Paracetamol

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

The substance Paracetamol was found to be non-genotoxic.

Link to relevant study records

Reference

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

STANDARD PLATE : Several modifications of the Ames test protocol have been used over the years in special circumstances. These include standard plate incorporation (no preincubation step prior to plating onto Petri dishes)

GLP compliance:

not specified

Type of assay:

bacterial reverse mutation assay

Species / strain / cell type:

S. typhimurium TA 98

Additional strain / cell type characteristics:

not specified

Species / strain / cell type:

S. typhimurium TA 100

Additional strain / cell type characteristics:

not applicable

Species / strain / cell type:

S. typhimurium TA 1535

Additional strain / cell type characteristics:

not specified

Species / strain / cell type:

S. typhimurium TA 1537

Additional strain / cell type characteristics:

not specified

Species / strain / cell type:

S. typhimurium TA 1538

Additional strain / cell type characteristics:

not specified

Species / strain / cell type:

S. typhimurium TA 97

Additional strain / cell type characteristics:

not specified

Metabolic activation:

with and without

Metabolic activation system:

With RAT, LIVER, S-9, AROCLOR 1254

Test concentrations with justification for top dose:

0.1-50 μg/Plate

Vehicle / solvent:

Dimethyl Sulfoxide

Untreated negative controls:

not specified

Negative solvent / vehicle controls:

yes

Remarks:

Dimethyl Sulfoxide

True negative controls:

not specified

Positive controls:

yes

Positive control substance:

other: 2-aminoanthracene

Remarks:

For strains tested with S9

Untreated negative controls:

not specified

Negative solvent / vehicle controls:

yes

Remarks:

Dimethyl Sulfoxide

True negative controls:

not specified

Positive controls:

yes

Positive control substance:

sodium azide

Remarks:

For strains TA100 and TA1535, tested in the absence of S9

Untreated negative controls:

not specified

Negative solvent / vehicle controls:

yes

Remarks:

Dimethyl Sulfoxide

True negative controls:

not specified

Positive controls:

yes

Positive control substance:

other: 4-nitro-o-phenylenediamine

Remarks:

For strains TA98 and TA1538,tested in the absence of S9

Untreated negative controls:

not specified

Negative solvent / vehicle controls:

yes

True negative controls:

not specified

Positive controls:

yes

Positive control substance:

9-aminoacridine

Remarks:

For strains  TA97 and TA1537,tested in the absence of S9

Species / strain:

S. typhimurium TA 98

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Species / strain:

S. typhimurium TA 100

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Species / strain:

S. typhimurium TA 1535

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Species / strain:

S. typhimurium TA 1537

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Species / strain:

S. typhimurium TA 1538

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Species / strain:

S. typhimurium TA 97

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Conclusions:

Paracetamol was tested for mutagenicity in the Salmonella/mammalian microsome assay. Six testor strains were used (TA1535, TA1537, TA1538, TA100, TA97 and TA98) and experiments were conducted in the presence and absence of a rat liver microsome activation system. Paracetamol did not show any evidence of mutagenic activity at concentrations ranging from 0.1 to 50 μg/Plate.

Executive summary:

Paracetamol was tested for mutagenicity in the Salmonella/mammalian microsome assay. Six testor strains were used (TA1535, TA1537, TA1538, TA100, TA97 and TA98) and experiments were conducted in the presence and absence of a rat liver microsome activation system. Paracetamol did not show any evidence of mutagenic activity at concentrations ranging from 0.1 to 50 μg/Plate.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vitro:

Varies studies available for Paracetamol mutagenecity were reviewed for from reliable sources having Klimisch rating 2 and th esummaries are presented below.

Genotoxicity invitro

Haworth et.al (Study ID : 413793NTP report)reported paracetamol to be non toxic when tested on salmonella strains following Ames test at concentrations ranging from 100-10000 µg/Plate with and without metabolic activation.

Another study in journal ENVIRON MUTAGEN 3:627-638,1981 also reported paracetamol to be non genotoxic in human lymphocytes for DNA damage.

 

Based on the prediction of QSAR prediction model 3.1 version for chromosome aberration test on Chinese hamster Lung (CHL) with S9 metabolic activation it was estimated that paracetamol does not exhibit positive chromosomal effect. 

NATIONAL TOXICOLOGY PROGRAM Technical Report Series No. 394 1993 also predicted the test chemical to be non toxic Salmonella typhimurium strains TAloo, TA1535, TA1537, and TA98 at concentrations of 100 to 10,000 µg/plate with a preincubation protocol in the presence and the absence of Aroclor 1254-induced male Sprague-Dawley rat or Syrian hamster liver S9.

Based on the above observations paracetamol is not classified as genotoxic.

Genetic toxicity Invivo-

As reported by Ph. Hantson et.al (Mutation Research 368 (1996) 293-300)Taking into account that the positive results which are barely significant and the much higher doses used in our study, we can, therefore, confirm that it is highly unlikely that paracetamol can produce chromosome aberrations in vivo in man and that "there is no unacceptable (if any) mutagenic/carcinogenic risk associated with a sensible use of paracetamol as an analgesic agent.

M -T King, conducted a study   according to which 4- hydroxyacetanilide did not induce sex-linked recessive lethal mutations (SLRL) in Drosophila melanogaster and is negative for gene mutation in vivo. neither induce an increase in the micronuclei in NMRI mice and is negative for gene mutation in vivo in an intraperitoneal application.

Same study reorted 4- hydroxyacetanilide did not induce an increase in the micronuclei in NMR1 mice and is negative for gene mutation in vivo by oral exposure.

The study reported by M -T King et.al( Mutation Research, 66 (1979) 33-43) indicated 4-hydroxyacetanilide failed to induce mutation in theSalmonella typhimuriumstrains TA1535, TA100, TA1538, TA98 and TA1537 and is negative for gene mutation in vitro.

 

 

By applying weight of evidence approach to the target substance Paracetamol , it can be concluded that the substance is non-genotoxic.

Gene toxicity invivo-

As per the study given by Ph. Hantson (Mutation Research 368 (1996) 293-300) Taking into account that the positive results which are barely significant and the much higher doses used in our study, we can, therefore, confirm that it is highly unlikely that paracetamol can produce chromosome aberrations in vivo in man and that "there is no unacceptable (if any) mutagenic/carcinogenic risk associated with a sensible use of paracetamol as an analgesic agent.

4- hydroxyacetanilide did not induce an increase in the micronuclei in NMR1 mice and is negative for gene mutation in vivo by oral exposure.

Justification for selection of genetic toxicity endpoint

In an Ames test , Paracetamol , in dimethyl sulfoxide from doses 100-10000 µg/Plate was not mutagenic in Salmonella typhimurium strains TA100,TA1535,TA1537 and TA98  with and without addition of S9 liver fractions from Aroclor induced hamsters. The same has been observed for rats as well.

Justification for classification or non-classification

Paracetamol shows negative activity as is the case for chromosome abberation for the same substance.