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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study published in a peer-reviewed journal. Performed before GLP and OECD guidelines were introduced. Experimental details documented, but no data on housing, no individual animal records (body weight, food consumption, mortality, etc.). Maximum dose (200 mg/kg bw) too low for limit test. Sufficient numbers of animals (10 M, 10 F per dose), hematology and histology performed, but not reported in detail. Death rates similar in all dose groups, all deaths attributed to faulty (intratracheal) administration, on the basis of necropsy findings.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Pharmacological and toxicological studies on salicylamide
Author:
Ichniowski CT & Hueper WC
Year:
1946
Bibliographic source:
J. Am. Pharm. Assoc. Sci. Ed., 1946, 35, 225-230

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Gavage application 13 weeks, 5 times/week, post mortem examination, hematology and histopathology in some animals, recovery time 3-7 weeks in some animals. No control group; application only five days per week; no data on acclimatization and housing; only summary data on weight development, rudimentary clinical laboratory data; high losses due to intratracheal application.
GLP compliance:
no
Remarks:
GLP not available at study time
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Substance type: Pure test substance
- Physical state: Solid; yellowish white crystalline powder
- Melting Point: 138°
- Taste: Practically tasteless

Test animals

Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Weight at study initiation: 100 - 130 g
- Fasting period before study: no
- Housing, diet, water, acclimation period: no data

ENVIRONMENTAL CONDITIONS
- no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% gum tragacanth in water
Details on oral exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): stability of test substance, tolerability of vehicle (confounding effect of alcohols)
- Concentration in vehicle: depending on dose
- Amount of vehicle (if gavage): 10 or 20 ml/kg bw
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 times per week, totally 67 doses
Doses / concentrations
Remarks:
Doses / Concentrations:
5, 25, 50, 100, and 200 mg/kg bw
Basis:
other: applied by gavage
No. of animals per sex per dose:
10 males, 10 females
Control animals:
no
Details on study design:
- Dose selection rationale: 1, 5, 10, 20, and 40 times average human adult dose
- Rationale for animal assignment (if not random): no data
- Rationale for selecting satellite groups: Some animals sacrificed at end of treatment, for hematologic studies; others injected with 4% formaldehyde for histologic examination, 3 - 7 weeks after cessation of treatment
- Post-exposure recovery period in satellite groups: 3 - 7 weeks
- Section schedule rationale (if not random): no data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes, but no results reported
- Time schedule: no data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes, but only summary findings reported
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption: No data
- Compound intake: total: 70 mg - 13400 mg / animal, calculated from gavage amounts

FOOD EFFICIENCY:
- No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: sacrifice at end of treatment
- Anaesthetic used for blood collection: No
- Animals fasted: No data
- How many animals: 19 (allocation to dose groups not stated)
- Parameters checked: prothrombin time, coagulation time, hemoglobin, erythrocyte count, leukocyte count (differential count in case of abnormal numbers)

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- post-mortem examination on all animals dying on test or sacrificed afterward

HISTOPATHOLOGY: Yes
- 46 treated surviving animals (allocation to dose groups unclear)

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
Significant, but fully attributed to technical accidents (intratracheal application), not related to test substance
Mortality:
no mortality observed
Description (incidence):
Significant, but fully attributed to technical accidents (intratracheal application), not related to test substance
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Weights: steady increased steadily. No dose effect. Male weight range 200-310 g at end of treatment (EOT), 240-370 g 4 weeks later. Female weight range 160-205 g at EOT, 185-235 g 4 weeks later.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Prothrombin times normal (29.26 - 36.55 sec); coagulation times relatively high (5-7 min); erythrocytes+hemoglobin: lower normal range. Leucocytes: wide range (300-5300 in 3 animals, >10000 in 2 animals), no influence on differential count
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Hyperemic hemorrhagic lungs, seropurulent pleurisy, pericarditis in animals dying - fully attributed to accidental intratracheal administration. No significant abnormal changes in rats necropsied at EOT.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No significant abnormal changes upon microscopical examination of internal organs at any dose.
Histopathological findings: neoplastic:
no effects observed

Effect levels

Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Maximum dose administered
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
No significant changes were observed at any dose, including the maximum. Non-guideline study, not considered to be reliable.