Alkyl phosphites

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: GLP study, conducted in accordance with OECD guidelines. Some details on test material are missing.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1996

Report date:

1996

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

and EU Method B1 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Test animals

Species:

rat

Strain:

other: Crl:CD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Inc, Kingston Facility, Stone Ridge, NY
- Age at study initiation: Males 8 weeks, females 9 weeks.
- Weight at study initiation: Males 213 to 227 grams, Females 187 to 200 grams.
- Fasting period before study: Witheld over night.
- Housing: Single housed in suspended stainless steel wire mesh cages.
- Diet: ad libitum, PMI certified Rodent Diet Meal 5002.
- Water: ad libitum.
- Acclimation period: 7 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 22 °C
- Humidity (%): 40 to 70%
- Air changes (per hr): Not stated.
- Photoperiod (hrs dark / hrs light): 12 hours light (07:00 to 19:00) 12 hours dark (19:00 to 07:00)

IN-LIFE DATES: From: To: 1996-05-02 to 1996-05-16

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

VEHICLE: No vehicle used

MAXIMUM DOSE VOLUME APPLIED: 2.04 ml/kg (calculated by dividing the dose level (2 g/kg) by the density (0.98 g/ml). The dose volume was then multiplied by the body weight to arrive at the calculated dose.

Method of Administration: The test material was administered (Day 0, approximately 8:49 am) as a single oral intubation via syringe and a stainless steel, straight, ball tipped feeding needle.

Doses:

Limit Test: 2000 mg/kg

No. of animals per sex per dose:

5 animals per sex per dose.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing: Animals were examined for viability twice daily Monday through Friday, and once daily at weekends. Clinical observations made at 1, 2, 4 and 6 hours post dosing and then daily thereafter for a period of 14 days. Bodyweights were taken on the day prior to dosing, the day of dosing, day 7 and 14, and at death for animals that succumbed prior to study termination.
- Necropsy of survivors performed: yes, a gross necropsy which included an examination of the external surface of the body, all orifices, the cranial, thoracic, and abdominal cavities and their contents was performed on all animals. Tissues containing gross abnormalities were taken and preserved in 10% neutral buffered formalin.

Statistics:

Statistical analysis included means and standard deviations of body weight and body weight change by group and sex.

Results and discussion

Preliminary study:

A limit test was conducted at 2000 mg/kg bw. Results are presented below.

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Apparent treatment-related deaths were limited to one female found dead on Day 1. This female was observed with red oral discharge and rales on Day
0.

One male observed with dyspnea, rales and impaired use of it's foreleg was humanely scarificed on Day 0 after an apparent dosing accident. This death was not considered treatment related.

Clinical signs:

other: Decreased qualitative food consumption and/or stool abnormalities (no stool, soft stool or small amount of stool) were observed in all surviving animals primarily during the first week of the study. During this same period, anogenital staining and/or unth

Gross pathology:

At postmortem examination, all animals which survived to study termination had stomach abnormalities which included adhesion to the liver, diaphragm, spleen, kidney, and/or peritoneum; thickening; misshapen cardiac portion; discolored mucosa; and/or sloughing of the mucosa. Four animals also had thickened, enlarged, and/or discolored spleens.
 
Postmortem examination of the male euthanized on Day 0 indicated a dosing error. Observations included discolored adrenals, tears in the esophagus and trachea, displaced ingesta, and a detached scapula.
 
The female which was found dead on Day 0 had discolored lungs as well as stomach abnormalities and anogenital staining. The death was considered treatment-related.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

In conclusion, transient clinical signs were observed in all animals. Post mortem examination indicated obvious stomach irritation. Apparent treatment-related mortality was limited to one female found dead on Day 0. Based on the results of this study, the LD50 for the test material was greater than 2000 mg/kg (the limit dose) in male and female rats.

Executive summary:

The acute oral toxicity of the test material was evaluated when administered as a single dose via oral intubation at a dose level of 2000 mg/kg to 5 male and 5 female Crl:CDBR rats. Clinical observations were made 1, 2, 4 and 6 hours after dose administration and once daily for 14 days. Body weights were recorded for all animals the day prior to dosing, the day of dosing (Day 0), Day 7, and Day 14. on Day 14, surviving animals were sacrificed and gross necropsies were performed.

 

Apparent treatment-related deaths were limited to one female found dead on Day 0. This female was observed with red oral discharge and rales prior to death. Additionally, one male was humanely sacrificed on Day 0 after a gavage accident. This death was not considered treatment-related.

 

Decreased qualitative food consumption and/or stool abnormalities (no stool, soft stool or small amount of stool) were observed in all surviving animals primarily during the first week of the study. During this same period, anogenital staining and/or unthrifty coat was observed in 50% of the surviving animals. In addition, there were limited occurrences of hypoactivity (2 males on Days 1,2, and/or 3); rales (1 male on Days 0 and 1); slight emaciation (1 male on Days 4-6); and clear oral discharge (one female on Day 0). All signs were reversible by Day 10. All animals displayed increases in body weight over their initial values.

 

At postmortem examination, all animals which survived to study termination had findings in the stomach indicative of irritation from the test material. These findings included adhesion to the liver, diaphragm, spleen, kidney, and/or peritoneum; thickening; misshapen cardiac portion; discolored mucosa; and/or sloughing of the mucosa. Four animals also had thickened, enlarged, and/or discolored spleens. The female found dead also was observed with stomach abnormalities as well as anogenital staining and discolored lungs.

 

In conclusion, transient clinical signs were observed in all animals. Postmortem examination indicated obvious stomach irritation. Apparent treatment-related mortality was limited to one female found dead on Day 0. Based on the results of this study, the LD50 for the test substance was greater than 2000 mg/kg (the limit dose) in male and female rats.