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Diss Factsheets

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vivo

Description of key information
Ames test (BASF SE, 40M0731/11M345, 2013): negative; bacteriotoxic effect HPRT test (BASF SE, 50M0731/11X364, 2012): negative; cytotoxic effect Chromosomal aberration test in vitro (BASF SE, 32M0731/11M346, 2013): clastogenic, cytotoxic Micronucleus test in vivo with HTMP: negative at 1500 mg/kg bw. (dose causing a single case of mortality)
Link to relevant study records
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
according to guideline
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
GLP compliance:
Shin Nippon Biomedical Laboratories, LTD. (Japan)
Type of assay:
micronucleus assay
Crj: CD(SD)
Details on test animals or test system and environmental conditions:
- Source: Charles River Japan, Inc
- Age at study initiation: 7 weeks old
- Weight at study initiation: 273-299g
- Acclimation period: 6 days
Route of administration:
oral: gavage
- Vehicle(s)/solvent(s) used: water
Duration of treatment / exposure:
2 days
Frequency of treatment:
Post exposure period:
24 hours
Doses / Concentrations:
0, 250, 500, 1000, 1500 mg/kg
actual ingested
No. of animals per sex per dose:
Control animals:
yes, concurrent vehicle
Positive control(s):
- Route of administration: oral: gavage
- Doses / concentrations: 20 mg/kg
Tissues and cell types examined:
immature erythrocytes (IE)
micronucleated immature erythrocytes (MNIE)
Details of tissue and slide preparation:
DETAILS OF SLIDE PREPARATION: The bone marrow cells suspension was smeared onto a clean slide. The slides were stained with acridine orange solution.

METHOD OF ANALYSIS: The coded smear slides were observed under a microscope.
The IE ratio, an indicator of suppression of bone marrow cell growth, was analyzed by Student's t-test. For the incidence of MNIE's, tables of Kastenbaum and Bowman were applied.
1 of 6 animals died at 1500mg/kg
Vehicle controls validity:
Negative controls validity:
not examined
Positive controls validity:

The micronucleated immature erythrocytes (MNIE) % values of this substance treatment groups were within 0.08 to 0.12% and no significant difference was observed in comparison with the negative control group (0.07%).

The immature erythrocytes (IE) % values were 47.30% at 250 mg/kg, 45.47% at 500 mg/kg, 43.90% at 1000 mg/kg and 39.96% at 1500 mg/kg, respectively, and these displayed significant differences in comparison with the negative control group (50.87%).

MNIE % and IE % were 3.50% and 40.20%, respectively in the positive control group, and showed significant differences in comparison with the negative control group. The negative control incidences of MNIE among tests was within the range of the laboratory background data and positive control ones showed remarkable increase.

This chemical dose not induce micronuclei under the test conditions employed.

Interpretation of results (migrated information): negative
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vivo:

In vitro data:


- Gene mutation in bacterial cells:


In a bacterial reverse mutation assay conducted according to OECD Guideline 471 and GLP, the test substance was evaluated for its mutagenic potential based on the ability to induce point mutations in selected loci of Salmonella typhimurium TA 1535, TA 100, TA 1537, TA 98 and E. coli WP2 uvrA (BASF SE, 40M0731/11M345, 2013; reliability score 1).The test concentrations ranged between 0.1 and 5400 μg/plate in the standard plate test (triplicate; with and without S9 mix of phenobarbital and β-naphthoflavone induced rats), and between 0.033 and 33 μg/plate in the preincubation test (triplicate; with and without S9 mix). Sterility and vehicle controls were added, as well as positive controls. A bacteriotoxic effect was observed in the standard plate test depending on the strain and test conditions at 10 μg/plate and above, in the preincubation assay at 3.3 μg/plate and above. Test substance precipitation was found at 5400 μg/plate with and without S9 mix. No twice or more increase of his+ or trp+ revertants compared to the negative control value or dose-dependency was noticed. According to the results of the present study, the test substance is not mutagenic in the Salmonella typhimurium and E. coli mutation assay under the experimental conditions chosen. The positive controls yielded the expected results.


- Gene mutation in mammalian cells:


The test substance was assessed for its potential to induce gene mutations at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus in Chinese hamster lung fibroblasts (V79) (BASF SE, 50M0731/11X364, 2013; reliability score 1). The GLP study was conducted according to OECD Guideline 476 (In Vitro Mammalian Cell Gene Mutation Test; HPRT locus). Two independent experiments were carried out, both with and without the addition of liver S9 mix from phenobarbital and beta-naphthoflavone induced rats. The evaluated test concentrations ranged between 0.09 and 41.67 μg/mL in the 1stexperiment and between 1.88 and 41.67 µg/mL in the 2ndexperiment. After an attachment period of two or three days and the respective treatment period (Experiment I: 4 h (-/+S9); Experiment II: 24 h (-S9), 4 h (+S9)) an expression phase of 7 - 9 days and a selection period of 8 days followed. The colonies of each test group were fixed, stained and counted. Relevant cytotoxic effects occurred in the first experiment at 41.67 μg/mL and above with and at 0.4 μg/mL and above without metabolic activation. In the second experiment cytotoxic effects occurred at 41.7 μg/mL and above with and at 12.5 μg/mL and above without metabolic activation. No relevant and reproducible increase in mutant colony numbers/106cells was observed up to the maximum concentration. Therefore, the test substance is considered to be non-mutagenic in this HPRT assay.


- Chromosomal aberration test in mammalian cells:


The test substance was assessed for its potential to induce structural chromosome aberrations in Chinese hamster lung fibroblasts (V79) in an OECD guideline study (OECD 473) which followed GLP requirements (BASF SE, 32M0731/11M346, 2013; reliability score 1). The following dose levels were evaluated: without S9 mix: 0.39 – 100 µg/mL, with S9 mix (S9 rat liver-mix, induced with phenobarbital and beta-naphthoflavone): 0.39 – 200 µg/mL. Ethanol was included as vehicle control and appropriate reference mutagens were used as positive controls (-S9 mix: ethylmethanesulfate; +S9 mix: cyclophosphamide). Exposure duration was 4 h and the recovery period 14 h. Colcemide was added 2 - 3 h before completion of culture. A dose-related statistically significant and biologically relevant increase in the number of structurally damaged metaphase cells was found both in the experiment with and without metabolic activation. It has therefore to be concluded that the test substance is mutagenic in the in vitro chromsome aberration test in the absence and presence of metabolic activation.

The ester hydrolysis product HTMP (CAS 2403-88-5) also caused effects in the chromosome aberration test in vitro (MHW, 1998), but it was found to be non genotoxic in the micronucleus study in vivo (OECD 474, GLP, Mitsui 2002). As discussed in the toxicokinetic section, HTMP is partly formed by acid-catalysed hydrolysis in the stomach, and carboxylic esters are readily hydrolysable by plasma esterases. In the micronucleus assay, the high dose group of 1500 mg/kg bw caused test-item related mortality in one of the rats. Therefore, systemic availabilty was shown. All other experimental data on HTMP shows that is of higher toxicity than its fatty acid acid. Therefore, the study with HTMP is suitable for the hazard assessment of this substance.

Justification for selection of genetic toxicity endpoint
In-vivo study

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. Based on the absence of genotoxicity with the carboxylic acid in vivo and on the outcome of the in-vitro studies with the substance itself, the substance is not considered to be classified for mutagenicity under Directive 67/548/EEC, as amended for the 31st time in Directive2009/2/EG.


Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008.

Based on the absence of genotoxicity with the carboxylic acid in vivo and on the outcome of the in-vitro studies with the substance itself,

the substance is not considered to be classified for mutagenicity under Regulation (EC) No. 1272/2008, as amended for the fifth time in Directive EC944/2013.