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EC number: 224-832-0 | CAS number: 4511-42-6
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Genetic toxicity in vitro
Description of key information
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- Endpoint:
- in vitro cytogenicity / chromosome aberration study in mammalian cells
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Study period:
- 2014-01-17 to 2014-05-22
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study in accordance with OECD guideline 473. Lactic acid used as read-across partner to L-lactide
- Qualifier:
- according to
- Guideline:
- OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
- Qualifier:
- according to
- Guideline:
- EU Method B.10 (Mutagenicity - In Vitro Mammalian Chromosome Aberration Test)
- GLP compliance:
- yes
- Type of assay:
- in vitro mammalian chromosome aberration test
- Species / strain / cell type:
- lymphocytes: peripheral human lymphocytes
- Additional strain / cell type characteristics:
- not specified
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9-mix
- Test concentrations with justification for top dose:
- dose range finding assay: 0, 10, 33, 100, 333, 901 µg/ml (equal to concentrations of 0, 0.1, 0.4, 1.1, 3.7 and 10 mM)
1 experiment: 0, 10, 100, 901 µg/ml (equal to concentrations of 0, 0.1, 1.1 and 10 mM)
2 experiment: 0, 100, 333, 666, 901 µg/ml (equal to concentrations of 0, 1.1, 3.7, 7.4 and 10 mM) - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: RPMI 1640 medium
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- Remarks:
- solvent: RPMI 1640
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- cyclophosphamide
- mitomycin C
- Remarks:
- solvent for positive controls: Hank´s Balanced Salt Solution (HBSS)
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in medium
DURATION
- Preincubation period: 48 ± 2 hours
- Exposure duration: experiment 1: 3 hours (with and without metabolic activation); experiment 2: 24 and 48 hours without metabolic activation and 3 hours with metabolic activation
- Expression time (cells in growth medium): experiment 1: 20 to 22 hours; experiment 2: 44 to 46 hours
- Fixation time (start of exposure up to fixation or harvest of cells): experiment 1: 24 hours; experiment 2: 48 hours
SPINDLE INHIBITOR (cytogenetic assays): colchicine 0.5 µg/ml medium during the last 2.5 to 3 hours of the culture period
STAIN (for cytogenetic assays): 5 % (v/v) Giemsa for 10 to 30 minutes
NUMBER OF CELLS EVALUATED: 100 per culture
DETERMINATION OF CYTOTOXICITY
- Method: mitotic index from at least 1000 cells - Evaluation criteria:
- A test substance was considered positive (clastogenic) in the chromosome aberration test if:
a) It induced a dose-related statistically significant (Chi-square test, one-sided, p < 0.05) increase in the number of cells with chromosome aberrations.
b) A statistically significant and biologically relevant increase in the frequencies of the number of cells with chromosome aberrations was observed in the absence of a clear dose-response relationship.
A test substance was considered negative (not clastogenic) in the chromosome aberration test if:
None of the tested concentrations induced a statistically significant (Chi-square test, one-sided, p < 0.05) increase in the number of cells with chromosome aberrations.
The preceding criteria are not absolute and other modifying factors might enter into the final evaluation decision. - Statistics:
- The incidence of aberrant cells (cells with one or more chromosome aberrations, gaps included or excluded) for each exposure group outside the laboratory historical control data range was compared to that of the solvent control using Chi-square statistics:
(N-1) (ad-bc)^2
X^2 = ------------------------
(a+b) (c+d) (a+c) (b+d)
Where:
a = the total number of aberrant cells in treated cultures to be compared with the control.
b = the total number of aberrant cells in the control cultures.
c = the total number of non aberrant cells in treated cultures to be compared with the control.
d = the total number of non aberrant cells in the control cultures.
N = sum of n0 and n1.
n0 = the total number of cells scored in the control cultures.
n1 = the total number of cells scored in the treated cultures.
(N-1) (ad-bc)^2
If P X^2 > ----------------------- (one-tailed) is small (p< 0.05) the hypothesis that the
(a+b) (c+d) (a+c) (b+d)
incidence of cells with chromosome aberrations is the same for both the treated and the solvent control group is rejected and the number of aberrant cells in the test group is considered to be significantly different from the control group at the 95 % confidence level. - Species / strain:
- lymphocytes: peripheral human lymphocytes
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- based on determination of the mitotic index.
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Effects of pH: At the highest concentration of the test substance (10 mM equal to 901 µg/ml) the pH was 7.1 compared to a pH of 7.8 in the solvent control.
- Effects of osmolality: At the highest concentration of the test substance (10 mM equal to 901 µg/ml) the osmolarity was 275 mOsm/kg compared to an osmolarity of 269 mOsm/kg in the solvent control.
- Water solubility: miscible
- Precipitation: No
RANGE-FINDING/SCREENING STUDIES: In the dose range finding test blood cultures were treated with 10, 33, 100, 333, 901 µg L(+)-lactic acid/ml culture medium (equal to concentrations of 0.1, 0.4, 1.1, 3.7 and 10 mM) with and without S9-mix.
COMPARISON WITH HISTORICAL CONTROL DATA: The number of cells with chromosome aberrations found in the solvent control cultures was within the laboratory historical control data range. - Remarks on result:
- other: strain/cell type:
- Remarks:
- Migrated from field 'Test system'.
- Conclusions:
- Interpretation of results (migrated information):
negative
L(+)-lactic acid is considered not clastogenic in the in vitro mammalian chromosomal aberration test, with and without metabolic activation. - Executive summary:
- In a mammalian cell cytogenetics assay peripheral human lymphocyte cultures were exposed to L(+)-lactic acid (90%), solved in RPMI 1640 cell culture medium. In the first and second experiment the doses were 0, 10, 100, 901 µg/ml for 3 hours with and without metabolic activation. In the second experiment additional treatment to doses of 0, 100, 333, 666 and 901 µg/ml was carried out for 24 and 48 hours exposure time. S9 was derived from phenobarbital plus ß-naphtoflavone treated rats and supplemented with cofactors.
L(+)-lactic acid was tested up to 901 µg/ml which was cytotoxic based on determination of the mitotic index after an exposure time of 24 and 48 hour. The percentage of the mitotic index after 24 hours of 901 µg/ml was 55 %, that after 48 hours of 901 µg/ml 59 %. Concentrations lower than 901 µg/ml did not cause a dose-dependent decrease in the percentage of the mitotic index after 24 and 48 hours of exposure. The mitotic index after 3 hours of exposure was lower compared to control (66 % in experiment 1, 84 % in experiment 2) but did not reach the threshold value of 45 ± 5 % according to OECD guideline 473 for cytotoxicity. Positive controls induced the appropriate response. There was no evidence for a concentration related positive response of chromosome aberration induced over background.
This study is classified as acceptable and satisfies the requirement for the in vitro mammalian chromosomal aberration test according to OECD 473.
Reference
Mitotic Indices:
Table1:
Mitotic index of human lymphocyte cultures treated with L(+)-lactic acid in the dose range finding test
L(+)-lactic acid concentration (µg/ml) | Number of metaphases:
Absolute | Number of metaphases:
Number of cells scored | Number of metaphases:
Percentage of control |
Without metabolic activation (-S9-mix) |
|
|
|
3 h exposure time, 24 h fixation time |
|
|
|
Control a) | 96 | 1004 | 100 |
10 | 99 | 1007 | 103 |
33 | 80 | 1045 | 83 |
100 | 60 | 1008 | 63 |
333 | 66 | 1009 | 69 |
901 | 63 | 1003 | 66 |
24 h exposure time, 24 h fixation time |
|
|
|
Control a) | 65 | 1007 | 100 |
10 | 62 | 1042 | 95 |
33 | 71 | 1041 | 109 |
100 | 66 | 1016 | 102 |
333 | 68 | 1048 | 105 |
901 | 36 | 1028 | 55 |
48h exposure time,48h fixation time |
|
|
|
Control a) | 68 | 1017 | 100 |
10 | 64 | 1026 | 94 |
33 | 51 | 1013 | 75 |
100 | 65 | 1010 | 96 |
333 | 57 | 1017 | 84 |
901 | 33 | 1033 | 49 |
With metabolic activation (+S9-mix) |
|
|
|
3 h exposure time, 24 h fixation time |
|
|
|
Control a) | 85 | 1044 | 100 |
10 | 70 | 1013 | 82 |
33 | 71 | 1008 | 84 |
100 | 68 | 1006 | 80 |
333 | 66 | 1020 | 78 |
901 | 71 | 1007 | 84 |
a.) culture medium
Table 2:
Mitotic index of human lymphocyte cultures treated with L(+)-lactic acid in the first cytogenetic assay
L(+)-lactic acid concentration (µg/ml) | Number of metaphases a)
Absolute | Number of metaphases a)
Number of cells scored | Percentage of control
|
Without metabolic activation (-S9-mix) |
|
|
|
3 h exposure time, 24 h fixation time |
|
|
|
Control b) | 3-36 | 1009-1028 | 100 |
10 | 3-35 | 1002-1012 | 103 |
100 | 3-28 | 1008-1033 | 90 |
901 | 1-9 | 1002-1040 | 34 |
MMC-C; 0.5 µg/ml | 4-7 | 1026-1031 | 16 |
MMC-C; 0.75 µg/ml | 7-5 | 1029-1004 | 17 |
With metabolic activation (+S9-mix) |
|
|
|
3 h exposure time, 24 h fixation time |
|
|
|
Control b) | 3-48 | 1040-1028 | 100 |
10 | 3-27 | 1013-1007 | 79 |
100 | 4-35 | 1035-1001 | 101 |
901 | 4-32 | 1008-1007 | 93 |
CP; 10 µg/ml | 21-14 | 1005-1025 | 43 |
a) Duplicate cultures
b) Culture medium
Table 5:
Mitotic index of human lymphocyte cultures treated with L(+)-lactic acid in the second cytogenetic assay
L(+)-lactic acid concentration (µg/ml) | Number of metaphasesa
Absolute | Number of metaphasesa
Number of cells scored | Percentage of control |
Without metabolic activation (-S9-mix) |
|
|
|
24 h exposure time, 24 h fixation time |
|
|
|
Control b) | 90-85 | 1000-1000 | 100 |
100 | 75-83 | 1000-1003 | 90 |
333 | 67-65 | 1008-1000 | 75 |
666 | 73-66 | 1001-1000 | 79 |
901 | 39-42 | 1002-1000 | 46 |
MMC-C; 0.2 µg/ml | 24-34 | 1000-1003 | 33 |
MMC-C; 0.3 µg/ml | 21-33 | 1003-1000 | 31 |
48 h exposure time, 48 h fixation time |
|
|
|
Control b) | 93-88 | 1005-1000 | 100 |
100 | 71-87 | 1001-1000 | 87 |
333 | 66-51 | 1000-1000 | 65 |
666 | 34-37 | 1000-1002 | 39 |
901 | 22-24 | 1003-1000 | 25 |
MMC-C; 0.1 µg/ml | 18-20 | 1002-1003 | 21 |
MMC-C; 0.15 µg/ml | 17-19 | 1000-1004 | 20 |
With metabolic activation (+S9-mix) |
|
|
|
3 h exposure time, 48 h fixation time |
|
|
|
Control b) | 88-87 | 1000-1000 | 100 |
10 | 66-75 | 1000-1045 | 81 |
100 | 62-64 | 1003-1005 | 72 |
901 | 71-63 | 1000-1000 | 77 |
CP; 10 µg/ml | 22-18 | 1005-1000 | -c.) |
a) Duplicate cultures
b) Culture medium
c) CP was fixed after 24 hours. Therefore, the mitotic index could not be calculated as percentage of control.Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Additional information
Due to the rapid hydrolysis of lactide into lactoyl lactic acid and subsequently lactic acid, under acid and neutral conditions, the toxicology of lactides can be understood in terms of the toxicology of lactic acid. As no data was available for L-lactide, genotoxicity studies of lactic-acid were used for read-across. L(+)-lactic acid was tested in three independent test system as not genotoxic, which were performed in accordance to the OECD guidelines 471 (Ames test), 473 (chromosome aberration) and 476 (gene mutation).
Based on the available data of the read-across partner lactic acid, L-lactide is considered to be non-genotoxic.
Justification for selection of genetic toxicity endpoint
An in vitro testing battery under GLP (OECD 471, OECD 476, OECD 473) has been conducted with a lactic acid, as degradation product of L-lactide.
Justification for classification or non-classification
Genotoxicity of the read-across partner L(+)-lactic acid was assessed in a standard in vitro testing battery under GLP. The substance was not genotoxic in any of the test systems. Therefore, based on the available data no classification of L-lactide is warranted.
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