Registration Dossier

Administrative data

Description of key information

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study with the longest duration and lowest NOAEL was chosen (key study).

Repeated dose toxicity: via oral route - systemic effects (target organ)cardiovascular / hematological: blood coagulation; digestive: liver; urogenital: testes

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
other: dietary admixture
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
TNT was administered as a dietary admixture, and the appropriate test diets were available ad libitum except during 17-19h fast prior to either blood collection in Test Week 13 or routine kill in Test Week 14.
Remarks:
Doses / Concentrations:
1, 5, 25, 125 or 300 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
Ten rats per sex received either 1, 5, 25, 125 or 300 mg/kg/day for 13 weeks. Thirty rats of each sex were included as untreated controls.
Control animals:
yes, concurrent no treatment
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 1 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
body weight and weight gain
food consumption and compound intake
gross pathology
haematology
Dose descriptor:
NOAEL
Effect level:
ca. 5 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
gross pathology
haematology
Critical effects observed:
not specified

Toxic effects following 125 mg/kg/day or greater included decrease food intake and body weight gain, elevated serum cholesterol levels, and anemia (reduced hemoglobin, hematocrit and RBC counts). Splenomegaly, hepatomegaly/hepatocytomegaly and testicular artrophy with degeneration of the seminiferous tubular epithelium were also seen at 125 and 300 mg/kg/day. Hemosiderin-laden macrophages, congestion of the splenic red pulp, methemoglobin production indicative of the bone marrow toxicity suggested hemolysis as the mechanism of anemia.

Conclusions:
The present study demonstrated that liver, testes and blood are the main target organs of TNT toxicity in the rats. Splenic lesions were also observed but were secondary to the hemolytic effect.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
1 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Klimisch rating 1.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

Taking into consideration harmonised classification, NOAEL values and the possible exposure to human the substance is classified as STOT RE 2, H373.