2,4-dinitrophenol

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vivo

Description of key information

Mitra AB, Manna GK. 1971, the authors concluded that 2,4-DNP was clastogenic under the assay conditions and attributed the effect to the compound’s electrophilic properties.

Link to relevant study records

Reference

Endpoint:

in vivo mammalian germ cell study: cytogenicity / chromosome aberration

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data have been obtained from secondary source.

Principles of method if other than guideline:

The method is based on a chromosome aberration assay in vivo. An intraperitoneal injection of three saturated solution concentrations was made on mice. After 24 hours bone marrow cells were analyzed. No further details were specified.

GLP compliance:

no

Type of assay:

chromosome aberration assay

Species:

mouse

Strain:

not specified

Sex:

not specified

Route of administration:

intraperitoneal

Post exposure period:

Mice were sacrified 24 hours posttreatment for analysis of bone marrow cells.

Remarks:

Doses / Concentrations:
0.25 ml
Basis:
other: saturated solution

Remarks:

Doses / Concentrations:
0.5 ml
Basis:
other: saturated solution

Remarks:

Doses / Concentrations:
1 ml
Basis:
other: saturated solution

Tissues and cell types examined:

Bone marrow cells was observed for chromosomal aberration analysis.

Sex:

not specified

Genotoxicity:

positive

Toxicity:

not specified

The authors concluded that 2,4-DNP was clastogenic under the assay conditions and attributed the effect to the compound’s electrophilic properties.

However there was no linear relationship between the frequency of chromosome aberrations and the dose of 2,4-dinitrophenol.

Conclusions:

Interpretation of results (migrated information): positive
2,4-DNP was clastogenic under the assay conditions due to compound’s electrophilic properties. However there was no linear relationship between the frequency of chromosome aberrations and the dose of 2,4-dinitrophenol.

Executive summary:

Data have been obtained from secondary source that mentions Mitra AB, Manna GK. 1971. Effect of some phenolic compounds on chromosomes of bone marrow cells in mice. Indian J Med Res 59:1442-1447.

The method is based on a chromosome aberration assay in vivo. Mice were injected intraperitoneally with 0.25, 0.50, and 1 mL of a saturated solution of 2,4-DNP, then sacrificed 24 hours posttreatment for analysis of bone marrow cells for chromosomal aberrations . No further details were specified.

The authors concluded that 2,4-DNP was clastogenic under the assay conditions and attributed the effect to the compound’s electrophilic properties.

However there was no linear relationship between the frequency of chromosome aberrations and the dose of 2,4-dinitrophenol.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (positive)

Additional information

Additional information from genetic toxicity in vivo:

Prokaryotic organisms: NEGATIVE

Results show that 2,4 -dinitrophenol on several test on prokaryotic organisms Salmonella Thypimurium (different strains TA1538, TA98, TA100, TA1535, TA1530, TA1537, G46, C7036, D3052, pSK1002) are negative for reverse mutation test and DNA damage test. Some of the tests were performed with and without S9 metabolic activation. (Chiu CW, Lee LH, Wang CY, et al. 1978, Gamer RC, Nutman CA. 1977, Anderson D, Styles JA. 1978, Kleinhofs A Smith JA. 1976, Probst GS et al. 1981, De Flora S. 1981, Kawai A, Goto S, Matsumoto Y, et al. 1987, Nakamura S, Oda Y, Shimada T, et al. 1987).

Other tests were performed on Escherichia coli, and 2,4-DNP was negative with and without activation for reverse mutation test (Probst GS, McMahon RE, Hill LE, et al. 1981) and also negative without activation on gene mutation by phage induction (Heinemann B, Howard AJ. 1964).

A study of Demerec M, Bertani G, Gibson JE. 1951 it shows a positive result without activation for reverse mutation test; however, the data appeared unreliable, based on extreme variation in survival and mutation rates within exposure groups.

 

Eucaryotic cells (in vitro): UNDEFINED

2,4 -DNP was negative with and without activation on Chinese hamster ovary mammalian cells by DNA damage (Swenberg JA, Petzold GL, Harbach PR. 1976) but positive in another study of Hilliard, CA Armstrong, MJ Bradt, CI Hill, RB Greenwood, SK and Galloway, SM, 1998.

In a screening of 218 compounds, 2,4 -DNP is negative without activation on rat hepatocytes by DNA damage unscheduled DNA synthesis (Probst GS, McMahon RE, Hill LE, et al. 1981).

The results showed also that 2,4 - DNP is positive without activation on: Mouse Lymphoma cells L1210 by DNA damage; human HeLa cells by DNA damage; Chinese hamster V79 cells by inhibition of replicative DNA synthesis (Hilton J, Walker M. 1977).

The effects of 2,4-DNP on DNA synthesis were related to lower ATP levels in cells exposed to 2,4-DNP, resulting in decreases in energy-dependent processes, including mitosis and DNA synthesis (Garrett and Lewtas 1983; Gautschi et al. 1973; Ghosh et al. 1989; Miyagawa 1977; Tsuda 1974).

Chromosomal aberration in vitro test showed that 2,4 -DNP is positive on human peripheral lymphocytes and on TK6 human lymphoblast by chromosomal aberrations in vitro (Huang, QG, Kong, lR, Liu, YB and Wang, IS, 1996; Hilliard, CA Armstrong, MJ Bradt, CI Hill, RB Greenwood, SK and Galloway, SM, 1998).

Data obtained from Fellows, MD and o'Donovan, MR, 2007, revealed positive results on mouse lymphoma L5178Y cells, (tk+/tk-)/Trifluorothymidine and by chromosomal aberration in vitro test by micronucleus, respectively.

 

In vivo:

Data obtained from chromosome aberration assay in vivo (Mitra AB, Manna GK. 1971).The authors concluded that 2,4-DNP was clastogenic under the assay conditions and attributed the effect to the compound’s electrophilic properties.However there was no linear relationship between the frequency of chromosome aberrations and the dose of 2,4-dinitrophenol.

Seiler JP. 1981 perfomed a testicular DNA synthesis inhibition. The rate of DNA synthesis in testicular cells of mice treated with 2,4-DNP was 55% less than that of untreated mice. The author suggested that the inhibition of DNA synthesis by 2,4-DNP was due to some other mechanism than genotoxicity, probably produced by 2,4-DNP-induced suppression of cellular metabolism and, therefore, DNA synthesis.

In a method based on determination of the ratio of the DNA synthesis measured in testicular cells of mice treated by gavage with 2,4 –DNP the rate of DNA synthesis in testicular cells of mice treated with 2,4-DNP was essentially the same as that of untreated mice. The authors concluded that 2,4-DNP was not genotoxic under these experimental conditions (Friedman MA, Staub J. 1976).

.

Justification for selection of genetic toxicity endpoint

A lot of negative studies on procariotic organisms are available (Salmonella Thypimurium (different strains TA1538, TA98, TA100, TA1535, TA1530, TA1537, G46, C7036, D3052, pSK1002)  and Escherichia coli. Positive results were observed in eukaryotic cells and in in vivo study. In cells results are discordant while the test of Mitra AB, Manna GK. 1971 by chromosome aberration assay in vivo concluded a positive result.

Justification for classification or non-classification

Positive result on in vivo experiment described in Mitra AB, Manna GK. 1971 by chromosome aberration assay.

The authors concluded that 2,4-DNP was clastogenic under the assay conditions and it can be attributed the effects to the compound’s electrophilic properties. However there was no linear relationship between the frequency of chromosome aberrations and the dose of 2,4-dinitrophenol.

Also VEGA Mutagenicity model (CAESAR) (version 2.1.7) was performed and attached. Unfortunately, the substance is out of the applicability domain, but similar structure are considered mutagenic (CAS 573-56-8). So, a definitive conclusion on mutagenic effect cannot be assess and the classification on mutagenic toxicity is considered inconclusive.