Phenothiazine

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Jan. 1977 to Feb. 1977

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well performed study prior to GLP meeting scientific principles and similar to previous OECD TG.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1977

Report date:

1977

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: As outlined in "Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics" by the staff of the Division of Pharmacology, Food and Drug Administration, Department of Health, Education and Welfare, pages 17-25

Deviations:

not specified

GLP compliance:

no

Remarks:

Prior to GLP

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Phenothiazine

EC Number:

202-196-5

EC Name:

Phenothiazine

Cas Number:

92-84-2

Molecular formula:

C12H9NS

IUPAC Name:

10H-phenothiazine

Details on test material:

- Name: Phenothiazine Purified
- Lot No. NB-36-145
- Phenothiazine Content 99.8%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Albino rats (Sprague Dawley strain) obtained fromSasco, Inc., Omaha, Nebraska. (U.S.D.A. License No. 47-A-B-98).
- Animals were 40-50 days of age.
- Animals are examined upon receipt to check for any apparent abnormal condition.
- Any animal which did not appear to be normal was discarded.
- Animals were then transferred to individual cages in a temperature controlled room where they acclimated for seven days prior to initiation of the study.
- Animals werde maintained in individual cages throughout the study period.
- Purina Rat Chow and clean water was provided for each animal on an ad libitum basis throughout the study period except that they are fasted twenty-four hours prior to administration of the test compounds.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

cotton seed oil

Doses:

- Dose-range-findings study: 2000 - 3170 - 5024 - 7964 - 12623 - (1257 - 1992) mg/kg
- Main study: Five Dose Level Study (0.1 log intervals) 600 - 755 - 951 - 1197 - 1508 mg/kg

No. of animals per sex per dose:

1 male and 1 female in range-finding-study (1257 mg/kg in 1 male - 1992 mg/kg in 1 female)
5 males and 5 females per dose in main study

Control animals:

no

Details on study design:

Duration of observation period following administration:
- 14 days

Frequency of observations and weighing:
- Each animal was observed by trained technicians at approx. two hour intervals during the first working day following adminstration of the test compound.
- Thereafter, observations were made two or three times each day for the remainder of the study.
- Animals were observed for any visual sign of weakness, abnormal breathing or abnormal body movement.
- Further, if animals appeared unconscious, they were removed from their cage, checked for any abdominal distention, oral and anal areas were examined for any change and they were tested for response to stimulus (noise and prodding)

Statistics:

- Method of Litchfield-Wilcoxon was applied

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 370 mg/kg bw

95% CL:

> 1 223 - <= 1 534

Mortality:

Please see table "Mortalitiy Data of Main Study" in section "Remarks on results including tables and figures" below

Clinical signs:

other: Please see section "Remarks on results including tables and figures" below for details.

Gross pathology:

Data only on dose-range finding study, please see section "Remarks on results including tables and figures" below for details. No gross pathology performed in main study due to the results of the dose-range-finding-study.

Other findings:

Please see section "Remarks on results including tables and figures" below for details.

Any other information on results incl. tables

RESULTS OF MAIN STUDY

Animals in treatment groups 600, 755 and 951 mg/kg were slightly weak through the first eight hours following intubation. Animals in treatment groups 1197 and 1508 mg/kg were semi-conscious through the first eight hours. Animals in the lowest dosage groups which survived were weak through the first six or seven days of the study before returning to normal. Animals in the two highest dosage groups, which survived, remained weak throughout the fourteen day study period. All animals had varying degrees of diarrhoea.

Table: Mortality Data of Main Study

Rat No. and Sex	Dosage mg/kg	Mortality
5 male and 5 female	600	1 male found dead the morning of 6th study day
5 male and 5 female	755	1 male found dead the morning of 3rd study day
5 male and 5 female	951	1 female found dead the morning of 2nd study day
5 male and 5 female	1197	1 male found dead the morning of 3rd study day and  1 male found dead the morning of 4th study day
5 male and 5 female	1508	1 male and 1 female  found dead the morning of 2nd study day;  1 male and 1 female  found dead the morning of 3rd study day;  1 male and 1 female  found dead the morning of 4th study day

RESULTS OF DOSE-RANGE-FINDING-STUDY

Within one hour after intubation all animals were semi-conscious. Breathing appeared to be normal. Faecal material indicated the animals had some diarrhoea. Post mortem examination revealed all organs to be normal in size and color except for the stomach. The stomach was filled with the test material and the blood vessels of the intestinal tract appeared to be injected. All animals treated died, except for the single male rat which was tested at a dose of 1257 mg/kg body weight.

Applicant's summary and conclusion

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on the data obtained and under the conditions this study was conducted, the LD50 of Phenothiazine Purified (Lot No. NB 36-145) is 1370 mg per kilogram body weight as calculated by Litchfield-Wilcoxon Statistical Method. The 95% confidence interval is 1223 to 1534 mg per Kg.

Executive summary:

Acute oral toxicity of phenothiazine was assessed in the present study. Animals in treatment groups 600, 755 and 951 mg/kg were slightly weak through the first eight hours following intubation. Animals in treatment groups 1197 and 1508 mg/kg were semi-conscious through the first eight hours. Animals in the lowest dosage groups which survived were weak through the first six or seven days of the study before returning to normal. Animals in the two highest dosage groups, which survived, remained weak throughout the fourteen day study period. All animals had varying degrees of diarrhoea.

Based on the data obtained and under the conditions this study was conducted, the LD50 of Phenothiazine Purified (Lot No. NB 36-145) is 1370 mg per kilogram body weight as calculated by Litchfield-Wilcoxon Statistical Method. The 95% confidence interval is 1223 to 1534 mg per kg. Classification according to 67/548/EEC phenothiazine is harmful, classification according to Regulation (EC) 1272/2008 would be Acute Toxicity Category 4 with H302.