Registration Dossier

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

As far as in vitro studies, the substance is a potential mutagen and further in vivo testing is necessary.

Link to relevant study records

Referenceopen allclose all

Endpoint:
in vitro gene mutation study in bacteria
Remarks:
Type of genotoxicity: genome mutation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1 Feb 1975 - 28 Feb 1978
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
GLP compliance:
no
Remarks:
The studies were conducted in 1978, before implemenation of OECD Guidelines (1981) and EU Guidelines (1988) as well as GLP principles. The studies were probably conducted according to TSCA guidelines.
Type of assay:
in vitro mammalian cell transformation assay
Species / strain / cell type:
S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
Details on mammalian cell type (if applicable):
The S-9 fraction from rat liver prepared according to the procedure of Ames Test.
Test concentrations with justification for top dose:
1000, 300, 100, 30 and 10 ug/plate (0.1 ml)
Details on test system and experimental conditions:
all strains/cell types tested
Species / strain:
S. typhimurium, other: TA-98, TA-1538 and TA-1537
Metabolic activation:
not specified
Genotoxicity:
ambiguous
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
True negative controls validity:
not specified
Positive controls validity:
not specified
Remarks on result:
other: Potential mutagen.

TNT exhibited significant increase in the number of revertants at 10 and 30 ug/plate.It produced both base-pair substitution and frame-shift mutations. As little as 10 ug/plate of TNT was mutagenic in the TA-98, TA-1538 and TA-1537 strains. When 30 ug/plate were used, TNT was positive in four test strains; at 300 ug/plate, TNT was positive in all five tester strains.

Conclusion: Potential mutagen.

Conclusions:
Potential mutagen. Further testing is necessary.
Endpoint:
in vitro gene mutation study in bacteria
Remarks:
Type of genotoxicity: gene mutation
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 471 (Bacterial Reverse Mutation Assay)
Qualifier:
according to guideline
Guideline:
EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
GLP compliance:
yes
Type of assay:
bacterial reverse mutation assay
Species / strain / cell type:
S. typhimurium TA 98
Species / strain / cell type:
S. typhimurium TA 100
Metabolic activation:
with and without
Metabolic activation system:
S9
Test concentrations with justification for top dose:
Five dose levels of each compound were prepared.
Positive controls:
yes
Positive control substance:
sodium azide
Remarks:
for strain TA100
Positive controls:
yes
Positive control substance:
other: 2,4,7-trinitro-9-fluorenone
Remarks:
for strain TA98
Positive controls:
yes
Positive control substance:
benzo(a)pyrene
Remarks:
to check activity of the S9 in each series of tests with each bacterial strain.
Species / strain:
S. typhimurium TA 100
Metabolic activation:
with and without
Genotoxicity:
negative
Remarks:
no mutagenicity
Cytotoxicity / choice of top concentrations:
other: Cytotoxic for H4IIE cells and CHO cells.
Species / strain:
S. typhimurium TA 98
Metabolic activation:
with and without
Genotoxicity:
positive
Remarks:
slightly mutagenic
Cytotoxicity / choice of top concentrations:
other: Cytotoxic for H4IIE cells and CHO cells.

Not mutagenic in strain TA 100; slightly mutagenic in strain TA 98. Further testing is necessary.

Conclusions:
Not mutagenic in strain TA 100; slightly mutagenic in strain TA 98. Further testing is necessary.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (positive)

Genetic toxicity in vivo

Description of key information

Negative response observed for TNT in the liver assay indicates that it is unlikely to be rat hepatocarcinogen.

Link to relevant study records
Reference
Endpoint:
in vivo mammalian cell study: DNA damage and/or repair
Remarks:
Type of genotoxicity: DNA damage and/or repair
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 486 (Unscheduled DNA Synthesis (UDS) Test with Mammalian Liver Cells in vivo)
Qualifier:
according to guideline
Guideline:
EU Method B.39 (Unscheduled DNA Synthesis (UDS) Test with Mammalian Liver Cells In Vivo)
GLP compliance:
yes
Type of assay:
unscheduled DNA synthesis
Species:
rat
Strain:
other: Alderley Park (AP) or Fischer 344 (F344)
Sex:
male
Route of administration:
oral: gavage
Duration of treatment / exposure:
12 hours
Frequency of treatment:
adminitered once
Remarks:
Doses / Concentrations:
100, 200, 500, 1000 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
2, 3 or 5 animals per dose
Control animals:
yes
Tissues and cell types examined:
Liver, blood.
Key result
Sex:
male
Genotoxicity:
negative
Toxicity:
no effects

TNT was inactive in each strain. Urine of the TNT-treated animals esd bright red due to the presence of TNT (in an acid medium) and their blood contained elevated levels of methaemoglobin. Nonetheless, hepatocyte, morphology was normal and showed no evidence of toxic picnosis.

Conclusions:
Interpretation of results (migrated information): negative
Negative response observed for TNT in the liver assay indicates that it is unlikely to be rat hepatocarcinogen. Nonetheless, high levels, of methaemoglobin were observed in the TNT-trerated rats and their urine was coloured red. These facts, together with the known toxicities of this agent suggest a possible carcinogenic hazard to the haemopoetic and urinary tissue of animals exposed chronically to it at toxic dose-levels.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vivo:

Justification for selection of genetic toxicity endpoint
In vivo study is supposed to be more relevant.

Justification for classification or non-classification

In vivo data available for TNT confirms negative response which is not sufficient for the classification of TNT as mutagenic.