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EC number: 203-219-1 | CAS number: 104-61-0
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
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- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
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- Stability: thermal, sunlight, metals
- pH
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- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
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- Endpoint summary
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- Environmental data
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- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
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- Toxicological Summary
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- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vivo
Description of key information
Link to relevant study records
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Study period:
- 1988
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Study conducted similarly to OECD Guideline 474 with minor deviations: no data on the housing conditions and individual body weight at the start of the test; number of micronucleated immature erythrocytes for individual animals not reported. 1000 polychromatic erythrocytes (PCE) were analysed per animal, which was a requirement of the old version of the OECD 474 (1983). The new version require the analysis of at least 2000 PCE. γ-Undecalactone, as aliphatic γ-lactone, is considered adequate for read-across purpose (see §"Toxicokinetics").
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- yes
- Remarks:
- no data on the housing conditions and body weight at the start of the test; number of micronucleated immature erythrocytes for individual animals not reported
- Principles of method if other than guideline:
- Not applicable
- GLP compliance:
- not specified
- Type of assay:
- micronucleus assay
- Species:
- mouse
- Strain:
- other: ddY mice
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Shizuoka Agricultural Cooperative Association for Laboratory Animals, Shizuoka, Japan
- Age at study initiation: 8 weeks
- Diet: Food pellets CE-2 (Japan Clea, Tokyo, Japan), ad libitum
- Water: ad libitum - Route of administration:
- intraperitoneal
- Vehicle:
- Olive oil
- Details on exposure:
- None
- Duration of treatment / exposure:
- - 250, 500, 1000 and 2000 mg/kg bw: One day
- 500 mg/kg bw: 4 days - Frequency of treatment:
- - 250, 500, 1000 and 2000 mg/kg bw: Single injection
- 500 mg/kg bw: 4 injections with 24 h intervals between the injections - Post exposure period:
- 24 h
- Remarks:
- Doses / Concentrations:
250, 500, 1000 and 2000 mg/kg bw
Basis:
other: actual injected - No. of animals per sex per dose:
- 6 males/dose
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- Mitomycin-C
- Source: Kyowa Hakko Ltd, Tokyo, Japan
- Route of administration: Intraperitoneal
- Doses: 2 mg/kg bw - Tissues and cell types examined:
- - Femora bones were removed for marrow extraction and the prepared slides were examined for polychromatic erythrocytes (PCEs) and total erythrocytes.
- Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION: The maximum doses of the test material were set at the supposed maximum tolerated dose referring to LD50.
DETAILS OF SLIDE PREPARATION: Mice were killed by cervical dislocation at 24 h after exposure. Femoral marrow cells were flushed out with fetal bovine serum and smeared on clean glass slides. Cells were fixed with methanol for 5 minutes and stained with Giemsa stain.
METHOD OF ANALYSIS:
- 1000 polychromatic erythrocytes (PCEs) per mouse were scored using a light microscope with a high power objective (X 100) and the no. of micronucleated polychromatic erythrocytes (MNPCEs) were recorded.
- Proportion of polychromatic erythrocytes (PCEs) among the total erythrocytes was evaluated by observing 1000 erythrocytes on the same slide. - Evaluation criteria:
- Result was considered as positive if 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).
- Statistics:
- Two-stage statistical procedure:
- 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 (Hayashi et al. 1985).
- In the second step, the dose-response relationship was tested by the Cochran- Armitage trend test (Armitage, 1955; Cochran, 1954; Margolin and Risko, 1988). - Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- - See table 7.6.2/1 for MNPCEs (%) and PCEs (%)
- Conclusions:
- Interpretation of results (migrated information): negative
Under the test conditions, γ-Undecalactone is not considered as clastogenic in an in vivo mouse bone marrow micronucleus assay according to the Directive 67/548/EEC and of the Regulation (EC) No. 1272/2008 (CLP). - Executive summary:
In an in vivo mouse bone marrow micronucleus assay performed similarly to OECD Guideline 474, groups of ddY male mice (6/dose) were injected with Undecalactone in olive oil at 250, 500, 1000 and 2000 mg/kg bw (single treatment) and 500 mg/kg bw (4 injections with 24 h intervals between the injections) by intraperitoneal route. The positive control group was injected with mitomycin C at 2 mg/kg bw. Mice were killed by cervical dislocation 24 h after an administration. Femoral marrow cells were flushed out with fetal bovine serum and smeared on clean glass slides. Cells were fixed with methanol for 5 minutes and stained with Giemsa stain. 1000 polychromatic erythrocytes (PCEs) per mouse were scored for recording the incidence of micronucleated polychromatic erythrocytes (MNPCEs). The proportion of PCEs among the total erythrocytes was also evaluated by observing 1000 erythrocytes on the same slide.
Mice treated with Undecalactone did not show any significant increase in the frequency of MNPCEs. Positive control (mitomycin C) induced a statistically significant increase in MNPCEs indicating the validity of the study.
Under the test conditions, Undecalactone is not considered as clastogenic in an in vivo mouse bone marrow micronucleus assay according to the Directive 67/548/EEC and of the Regulation (EC) N° 1272/2008 (CLP).
γ-Undecalactone, as aliphatic γ-lactone, is considered adequate for read-across purpose (see §"Toxicokinetics").
Reference
Table 7.6.2/1: Results of micronucleus test
Groups |
Dose (mg/kg bw) |
No. of doses |
Time between doses (24 h) |
Sampling time (h) |
MNPCEs (%) |
PCEs (%) |
Mortality |
Vehicle (Olive oil) |
0 |
1 |
- |
24 |
0.10 ± 0.06 |
54.6 ± 6.4 |
0/6 |
Undecalactone |
250 |
0.25 ± 0.12 |
51.6 ± 7.7 |
||||
500 |
0.08 ± 0.08 |
43.9 ± 7.4 |
|||||
1000 |
0.18 ± 0.08 |
43.7 ± 9.2 |
|||||
2000 |
0.25 ± 0.07 |
52.3 ± 3.0 |
|||||
500 |
4 |
24 |
0.08 ± 0.10 |
48.7 ± 8.1 |
|||
Mitomycin-C |
2 |
1 |
- |
4.78 ± 1.40* |
43.5 ± 4.6 |
MNPCEs - Micronucleated polychromatic erythrocytes; PCEs - Polychromatic erythrocytes;
* value of MNPCE differ significantly from the historical control (p < 0.01)
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Additional information
Table 7.6/1: Summary of genotoxicity tests
Test n° |
Test / Guideline Reliability |
Focus |
Strains / Cells tested |
Metabolic activation |
Test concentration |
Statement |
1
Ishidate, 1984 |
Ames Test (eq. OECD 471) WoE, rel. 4 |
γ-Undecalactone
Gene mutation |
TA 1535, TA 1537, TA92, TA94, TA 98, TA 100 |
-S9 +S9 |
Up to 5000 µg/plate |
-S9 : non mutagenic +S9 : non mutagenic |
2
Masayuki Kato, 2002 |
Ames Test (eq. OECD 471) WoE, rel. 2 |
γ-Caprolactone
Gene mutation |
TA 1535, TA 1537, TA 98, TA 100, WP2uvrA |
-S9 +S9 |
Up to 5000 µg/plate |
-S9 : non mutagenic +S9 : non mutagenic |
3 Woods, 2012
|
ML/TK test (OECD 476) K, rel. 1 |
γ-Nonalactone
Gene mutation |
mouse lymphoma L5178Y cells |
-S9 +S9 |
Up to 800 µg/mL –S9 Up to 1562 µg/mL (10mM) +S9 |
-S9 : non mutagenic +S9 : non mutagenic |
4
Honarvar, 2009 |
In vivo micronucleus (OECD 474, K, rel.1) |
γ-Nonalactone
Chromosomal aberration |
Bone marrow cells (femur) |
NA |
Up to 2000 mg/kg bw |
Not clastogenic |
5
Hayashi, 1988 |
In vivo micronucleus (eq. OECD 474) S, rel. 2 |
γ-Undecalactone
Chromosomal aberration |
Bone marrow cells (femur) |
NA |
Up to 2000 mg/kg bw |
Not clastogenic |
6
Kawamura, 2002 |
CHL/IU CAT (Japanese guideline) S, rel. 2 |
γ-Caprolactone
Chromosomal aberration |
Chinese hamster lung cells |
-S9 +S9 |
Up to 5000 µg/mL |
Not clastogenic |
Gene mutation Assays (Tests n° 1-3):
Two Bacterial Reverse mutation Assays(Ames test)were performed similarly to the OECD 471 test guideline with the read-across substance γ-Undecalactone and γ-Caprolactone (See §”Toxicokinetics” for read-across justification). Both tests were used in a weight-of evidence approach as only four strains of bacteria were used in the Test n°1 whereas all required strains were used in Test n°2. No significant increases in the frequency of revertant colonies were recorded for any of the bacterial strains in both tests, with any dose of the test materials up to limit concentration, either in the presence or absence of metabolic activation. The tests indicate that γ-Undecalactone and γ-Caprolactone did not induce gene mutations in bacteria whereas all positive control chemicals (with and without metabolic activation) induced significant increase of colonies. Based on this weight-of evidence, γ-Nonalactone is therefore considered as non-mutagenic according to the Ames test.
Inability to produce gene mutation was confirmed in mammals using anin vitroforward mutation assay in mouse lymphoma TK L5178Y cells(ML/TK test)(Test n°3). None of the dose levels up to the cytotoxicity limit with ɣ-Nonalactone, either with or without metabolic activation, induced significant mutant frequency increases in the initial, or repeat tests. ɣ-Nonalactone does not induce forward mutations at the TK locus in L5178Y mouse lymphoma cells under activation and non activation conditions whereas both positive control chemicals (with and without metabolic activation) induced significant mutant frequency increases.ɣ-Nonalactone is therefore considered as negative for inducing forward mutations at the TK locus in L5178Y mouse lymphoma cells under activation and non-activation conditions used in this assay. This result confirms the results of both Ames tests and extends the non-mutagenic effect of ɣ-Nonalactone to mammalian cells.
Chromosomal aberration (Tests n°4-5)
The clastogenic and aneugenic potential of γ-Nonalactone was determined using anin vivomammalian erythrocytes micronucleus assay (Test n°4), which measured the potential of a substance to increase the incidence of the structural and numerical chromosome aberrations in mice bone marrow erythrocytes. None of the dose level, up to the limit dose of 2000 mg/kg bw, induced increase in the frequency of micronucleated polychromatic erythrocytes (fMPCE) in bone marrow, whereas positive control chemical induced significant increase in the fMPCE. γ-Nonalactone was therefore considered as negative for inducing chromosomal aberrations in mice bone marrow erythrocytes under the conditions used in this study. In another micronucleus assay (Test n°5), the same results were observed with γ-Undecalactone up to 2000 mg/kg bw, supporting the absence of clastogenicity and aneugenicity of C9-C11 γ-lactones. Thein vitrochromosome aberration study (Test n°6) conducted on the read-across substance, ɣ-Caprolactone, using Chinese hamster lungs cells confirmed the absence of clastogenicity of the family members.
γ-Nonalactone is therefore considered as non-clastogenic and non-aneugenic.
Justification for selection of genetic toxicity endpoint
See Table 7.6/1 below
Justification for classification or non-classification
Harmonized classification:
γ-Nonalactone has no harmonized classification for human health according to the Regulation (EC) No. 1272/2008 including the ATP2.
Self classification:
Based on the available data, no additional classification is proposed according to the Regulation (EC) No. 1272/2008 (CLP) and the Directive 67/548/EEC.
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