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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
disregarded due to major methodological deficiencies
Study period:
1977
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Relevant methodological deficiencies, and documentation insufficient for assessment.
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1977
Report Date:
1977
Reference Type:
review article or handbook
Title:
Unnamed
Year:
1988
Report Date:
1987

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
chronic toxicity test
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): tributylamine, not further specified

Test animals

Species:
rabbit
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
no data

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
6 months
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0.6 mg/kg bw/day (nominal)
Dose / conc.:
6 mg/kg bw/day (nominal)
No. of animals per sex per dose:
no data; presumably 8 per group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: 1/100 and 1/1000 of the acute oral LD50

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: no details

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: no details

BODY WEIGHT: Yes
- Time schedule for examinations: no details

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

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined:


HAEMATOLOGY: Yes
- Time schedule for collection of blood: monthly
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked: numbers of erythrocytes, leucocytes, reticulocytes, hemoglobin content, differential white blood cell counts

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: monthly
- Animals fasted: No data
- How many animals: No data
- Parameters checked: Alanine-aminotransferase, aspartate-aminotransferase, prothrombin activity

URINALYSIS: No data

OTHER: determination of immune reactivity (agglutinine titers) after immunisation with thypoid-parathyphoid vaccine, acivity of monoamine and diamine oxidases
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (stomach, small intestine, liver, heart, spleen)
HISTOPATHOLOGY: Yes (stomach, small intestine, liver, heart, spleen)
Statistics:
A nonparameteric method (Van Varden) and the t-Student-Fisher-test were used for statistical analysis

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
at 6 mg/kg bw/day decrease in the prothrombin activity starting at 3 months of dosing until the end of the study
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
at 6 mg/kg bw/day a decrease in the activity of the liver diamine oxidase activity, but not of monoamine oxidase activity, at termination after 6 months of dosing; a slightly reduced increase of the agglutinine titer after immunisation.
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
There were no statistically significant effects in the group at 0.6 mg/kg bw/day.

Findings and effects in the 6 mg/kg bw/day group:

CLINICAL CHEMISTRY:
Serum GOT: a single slightly elevated value observed after after 5 months (p<0.01) is regarded to be of no biological significance, because it was low and absent at month 6. There was no other difference compared to controls at any other reading.
Serum GPT: a single slightly elevated value observed after after 3 months (p<0.05) is regarded to be of no biological significance. There was no other difference compared to controls at any other reading.
Prothrombin activity: a statistically significant decrease (p<0.05) of the prothrombin activity after month 3 of exposure to end of study (58-66%) was reported.

GROSS PATHOLOGY
Water retention in the mucuos coat of the small intestine; Liver: fatty degeneration and focal necrotic changes reported.

HISTOPATHOLOGY: NON-NEOPLASTIC
Hypoplasia of white spleen pulp, red pulp with a large number of plasma cell; Liver: increased number of binuclear heptocytes, cellular and nuclear polymorphisms, round cell infiltration in peripheral liver lobules, infiltration of plasma cells, hypertrophic Kupffer cells

OTHER FINDINGS: delayed increase of agglutinine titer after immunisation with thypoid-parathyphoid vaccine at 14 days after immunisation (p<0.05), decreases in the activity of the diamine oxidase activity in the liver (p<0.05) at termination. No changes in liver monoamine oxidase activity noted..

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
0.61 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Dose descriptor:
LOAEL
Effect level:
6.1 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Study insufficient for assessment
Executive summary:

Rabbits (n=24) of unspecified strain and sex were assigned to three groups. The animals received tributylamine with the drinking water at nominal dose levels of 0, 0.6, and 6 mg/kg bw and day daily for 6 months. The study did not follow a guideline test protocol.

There were no effects with respect to general constitution, behaviour or mortality, or hematology in any of the animal groups.

 

Effects were reported to occur in the group at 6 mg/kg bw/day group, in terms of a decrease in the prothrombin activity starting at 3 months of dosing until the end of the study; a decrease in the activity of the liver diamine oxidase activity, but not of monoamine oxidase activity, at termination after 6 months of dosing; a slightly reduced increase of the agglutinine titer after immunisation. Regarding histopathology, a number of findings (water retention in the mucous coat of the small intestine mucosa; hypoplasia of the spleen white pulp as well as red pulp infiltration with plasma cell; fatty degeneration and focal necrotic changes in the liver) were briefly reported, but there is no documentation (tables, photographs) which would substantiate this or would allow a review and independent interpretation of the findings (Din Min, 1977).

 

Overall, there are severe methodological deficiencies. The animal number is low, only two dose levels were tested, the dose levels were too low to cause clear toxicity (the above mentioned effects were either small in size; or were single observations without biological relevance; or were observations without clearly representing an adverse effect), a limited number of parameters and tissues was examined. Finally, the documentation is too poor to substantiate the reported findings and an independent interpretation of the findings is therefore not possible.

 

The study was not conducted according to a test guideline or according to GLP.