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Toxicological information

Genetic toxicity: in vitro

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Administrative data

Endpoint:
in vitro gene mutation study in bacteria
Remarks:
Type of genotoxicity: gene mutation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23.03.0998-08.04.1988
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Method similar to OECD guideline and GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report date:
1988

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
INTRODUCTION
This report describes experiments performed in a short term test using the procedure of the Salmonella / mammalian-microsome-mutagenicity test (Ames Test) to assess the mutagenic potential of the test-material in amino acid-dependent strains of Salmonella typhimurium and a strain of Escherichia coli described by Green. By the use of liver homogenate the test takes into account the mammalian metabolism of the compound to be tested. The requirement for metabolic activation was investigated by incorporating into the test an activation system by nicotinamide-adenin dinucleotide phosphate (NADP+)-cytochrome P450 dependent mixed function oxidase enzymes of the liver. The 9000 g supernatant of rat liver homogenate has been shown to be very useful in metabolic activation of foreign compounds. The animals were pretreated with Aroclor 1254 as an inducer of several dru^q metabolizing enzymes.

In the Ames test with Salmonella typhimurium strains the effect of the test compound upon the number of back mutations to histidine prototrophy using histidine auxotrophic mutants is investigated. Using Escherichia coli WP2uvrA, a tryptophan dependent auxotroph strain, mutagenicity is based on reversion to tryptophan independence. The strains TA 100 and TA 1535 were originally derived by a substitution mutation, the strains TA 1537, TA 1538 and TA 98 by frame shift mutations from histidine prototrophic bacteria. All five Salmonella strains are deficient in the complete structure of their lipopolysaccharide layer and in DNA excision repair system. TA 98 and TA 100 possess a modified postreplication DNA repair system which frequently causes an increase in the rate of mutations. Strain WP2uvrA carries a defect in one of the genes for tryptophan biosynthesis and is deficient in the uvrA system of DNA repair. The reversion can be induced by a base change (substitution).
GLP compliance:
yes
Type of assay:
bacterial reverse mutation assay

Test material

Constituent 1
Chemical structure
Reference substance name:
Dichloroacetyl chloride
EC Number:
201-199-9
EC Name:
Dichloroacetyl chloride
Cas Number:
79-36-7
Molecular formula:
C2HCl3O
IUPAC Name:
2,2-dichloroacetyl chloride
Details on test material:
- Name of test material (as cited in study report): Dichloroacetyl chloride
- Physical state: colourless liquid
- Analytical purity: 97%
- Lot/batch No.: 962 dated jan, 9th, 1988
- Storage condition of test material: dark at 4º

Method

Target gene:
Histidine synthesis and DNA repair.
Species / strainopen allclose all
Species / strain / cell type:
other: Salmonella typhimurum TA 98, TA100, TA1535, TA1537, TA1538
Species / strain / cell type:
E. coli WP2 uvr A
Metabolic activation:
with and without
Metabolic activation system:
S-9 fraction
Test concentrations with justification for top dose:
Dose range finding
The first experiment was performed with all tester strains using three plates per dose to get information on mutagenicity and toxicity for calculation of an appropriate dose range. A reduced rate of spontaneously occuring colonies as well as visible thinning of the bacterial lawn were used as indicatorfor Toxicity. Thinning of the bacterial lawn was controlled microscopically.

In combination with the second experiment, toxicity testing was performed as follows: 0.1 ml of the different dilutions of the test compound were thoroughly mixed with 0.1 ml of 10-^6 dilution of the overnight culture of TA 100 and plate with histidine and biotin rich top agar (3 plates per dose). The solvent control is compared with the number of colonies per plate in the presence of the test compound. Results are given as a ratio of these values (= surviving fraction).
Vehicle / solvent:
- Vehicle(s)/solvent(s): DMSO
Controlsopen allclose all
Negative solvent / vehicle controls:
yes
Remarks:
DMSO
Positive controls:
yes
Remarks:
without metabolic activation
Positive control substance:
9-aminoacridine
Remarks:
Migrated to IUCLID6: TA 1537
Positive controls:
yes
Remarks:
without metabolic activation
Positive control substance:
sodium azide
Remarks:
Migrated to IUCLID6: TA 100, TA 1535
Positive controls:
yes
Remarks:
without metabolic activation
Positive control substance:
2-nitrofluorene
Remarks:
Migrated to IUCLID6: TA 98, TA 1538
Positive controls:
yes
Remarks:
without metabolic activation
Positive control substance:
N-ethyl-N-nitro-N-nitrosoguanidine
Remarks:
Migrated to IUCLID6: WP2uvrA
Positive controls:
yes
Remarks:
with metabolic activation
Positive control substance:
benzo(a)pyrene
Remarks:
Migrated to IUCLID6: TA98, TA100, TA1535; TA1537, TA1538, WP2uvrA
Positive controls:
yes
Details on test system and experimental conditions:
METHOD OF APPLICATION:
Top agar is prepared for the Salmonella strains by mixing 100 ml agar (0.6 % agar, 0.5 % NaCl) with 10 ml of a 0.5 mM histidine-biotin solution. With E. coli histidine is replaced by tryptophan (2.5 ml, 0.5 mM). The following ingrcdients arc added (in order) to 2 ml of moltcn top agar at 45 °C:
0.1 ml of an overnight nutrient broth culture of the bacterial tester strain
0.1 ml test compound solution
0.5 ml S-9 Mix (if required) or buffer
After mixing, the liquid is poured into a petridish with minimal agar (1.5 % agar, Vogel-Bonner E mcdium with 2 % glucosc). After incubation for 48 to 72 hour at 37 °C in the dark, colonics (his+ rcvcrtants) arc counted. DDURATION
- Exposure duration: 48 to 72 hours at 37º in the dark
DETERMINATION OF CYTOTOXICITY
-method: the cytotoxicity was rated as follows:
ib - incomplete bacterial lawn
nb - no bacterial lawn
p - visible precipitation of the test compound on the plates
Evaluation criteria:
The test was considered positive if there us a dose related increase in the number of relevants or a biologically relevant increase for at leas one concentration.

Results and discussion

Test resultsopen allclose all
Species / strain:
S. typhimurium TA 98
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Untreated negative controls validity:
valid
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 100
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Untreated negative controls validity:
valid
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 1535
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Untreated negative controls validity:
valid
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 1537
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Untreated negative controls validity:
valid
Positive controls validity:
valid
Species / strain:
S. typhimurium TA 1538
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Untreated negative controls validity:
valid
Positive controls validity:
valid
Species / strain:
E. coli WP2 uvr A
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Untreated negative controls validity:
valid
Positive controls validity:
valid
Additional information on results:
The test compound did not cause a significant increase in the number of revertant colonies with any of the tester strains either in the absence or presence of S-9 Mix. No dose dependent effect was obtained.
It is concluded that the test substance is not mutagenic in these bacterial test systems either in the absence or in the presence of an exogenous metabolizing system.
This test was performed according to the methods described. No unforeseen circumstances were observed which have affected the quality and integrity of this study.

TEST-SPECIFIC CONFOUNDING FACTORS:
Precipitation: No precipitation of the test item was noted al the dose tested levels.

RANGE-FINDING/SCREENING STUDIES:
The first experiment was performed with all tester strains using three plates per dose to get information on mutagenicity and toxicity for calculation of an appropriate dose range. A reduced rate of spontaneously occuring colonies as well as visible thinning of the bacterial lawn were used as indicator for Toxicity. Thinning of the bacterial lawn was controlled microscopically.
In combination with the second experiment, toxicity testing was performed as follows: 0.1 ml of the different dilutions of the test compound were thoroughly mixed with 0.1 ml of 10 -6 dilution of the overnight culture of TA 100 and plate with histidine and biotin rich top agar (3 plates per dose). The solvent control is compared with the number of colonies per plate in the presence of the test compound. Results are given as a ratio of these values (= surviving fraction).

Remarks on result:
other: all strains/cell types tested
Remarks:
Migrated from field 'Test system'.

Any other information on results incl. tables

Dichloroacetyl chloride was tested for mutagenicity with Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, TA 1538 and E coli WP2uvrA in the absence and presence of a metabolic activation system. The results obtained with the test material and positive control compounds are presented in the tables: 1 -14a. The number of colonies per plate with each strain as well as mean values of 3 plates, corrected to the next whole number are given.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information):
negative with and without metabolic activation

Dichloroacetyl chloride is not a mutagenic in these bacterial test systems either with or without exogenous metabolic activation at the dose level investigated.
Executive summary:

Dichloroacetyl chloride was tested for mutagenicity with Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537, TA 1538 and E coli WP2uvrA in the absence and presence of a metabolic activation system. The results obtained with the test material and positive control compounds are presented in the tables. The number of colonies per plate with each strain as well as mean values of 3 plates, corrected to the next whole number are given.

Dichloroacetyl chloride is not a mutagenic in these bacterial test systems either with or without exogenous metabolic activation at the dose level investigated.