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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well performed GLP and OECD Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report date:
1993

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
p-aminobenzamide
EC Number:
220-612-3
EC Name:
p-aminobenzamide
Cas Number:
2835-68-9
Molecular formula:
C7H8N2O
IUPAC Name:
4-aminobenzamide

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- WISKf (SPF71)
- Source: Hoechst AG, breeding colony
- Age at study initiation: Approximately 6 weeks
- Weight at study initiation: 110 - 123 g (male); 99 - 125 g (female)
- Fasting period before study: none
- Housing: group housing of 5 animals per sex in Macrolon cages type 4 on soft wood granulate
- Diet (e.g. ad libitum): rat diet Altromin 1324, ad libitum
- Water (e.g. ad libitum): tap water in plastic bottles, ad libitum
- Acclimation period: approx. 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.0 ± 3.0°C
- Humidity (%):30-70%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: sesame oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Formulations (w/v) 0.48, 2.4 and 12.0 % were prepared daily immediately before treatment; the test item was suspended homogenously in the vehicle by means of magnetic stirrer. 5 mL/kg bw were administered.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Test substance formulations in sesame oil were noted as stable for at least 4 hours and formed a homogeneous suspension at the concentrations tested. Analysis of the accuracy of dose preparations revealed mean values within the range of about 84-103 % of nominal, which was considered to represent an acceptable level of accuracy for formulations of this type.
Duration of treatment / exposure:
28 days treatment
Frequency of treatment:
28 applications within 29 days, 7 days/week; application between 7.00 and 12.00 a.m.. Animals were dosed up to the day prior to necropsy.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
24 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
120 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
600 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
5 (with 5 additional animals/sex in the control group)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: in a preliminary study groups of 3 male and 3 female rats received the test item by oral gavage at dose levels of 500 or 1000 mg/kg bw per day over a period of 14 days. in the high dose group, the animals showed unspecific symptoms, impairments of motility and breathing, pale skin and closed palpebral fissures. Development of body weight was impaired. Dark discoloration of the spleen was observed at necropsy.
One animal treted with 500 mg/kg bw per day showed unspecific symptoms, impairment of motility and breathing after 14 days as well as impaired body weight development. The caecum was filled with gas at necropsy. Neither symptoms nor macroscopically visible changes were observed in the other animals.
Based on these results the test substance was tested at the dose levels of 0, 24, 120 and 600 mg/kg bw per day.
Positive control:
not applicable

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations included: mortality, viability
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: at the start of the study and then twice weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: twice weekly
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study):
- Time schedule for examinations: once weekly over a period of 16 h, results given as water consumption/animal/16 h
OPHTHALMOSCOPIC EXAMINATION: opacity of the refracting media of the eyes
HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of treatment
- Anaesthetic used for blood collection: Yes (Ketanest (R))
- Animals fasted: No
- How many animals: 40 (end of treatment)
- Parameters examined: Erythrocyte count, Hemoglobin, Hematocrit, mean cellular volume (MCV), mean cellular hemoglobin (MCH), mean cellular hemoglobin conc. (MCHC), Leucocyte count, Thrombocyte count, differential leucocyte count and red cell morphology, Reticulocyte count, Heinz bodies, coagulation time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of treatment
- Animals fasted: No
- How many animals: 40 (end of treatment)
- Parameters examined: Alanine aminotransferase, Aspartate aminotransferase, Alkaline phosphatase, Total Protein, Albumin, Total Bilirubin, Urea nitrogen, Creatinine, Glucose, Cholesterol, Triglyderides, Sodium, Potassium, Chloride, Calcium, Inorganic Phosphorus, Uric acid, Bilirubin total, Bilirubin direct
URINALYSIS: Yes
- Time schedule for collection of blood: end of treatment
- Animals fasted: Yes
- How many animals: 40 (urine collected overnight from day 26 to 27)
- Parameters examined: Appearance, Volume, Colour, Specific gravity, pH, Protein, Hemoglobin, Glucose, Ketone, Bilirubin, Urobilinogen, Sediment
NEUROBEHAVIOURAL EXAMINATION: Yes
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. All animals were necropsied and descriptions of all macroscopic abnormalities recorded.

The following organ weights (and terminal body weight) were recorded from the animals on the scheduled day of necropsy: Heart, lung, liver, kidneys, spleen, ovaries, testes, epididymides, adrenals, brain, thymus

HISTOPATHOLOGY: the following tissues or organs (or pieces of them) were preserved in a suitable fixative and processed for histopathological investigations: heart, liver, kidneys, adrenals, spleen, lung, brain, thymus, ovaries, testes, epididymides, trachea, stomach, jejunum, colon, urinary bladder, uterus, prostata, seminal vesicles, skeletal muscle, N. ischiadicus, femur with bone marrow, spinal cord, lymph nodes, throid glands (high dose group)
Other examinations:
None

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
both sexes in high dose group
Mortality:
mortality observed, treatment-related
Description (incidence):
both sexes in high dose group
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
both sexes in high dose group
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
both sexes in high dose group
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
both sexes in high dose group
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
both sexes in high dose group
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
both sexes in high dose group
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
both sexes in high dose group
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
both sexes in high dose group
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
both sexes in high dose group

Effect levels

Dose descriptor:
NOAEL
Effect level:
>= 120 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No test item related effects were observed in male and female rats after repeated application of 120 mg/kg bw per day.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

Groups of 5 male and 5 female Wistar rats received the test item by oral gavage at dose levels of 0, 24, 120 and 600 mg/kg bw per day for 28 days and were necropsied at day 29.

Behaviour and state of health were observed daily in all groups. Body weights and food consumption were recorded twice weekly, water consumption once weekly.

Hematological examinations and clinical chemistry were carried out at the termination of the study. Urine analysis was also performed at the end of the study.

No compound-related effects were observed in male and female Wistar rats after repeated application of 120 mg/kg bw. With regard to the present study the no observed effect level is 120 mg/kg bw per day.