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EC number: - | CAS number: -
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Genetic toxicity: in vitro
Administrative data
- Endpoint:
- in vitro gene mutation study in mammalian cells
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- read-across based on grouping of substances (category approach)
- Adequacy of study:
- key study
- Study period:
- 14-May-2001 to 11-Feb-2002
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- 1. HYPOTHESIS FOR THE CATEGORY APPROACH (ENDPOINT LEVEL)
The members of the category are all alcohol esters of dicarboxylic acids. All category members are manufactured by reacting an alcohol (methanol, butanol or isobutanol) with single dicarboxylic acids, succinic, glutaric or adipic acids or mixtures of these acids. The ester bonds are effectively metabolised by the body releasing the component alcohols and acids. The difference between members involves 3 parameters: 1) the alcohol used to esterify the acids, 2) the length of the acid molecule (4C, 5C or 6C) and 3) the presence of individual esters or mixtures thereof.
2. CATEGORY APPROACH JUSTIFICATION (ENDPOINT LEVEL
The toxicity profile of the members (ecotoxicity and human health toxicity and the environmental fate) is consistent. All have low acute toxicity potential, are not sensitising, are mildly irritating to eyes and upper respiratory tract (where vapour pressure allows exposure), are not genotoxic or clastogenic (in vivo) and have minimal systemic toxicity. Data are available predominantly for the methyl esters (individual and mixture), dibutyl adipate and diisobutyl esters (mixture). Within the category, read across is used to cover the higher tier human health toxicity studies predominantly.
See attached document with the justification for the category/read-across approach.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 002
- Report date:
- 2002
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 476 (In Vitro Mammalian Cell Gene Mutation Test)
- GLP compliance:
- yes
- Type of assay:
- mammalian cell gene mutation assay
Test material
- Reference substance name:
- Dimethyl glutarate
- EC Number:
- 214-277-2
- EC Name:
- Dimethyl glutarate
- Cas Number:
- 1119-40-0
- Molecular formula:
- C7H12O4
- IUPAC Name:
- dimethyl glutarate
- Details on test material:
- Clear liquid
Purity: 99.61%
Batch Number: H931363-A
Supplier: DuPont
Constituent 1
Method
- Target gene:
- HPRT locus
Species / strain
- Species / strain / cell type:
- Chinese hamster Ovary (CHO)
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9
- Test concentrations with justification for top dose:
- Preliminary toxicity test: 78-5000 ug/L (halving concentrations)
-S9: 315-5000 ug/L (5 halving concentrations) in Test 1 and Test 2
+S9: 400, 500, 600, 700, 800, and 900 ug/L in Test 1
+S9: 600, 800, 900, 1000, 1100 and 1200 ug/L 9 in Test 2 - Vehicle / solvent:
- DMSO
Controlsopen allclose all
- Positive controls:
- yes
- Positive control substance:
- ethylmethanesulphonate
- Remarks:
- Positive control in absence of S9
- Positive controls:
- yes
- Positive control substance:
- 3-methylcholanthrene
- Remarks:
- Positive contol in presence of S9
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO
- Details on test system and experimental conditions:
- Dimethyl glutarate was evaluated for its mutagenic potential in Chinese hamster ovary cells. The test system evaluated the potential of DMG to induce a forward mutation at the functionally hemizygous hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus. A prelimiary toxicity test was performed on cell suspensions in nutrient medium in presence and absence of S9. Cells were incubated for 20 hours at 37C in a humid atmosphere fo 5% CO2 in the air prior to exposure to the test substance on Day 1. Two mL of S9 or nutirent medium were added to the cell suspension followed by 120 ul of the test material or control solvent. The treated cell suspension were returned to the incubator for an additional 4 hour. Cell suspension were covered during incubation to prevent loss of test material.
At the end of treatment, the cells were harvested, washed and seeded on 3 60 mm dishes (200 cells per dish) with nutrient medium. The plates were incubated for at least 7 days, then growing colonies were fixed stained and counted. Cell survival was expressed as the plating efficiency relative to solvent controls. Concentrations for the main test were chosen based on these results.
For the main test, cell suspensions were prepared as described above except that duplicate cultures were used for each test concentration and positive control and quadruplicate culture for solvent controls. At least 5 serial dilutions were used at concentrations expected to span LC80 to LC0. Following exposure to test substance for 4 hours and plating as described above, 10x6 cells were seeded in a flask and incubated for 7 days to allow expression of the mutant phenotype. The cultures were subcultured on days 4 or 5 and after a total of 7 days were harvested by trypsinization (Day 8). the cells were harvested, washed and seeded on 3 60 mm dishes (200 cells per dish) with nutrient medium. The plates were incubated for at least 7 days, then growing colonies were fixed stained and counted. Cell survival was expressed as the plating efficiency relative to solvent controls. Concentrations for the main test were chosen based on these results. - Evaluation criteria:
- Cytotoxicity - [Total colonies on plates (treated)/total conlonies on plates (untreated)] x 100
Plating efficiency (PE)- [Total number of viable colonies for each treated group/number of plates scored for colony formation x 200] x 100
Mutation frequency (MF) - [Total number of mutant colonies x 5*/PE x number ofuncontaminated plates] x 100
*5 represents a correction factor for the number of uncontaminated plates which normally equals 5, but may have been less
Criteria for a positive response were:
1) Demonstration of a statistically significant increase in mutation frequency
2) Evidence of a dose-relationship over at least two dose-levels
3) Demonstration of reproduibility in any increases in mutant frequency
4) Mean mutation frequency should fall outside the upper limit of historical control range of 20 mutants per million survivors with acorresponding survival rate of 20% or greater
Results and discussion
Test results
- Species / strain:
- Chinese hamster Ovary (CHO)
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
Any other information on results incl. tables
Test 1: Dimethyl Glutarate in the absence of S9
Concentration |
Mean Relative Survival Day 1 |
Mean Relative Survival Day8 |
Mean Mutation Frequency |
0 |
100 |
100 |
7.47 |
313 |
119 |
100 |
9.34 |
625 |
120 |
109 |
2.21 |
1250 |
93 |
94 |
6.92 |
2500 |
81 |
96 |
4.58 |
5000 |
78 |
95 |
8.60 |
EMS ¿Positive control |
99 |
80 |
392.67* |
*p<0.001
Test 2: Dimethyl Glutarate in the absence of S9
Concentration |
Mean Relative Survival Day 1 |
Mean Relative Survival Day8 |
Mean Mutation Frequency |
0 |
100 |
100 |
11.35 |
313 |
105 |
98 |
12.69 |
625 |
94 |
102 |
9.81 |
1250 |
104 |
99 |
11.88 |
2500 |
97 |
95 |
7.9 |
5000 |
83 |
102 |
20.06 |
EMS ¿Positive control |
76 |
94 |
449.50* |
*p<0.001
Test 1: Dimethyl Glutarate in the presence of S9
Concentration |
Mean Relative Survival Day 1 |
Mean Relative Survival Day8 |
Mean Mutation Frequency |
0 |
100 |
100 |
10.51 |
400 |
100 |
96 |
2.89 |
500 |
88 |
92 |
8.79 |
600 |
82 |
92 |
2.96 |
700 |
82 |
98 |
2.84 |
800 |
29 |
94 |
4.09 |
900 |
82 |
97 |
9.59 |
3-MC- positive control |
100 |
94 |
202.53* |
*p<0.001
Applicant's summary and conclusion
- Conclusions:
- Dimethyl glutarate did not demonstrate mutagenic potential in the in vitro HPRT cell mutation assay in the presence and absence of S9 metabolic activation.
- Executive summary:
Dimethyl glutarate was tested for mutagenic potential in an in vitro mammalian cell mutation assay. This test system is based on detection and quantitation of forward mutation at the functionally hemizygous hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus in Chinese hamster ovary (CHO) cells.
The test was repeated more than twice, but several tests, particularly in the presence of S9 mix, were rejected, because there were insufficient mutagenicity data to claim a valid test. The results of four independent tests, two in the absence of exogenous metabolic activation (S9 mix), and two in the presence of S9 mix are reported.
In the preliminary toxicity test, cultures were exposed to 7 halving concentrations ranging from 78- 5000 µg/ml. In the absence of S9 mix, cultures were exposed to 5 halving concentrations ranging from 313-5000 µg/ml in both mutagenicity tests. In the presence of S9 mix, cultures were exposed to 400, 500, 600, 700, 800 or 900 µg/ml in the first mutagenicity test, and to 600, 800, 900, 1000, 1100 and 1200 µg/ml in the second. In all tests exposure was for 4 hours.
The preliminary toxicity test showed Day 1 relative cell survival of 65% after exposure to 5000 µg/ml in the absence of S9 mix and no survival after exposure to 1250 µg/ml or higher concentrations in the presence of S9 mix. In the main mutagenicity tests, slight toxicity was observed after exposure to dimethyl glutarate in tests in the absence of S9 mix, so that Day 1 relative cell survival was reduced to 78% or 83% by 5000 µg/ml in the first and second main test respectively. In the presence of S9 mix, Day1 relative cell survival was reduced to 82% by 900 µg/ml in the first main test, and to 27% by 1200 µg/ml in the second.
No significant increases in mutant frequency were observed in any of the tests either in the absence or presence of S9 mix, nor was there evidence of a concentration-response relationship. In all tests the positive control substances increased mutant frequencies significantly (P<0.001)
In the presence of S9 mix, dimethyl glutarate failed to reduce the Day1 cell survival to 10-20% of solvent control values, but it is considered that a sufficient number of high concentrations in a toxic range were tested to assess mutagenic potential adequately.
It was concluded that dimethyl glutarate did not demonstrate mutagenic potential in this in vitro HPRT cell mutation assay in either the absence or presence of S9 metabolic activation, under the experimental conditions described.
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