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Administrative data

Key value for chemical safety assessment

Genetic toxicity in vivo

Description of key information
Tartaric acid and its salts do not have genetic toxicity.
Link to relevant study records
Reference
Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
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: The study has been assessed for the use in a category approach. According to the methodology and to the extent of available details, the study has been judged as reliable with restrictions.
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Deviations:
no
Remarks:
No significant deviation.
GLP compliance:
not specified
Type of assay:
micronucleus assay
Test material information:
Composition 1
Species:
mouse
Strain:
other: ddY
Sex:
male
Details on test animals and environmental conditions:
Animals were fed with pellets CE-2 and water ad libitum.
Route of administration:
intraperitoneal
Vehicle:
saline solution
Duration of treatment / exposure:
1st study: single intraperitoneal administration was performed.
2nd study: multiple administrations; four injections with 24-hr intervals between them were performed.
Frequency of treatment:
1st study: single intraperitoneal administration was performed.
2nd study: multiple administrations; four injections with 24-hr intervals between them were performed.
Post exposure period:
Sampling were performed after 26 hours from the last injection.
Remarks:
Doses / Concentrations:
900 mg/Kg
Basis:
other: single dose injected by i.p. route
Remarks:
Doses / Concentrations:
2700 mg/Kg
Basis:
other: single dose injected by i.p. route
Remarks:
Doses / Concentrations:
1800 mg/Kg
Basis:
other: single dose injected by i.p. route
Remarks:
Doses / Concentrations:
3600 mg/Kg
Basis:
other: single dose injected by i.p. route
Remarks:
Doses / Concentrations:
1000 mg/Kg
Basis:
other: doser level used in multiple administration study (2nd study)
No. of animals per sex per dose:
6 males per dose level.
6 males per negative control.
3 males per positive control.
Control animals:
yes, concurrent vehicle
Positive control(s):
Mitomicyn C (MMC) was used as positive control.
Tissues and cell types examined:
The proportion of polychromatic erythrocytes (PCEs) among the total erythrocytes was also evaluated by observing 1000 erythrocytes on the same slide.
Statistics:
Before evaluating the test data statistically, the frequencies of MNPCEs in concurrent negative and positive control groups were compared with the control charts of historical data to confirm the technical validity of the experiment. To estimate the true spontaneous level, it should be more reliable to use historical control data instead of the results from concurrent controls which could fluctuate.
According to the historical negative control data accumulated separately in the two laboratories, the number of MNPCEs per mouse followed binomial distributions with P = 0.00200 and n = 1000.
A two-stage statistical procedure was used. In the first step of the procedure the frequency of MNPCEs in each treatment group was compared with the binomial distribution specified by historical control data from the laboratory where the test was performed. In the second step, the dose-response relationship was tested by the Cochran-Armitage trend test (Armitage, 1955; Cochran, 1954; Margolin & Risko, 1988). A positive result was recorded only when one or more treatment group(s) showed a statistically significant difference (P< 0.01) from the spontaneous level of MNPCEs and the trend test indicated a positive dose response (P < 0.05). This procedure was not applied to tests with multiple treatments which, in most cases, contained only one dose group. Such data were evaluated statistically using the first step only.
A Monte-Carlo simulation study showed that the probability of a type I error (the probability of a false positive), in this two-step procedure was, in general, closer to the nominal significance level (P= 0.01) than that of the usual conditional binomial test (Kastenbaum & Bowman, 1970) which has been widely used to evaluate micronucleus test data.
Similarly, this method was a more powerful method of analysis than the conditional binomial test. A detailed description of this statistical procedure will be reported separately.
Sex:
male
Genotoxicity:
negative
Toxicity:
yes
Remarks:
Four males were died following single administration of 3600 mg/kg of the substance.
Vehicle controls valid:
yes
Negative controls valid:
not specified
Positive controls valid:
yes
Additional information on results:
The absence of genotoxicity (intended as frequencies of micronucleates PCEs) was observed togheter with a reduction of frequencies of PCEs which could be related to the capability of the substance of reaching the target (PCE).
Conclusions:
Interpretation of results (migrated information): negative
The test substance was found negative following single and multiple administrations. Indeed, the substance does not showed a significant induction of micronuclei in this test when compared with negative control and historical control data.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vivo:

Tartaric acid was tested in several mutagenicity and clostogenicity tests both in vitro and in vivo. In particular, it was assayed by means of host-mediated assays, in vitro and in vivo mammalian chromosome aberration tests, bacterial reverse mutation assays (e.g. Ames test) and a in vitro DNA damage/repair assay (unscheduled DNA synthesis in mammalian cells in vitro). The substance was found non-mutagen/non-clastogenic in almost all tests, except for a positive result from a host-mediated assay on Saccharomyces D3 and an ambiguous result from a dominant lethal assay. However, in both cases, the replication of these tests gave negative results.

 

Also data available for the tarataric acid salts confirm the absence of mutagenicity/clastogenicity of this category of substances. In particular, (i) a series of bacterial reverse mutation assays and an in vitro mammalian chromosome aberration test showed negative results for potassium hydrogen tartrate; (ii) a single negative result from a Ames test is available for sodium hydrogen tartrate; (iii) a negative result from Ames test is available for disudium tartrate which, instead, was found to be positive in an in vitro mammalian chromosome aberration test. (iv) This positive result has been undermined by the absence of clastogenicity registered in in vivo micronucleus tests performed through both single-dose and repeated-dose administration.

Overall, the mutagenic/clastogenic activity mey be excluded for both tartaric acid and its salts.


Justification for selection of genetic toxicity endpoint
Although an endpoint study record has been selected, the assessment of the genetic toxicity is based on the weight of evidence since several good quality data support the absence of mutagenicity/clastogenicity.

Justification for classification or non-classification

According to Directive 67/548/EEC and to Regulation (EC) n. 1272/2008, the substances should not be classified for the genetic toxicity because the available data are judged as "conclusive but not sufficient for classification".