:
The median lethal dose of Tritolyl Phosphite (BU) after single administration to female rats, observed over a period of 14 days is between 300 mg/kg body weight and 2000 mg/kg body weight.
Executive summary:

Three groups, each of three female HanRcc:WIST (SPF) rats, treated with Tritolyl Phosphite (BU) by oral gavage administration at a dosage of 2000 mg/kg or 300 mg/kg body weight. The test item was diluted in vehicle (corn 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 animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs within the first 30 minutes and approximately 1, 2, 3, and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3, and 5 hours after administration on test day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically. 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 group treated at 300 mg/kg 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 (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 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 discolored kidneys (tan) at necropsy. Otherwise, no macroscopic findings were recorded at necropsy. The median lethal dose of Tritolyl Phosphite (BU) after single administration to female rats, observed over a period of 14 days is: LD50 (female rat): 300 mg/kg body weight < LD50 (female rat) < 2000 mg/kg body weight.