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EC number: 203-784-4 | CAS number: 110-62-3
- 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
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- Oxidation reduction potential
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- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
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- Endpoint summary
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- Environmental data
- Additional information on environmental fate and behaviour
- 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
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
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- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Description of key information
The existing in vitro mutagenicity data for n-valeraldehyde provide partially contradictionary results. Negative results were obtained in the bacterial reverse mutation (Ames) assay, which is lacking one tester strain. Negative results were also obtained in an in vitro SCE in human lymphocytes and an in vitro UDS test in human hepatocytes. But, positive results in vitro were obtained in an UDS test in rat hepatocytes, an alkaline elution test in CHO cells and a HPRT-test in V79 cells.
Link to relevant study records
- Endpoint:
- in vitro DNA damage and/or repair study
- Remarks:
- Type of genotoxicity: DNA damage and/or repair
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Acceptable, well-documented publication which meets basic scientific principles (limited reporting)
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 482 (Genetic Toxicology: DNA Damage and Repair, Unscheduled DNA Synthesis in Mammalian Cells In Vitro)
- Deviations:
- yes
- Remarks:
- : limited reporting
- Principles of method if other than guideline:
- No guideline stated but the test method used is similar to OECD test guideline 482. Five n-alkanals were tested.
- GLP compliance:
- no
- Type of assay:
- DNA damage and repair assay, unscheduled DNA synthesis in mammalian cells in vitro
- Species / strain / cell type:
- hepatocytes: primary cultures from livers of two human subjects
- Details on mammalian cell type (if applicable):
- - primary human hepatocyte cultures were isolated from apparently healthy fragments of human livers obtained from one male and one femal human subject. Liver fragments were discarded during the course of prescribed surgery. As checked by both macroscopic and histological examinations, these fragments were devoid of appreciable alterations.
- primary hepatocytes were isolated by collagenase perfusion. The portion of viable cells was 65% and 83% respectively.
- Type and identity of media: Williams' medium E - Test concentrations with justification for top dose:
- 0, 3, 10, and 30 mM (0, 0.26, 0.86, and 2.58 mg/mL); in addition 100 mM (8.61 mg/mL) for the determination of cytotoxicity
- Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: non
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- no
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- N-dimethylnitrosamine
- Remarks:
- Migrated to IUCLID6: concentration: 5 mM (0.37 mg/mL)
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in medium
DURATION
- Exposure duration: 20 h; cells were simultaneously exposed to test compound and tritiated thymidine (10 µCi/mL [methyl-3H]thymidine))
- Expression time (cells in growth medium): 20 h
- Fixation time (start of exposure up to fixation or harvest of cells): 20 h
STAIN (for cytogenetic assays): hematoxylin and eosin (after development of autoradiographs)
NUMBER OF REPLICATIONS: two cultures from distinct rats each
NUMBER OF CELLS EVALUATED: total of 200; 100 (2 slides) per culture
DETERMINATION OF CYTOTOXICITY
- Method: determination of viability (percent survival) by counting cells (1000/dish) after staining exposed cell cultures with 0.4% trypan blue - Evaluation criteria:
- A compound is considered positive if a dose-dependent increase is observed in net nuclear grains for at least two points and both increased points are above the justified laboratory-specific threshold, and/or statistical significance is demonstrated for both points (Internation Workshop on Standardization of Genotoxicity Test Procedures, Melbourne, 1992)
An absolute threshold for a positive response (i.e. 5 net nuclear grains) was not used. - Statistics:
- Statistical significance compared to controls was assessed by Student's t-test (two-tailed)
- Species / strain:
- hepatocytes: primary cultures from livers of two human subjects
- Metabolic activation:
- not specified
- Genotoxicity:
- negative
- Remarks:
- see table below
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- see table below
- Vehicle controls validity:
- not examined
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Remarks on result:
- other: all strains/cell types tested
- Remarks:
- Migrated from field 'Test system'.
- Conclusions:
- In a UDS test similar to OECD test guideline 482, no increase in DNA repair could be observed after treatment of primary human hepatocytes with valeraldehyde. Valeraldehyde was demonstrated to be negative and not to induce a mutagenic response in primary human hepatocytes.
- Executive summary:
In an unscheduled DNA synthesis assay, primary cultures of human hepatocyte were exposed to valeraldehyde (purity 98%) at concentrations of 0, 0.26, 0.86, and 2.58 mg/ml for 20 h in the presence of tritium labeled thymidine. Human hepatocytes were obtained from discarded liver fragments during prescribed surgery of two human subjects.
Valeraldehyde was tested up to concentrations indicating the beginning of cytotoxicity. Treated cells did not show any statistically significant increases in DNA synthesis. The positive controls induced the appropriate response. There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures (nuclear silver grain counts) was induced. Primary cultures of human hepatocytes were demonstrated to be negative in this unscheduled DNA synthesis assay (Martelli 1994).
This study is classified as acceptable. It satisfies the requirement of Test Guideline OECD 482 for DNA damage and repair (deviation: limited reporting).
- Endpoint:
- in vitro gene mutation study in mammalian cells
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Acceptable, adequately-documented publication which meets basic scientific principles (deviations from guideline: only tests without metabolic activation, only 3 concentrations tested, positive control substance differing from TG, limited reporting)
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 476 (In Vitro Mammalian Cell Gene Mutation Test)
- Deviations:
- yes
- Remarks:
- only tests without metabolic activation, only 3 concentrations tested, positive control substance differing from TG, limited reporting
- Principles of method if other than guideline:
- Pre-guideline study, but the method used is similar to OECD test guideline 476 (In Vitro Mammalian Cell Gene Mutation Test). The mutagenic effect was examined for 2 target genes (HPRT locus - resistance to 6-thioguanine (TG) and Na/K-ATPase locus - resistance to ouabain (OUA)). Five n-alkanals were tested.
- GLP compliance:
- no
- Type of assay:
- mammalian cell gene mutation assay
- Target gene:
- HGPRT and Na/K-ATPase locus
- Species / strain / cell type:
- Chinese hamster lung fibroblasts (V79)
- Details on mammalian cell type (if applicable):
- The cells for this study were obtained from NIH, Coriell Institute for Medical Research (Camden, NJ, USA)
- Metabolic activation:
- without
- Test concentrations with justification for top dose:
- 0, 3, 10, 30 mM (0.26, 0.86, 2.58 mg/mL)
- Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: no data
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- no
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: N-methyl-N-nitrosourea (MNU; 0.3 and 1.0 mM)
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: preincubation in serum free medium
DURATION
- Preincubation period: 60 min
- Exposure duration: 60 min
- Expression time (cells in growth medium): 6 days
- Selection time (if incubation with a selection agent): 8 days
SELECTION AGENT (mutation assays): 6-thioguanine
NUMBER OF REPLICATIONS: 10 petri plates
NUMBER OF CELLS EVALUATED: 3 x 10E05 per plate
DETERMINATION OF CYTOTOXICITY
- Method: other: relative survival - Evaluation criteria:
- The test result is considered as positive (test substance mutagenic) if the mutant frequency induced by the test substance is threefold higher than the spontaneous mutant frequency (mutant frequency in negative controls).
- Statistics:
- Significance levels were determined according to Kastenbaum and Bowman (1970, Mutat Res 9, 527-549)
- Key result
- Species / strain:
- Chinese hamster lung fibroblasts (V79)
- Metabolic activation:
- without
- Genotoxicity:
- positive
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- highest dose relative survival 56%
- Vehicle controls validity:
- not examined
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Conclusions:
- Interpretation of results: positive without metabolic activation
In a mammalian in vitro gene mutation test (HPRT assay), valeraldehyde induced a dose dependent, more than 3-fold, statistically significant increase in mutant colonies compared to negative controls and was demonstrated to be mutagenic in the test system under the test conditions used. - Executive summary:
In a mammalian cell gene mutation assay (forward mutation at the HPRT locus and the Na/K-ATPase locus), V79 cells (Chinese hamster lung fibroblasts) cultured in vitro were exposed to valeraldehyde (purity 98%) in the absence of mammalian metabolic activation at concentrations of 0, 0.26, 0.86, and 2.58 mg/mL.
Valeraldehyde was tested up to cytotoxic concentrations (highest dose 56% survival). At the highest dose, increase in mutation frequency was about fivefold of controls (66.6 versus 13.3) The positive controls did induce the appropriate response. There was a concentration related positive response of induced mutant colonies over background. In this test, valeraldehyde was demonstrated to show a positive mutagenic response under the test conditions used (Brambilla 1989).
This study is classified as acceptable. Though pre-guideline, this study satisfies the requirement for Test Guideline OECD 476 for in vitro mutagenicity data (mammalian forward gene mutation) with some restrictions (only tests without metabolic activation, only 3 concentrations tested, positive control substance differing from TG, limited reporting).
- Endpoint:
- in vitro DNA damage and/or repair study
- Remarks:
- Type of genotoxicity: DNA damage and/or repair
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Acceptable, well-documented publication which meets basic scientific principles (limited reporting)
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 482 (Genetic Toxicology: DNA Damage and Repair, Unscheduled DNA Synthesis in Mammalian Cells In Vitro)
- Deviations:
- yes
- Remarks:
- limited reporting
- Principles of method if other than guideline:
- No guideline stated but the test method used is similar to OECD test guideline 482. Five n-alkanals were tested.
- GLP compliance:
- no
- Type of assay:
- other: in vitro UDS assay
- Species / strain / cell type:
- hepatocytes: primary cultures from livers of male Sprague-Dawley rats
- Details on mammalian cell type (if applicable):
- - primary hepatocytes were isolated from rat liver by collagenase perfusion as described by Williams (1977, Cancer Res 37, 1845-1851). Cells were at least 80% viable.
- Type and identity of media: Williams' medium E - Test concentrations with justification for top dose:
- 0, 3, 10, and 30 mM (0, 0.26, 0.86, and 2.58 mg/mL); in addition 100 mM (8.61 mg/mL) for the determination of cytotoxicity
- Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: none
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- no
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- N-dimethylnitrosamine
- Remarks:
- concentration: 5 mM (0.37 mg/mL)
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in medium
DURATION
- Exposure duration: 20 h; cells were simultaneously exposed to test compound and tritiated thymidine (10 µCi/mL [methyl-3H]thymidine))
- Expression time (cells in growth medium): 20 h
- Fixation time (start of exposure up to fixation or harvest of cells): 20 h
STAIN (for cytogenetic assays): hematoxylin and eosin (after development of autoradiographs)
NUMBER OF REPLICATIONS: two cultures from distinct rats each
NUMBER OF CELLS EVALUATED: total of 200; 100 (2 slides) per culture
DETERMINATION OF CYTOTOXICITY
- Method: determination of viability (percent survival) by counting cells (1000/dish) after staining exposed cell cultures with 0.4% trypan blue - Evaluation criteria:
- A compound is considered positive if a dose-dependent increase is observed in net nuclear grains for at least two points and both increased points are above the justified laboratory-specific threshold, and/or statistical significance is demonstrated for both points (Internation Workshop on Standardization of Genotoxicity Test Procedures, Melbourne, 1992)
An absolute threshold for a positive response (i.e. 5 net nuclear grains) was not used. - Statistics:
- Statistical significance compared to controls was assessed by Student's t-test (two-tailed)
- Key result
- Species / strain:
- hepatocytes: primary culture from livers of male Sprague-Dawley rats
- Metabolic activation:
- not specified
- Genotoxicity:
- positive
- Remarks:
- see table below
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- see table below
- Vehicle controls validity:
- not examined
- Untreated negative controls validity:
- valid
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- COMPARISON WITH HISTORICAL CONTROL DATA: results for controls are within the range of historical control data
- Conclusions:
- Interpretation of results:
positive response is only weak positive
In a UDS test similar to OECD test guideline 482, a statistically significant increase in DNA repair (about 4-fold of controls) was observed after treatment of primary rat hepatocytes with valeraldehyde. Though the response was weak and did not reach the value of 5 net nuclear grains, the effect is considered as positive. - Executive summary:
In an unscheduled DNA synthesis assay, primary rat hepatocyte cultures were exposed to valeraldehyde (purity 98%) at concentrations of 0, 0.26, 0.86, and 2.58 mg/ml for 20 h in the presence of tritium labeled thymidine.
Valeraldehyde was tested up to cytotoxic concentrations. Treated cells showed statistically significant increases in DNA synthesis (controls 0.63 NNG, treated cells between 2.30 and 2.65 NNG; p < 0.001). The positive controls induced the appropriate response (33.41 NNG). There was evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures (nuclear silver grain counts) was induced but only to a very moderate extent (Martelli 1994).
This study is classified as acceptable. It satisfies the requirement of Test Guideline OECD 482 for DNA damage and repair (deviation: limited reporting).
- Endpoint:
- in vitro gene mutation study in bacteria
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with national standard methods with acceptable restrictions
- Remarks:
- only 4 strains of S. thyphimurium tested
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Deviations:
- yes
- Remarks:
- only 4 strains of S. thyphimurium tested
- GLP compliance:
- not specified
- Type of assay:
- bacterial reverse mutation assay
- Target gene:
- his
- Species / strain / cell type:
- S. typhimurium, other: TA97, TA 98, TA 100, TA1535
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9 mix from livers of induced maled Sprague Dawley rats and induced male Syrian hamsters (10% and 30% each)
- Test concentrations with justification for top dose:
- 0, 10, 33, 100, 333, 1000, 2000 µg/plate
- Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: DMSO
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- other: without metabolic activation: 9-aminoacridine (TA97), sodium azide (TA 100, TA 1535), 2-nitrofluorene (TA 98); with metabolic activation: 2-aminoanthracene
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: preincubation
DURATION
- Preincubation period: 20 min at 37°C
- Exposure duration: 2 days
- Expression time (cells in growth medium): 2 days at 37°C
DETERMINATION OF CYTOTOXICITY
- Method: no data - Evaluation criteria:
- Number of mutant colonies of positive controls must be significantly increased over the spontaneous control numbers for the test to be considered valid.
Numbers of mutant colonies of test plates have to be significantly increased over the mutant colony numbers of negative control plates. - Statistics:
- Mean and standard error of the mean of replicate plates were calculated
- Species / strain:
- S. typhimurium, other: TA97, TA 98, TA 100, TA1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- starting from a concentration of ca. 1000 µg/plate depending on strain and experimental conditions (metabolic system)
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Conclusions:
- Interpretation of results:
negative with and without metabolic activation
n-Pentanal (valeraldehyde) was not mutagenic in Salmonella typhimurium strains TA 97, TA 98, TA100 and TA1535 with and without metabolic activation.
According to OECD 471, valeraldehyde is not mutagenic to Salmonella typhimurium. - Executive summary:
In a reverse gene mutation assay in bacteria, strains of S. typhimurium (TA 97, TA 98, TA 100, and TA 1535) were exposed to n-pentanal (valeraldehyde) at concentrations of 0, 10, 33, 100, 333, 1000, and 2000 µg/plate in the presence and absence of mammalian metabolic activation (S9 mix from induced rabbit and rat liver). Preincubation was 20 min before plating.
Valeraldehyde was tested up to the limit concentration of 2000 µg/plate. With the two highest concentrations, fractional cytotoxicity was observed depending on strain and metabolic activation. The positive controls induced the appropriate responses in the corresponding strains. Valeraldehyde did not increase the number of revertants in any of the test strains. There was no evidence of induced mutant colonies over background (NTP, 1988).
This study is classified as acceptable. It was performed according to OECD test guideline 471 with minor restrictions (only 4 strains of S. thyphimurium tested).
Referenceopen allclose all
Results of UDS test with primary human hepatocytes
Treatment |
Concentration [mg/mL] |
% Cell survival |
NUC* (mean ± SD) |
CYT* (mean ± SD) |
NNG* (mean ± SD) |
% Repair** |
|
Subject 1 |
Subject 2 |
||||||
Controls |
|
92 |
97 |
8.88 ± 3.36 |
8.33 ± 3.12 |
0.55 ± 1.69 |
1 |
Valeraldehyde |
0.26 |
91 |
95 |
10.01 ± 3.33 |
9.16 ± 2.40 |
0.85 ± 2.07 |
6 |
0.86 |
90 |
95 |
11.40 ± 4.21 |
10.54 ± 3.84 |
0.86 ±2.63 |
5 |
|
2.58 |
87 |
91 |
9.09 ± 5.12 |
8.00 ± 4.25 |
1.09 ± 3.02 |
8 |
|
DMNA**** |
0.37 |
80 |
93 |
24.64 ± 5.38 |
6.51 ± 3.94 |
18.13 ± 4.95*** |
90 |
* NUC: nuclear grain count; CYT: cytoplasmic grain count; NNG:net nuclear grains
** Percentage repair is the percentage of cells with net nuclear labeling ≥ 5 grains
*** p < 0.001
**** DMNA: N,N-Dimethylnitrosamine
No increase of net nuclear grains was observed in valeraldehyde treated cell cultures. The number of cells in repair was always below 10%.
Mutation Frequency and Relative Survival
Substance |
Concentration |
HPGRT locus |
Na/K-ATPase locus |
||
Mutation Frequency |
Relative Survival |
Mutation Frequency |
Relative Survival |
||
Valeraldehyde |
0 |
13.3 ± 4.7 |
0.93 ± 0.01 |
1.8 ± 1.5 |
0.78 ± 0.07 |
3 (0.26) |
18.6 ± 2.7 |
0.87 ± 0.06 |
2.6 ± 2.5 |
0.89 ± 0.09 |
|
10 (0.86) |
36.7 ± 10.0** |
0.73 ± 0.22 |
4.3 ± 3.1* |
0.66 ± 0.26 |
|
30 (2.58) |
66.6 ± 18.5** |
0.56 ± 0.26 |
6.5 ± 2.3** |
0.44 ±0.13 |
|
MNU |
0 |
15.1 ±0.3 |
0.89 ± 0.04 |
|
|
0.3 (0.031) |
38.1 ± 5.3** |
0.84 ± 0.04 |
|
|
|
1.0 (0.1) |
106.8 ± 33.3** |
0.64 ± 0.12 |
|
|
|
EMS (pos. control) |
0 |
|
|
1.4 ± 0.8 |
0.81 ± 0.08 |
8 (0.99) |
|
|
18.1 ± 4.6** |
0.69 ± 0.05 |
|
16 (1.99) |
|
|
28.4 ± 7.0** |
0.59 ± 0.14 |
* P < 0.05 ** P < 0.01
Results of UDS test with primary rat hepatocytes
Treatment |
Concentration [mg/mL] |
% Survival* |
NUC** (mean ± SD) |
CYT** (mean ± SD) |
NNG** (mean ± SD) |
% Repair*** |
Controls |
|
96.3 ± 2.18 |
10.27 ± 4.52 |
9.64 ± 5.03 |
0.63 ± 4.76 |
5 |
Valeraldehyde |
0.26 |
92.0 ± 3.60 |
11.00 ± 5.24 |
8.65 ± 3.05 |
2.35 ± 4.24**** |
26 |
0.86 |
90.7 ± 5.03 |
14.44 ± 4.16 |
12.14 ± 5.10 |
2.30 ± 3.78**** |
23 |
|
2.58 |
75.0 ± 22.72 |
15.13 ± 4.01 |
10.88 ± 4.25 |
2.65 ± 3.88**** |
22 |
|
8.61 |
36.3 ± 31.94 |
- |
- |
- |
- |
|
DMNA***** |
0.37 |
93.0 ± 5.14 |
40.66 ± 21.50 |
7.25 ± 5.1 |
33.41 ± 23.11**** |
91 |
* Data are means ± SD of three independent assays
** NUC: nuclear grain count; CYT: cytoplasmic grain count; NNG: net nuclear grains
*** percentage repair is the percentage of cells with net nuclear labeling ≥ 5 grains
**** p < 0.001
***** DMNA: N,N-Dimethylnitrosamine
Since valeraldehyde caused a marginal and not significant increase of cytoplasmic labeling, the increase in the number of net nuclear grains can definitely attributed to DNA repair synthesis. The occurrence of DNA repair is supported by the parallel increase in the number of cells in repair.
Tables presenting the revertant counts for all tests including information on cytotoxicity are appended under attached background material.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (positive)
Genetic toxicity in vivo
Description of key information
No in vivo genotoxicity studies have been identified with n-valeraldehyde. Negative results were obtained in an in vivo micronucleus assay with the structural similar iso-valeraldehyde, which is considered to be representative for valeraldehyde.
Link to relevant study records
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2000-10-09 - 2001-02-13
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)
- GLP compliance:
- yes
- Remarks:
- Experimental Toxicology and Ecology, BASF AG
- Type of assay:
- micronucleus assay
- Species:
- mouse
- Strain:
- NMRI
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Deutschland
- Age at study initiation: 5 - 8 weeks
- Weight at study initiation: mean ca. 28 g
- Assigned to test groups randomly: yes
- Housing: housed individually in Makrolon cages, type MI
- Diet (e.g. ad libitum): ad libitum, Kliba Haltungsdiät, Provimi Kliba SA, Kaiseraugst, Switzerland
- Water (e.g. ad libitum): ad libitum, drinking water from bottles
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12 - Route of administration:
- intraperitoneal
- Vehicle:
- - Vehicle(s)/solvent(s) used: DMSO
- Justification for choice of solvent/vehicle: Due to the limited solubility of the test substance in water, DMSO was selected as the vehicle, which had been demonstrated to be suitable in the in vivo micronucleus test and for which historical data are available. - Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
All test substance formulations were prepared immediately before administration - Duration of treatment / exposure:
- single injection
- Frequency of treatment:
- one single application
- Post exposure period:
- 24, 48 h
- Remarks:
- Doses / Concentrations:
0, 25, 50, 100 mg/kg bw
Basis:
nominal conc. - No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- Cyclophosphamide (CPP), 20 mg/kg body weight for clastogenic effects
Vincristirie Sulphate (VCR), 0,15 mg/kg body weight for aneugenic effects
- Justification for choice of positive control(s): The stability of CPP and VCR is well-defined under the selected conditions, since both positive control articles are well-defined clastogens and aneugens respectively
- Route of administration: intraperitoneally - Tissues and cell types examined:
- polychromatic and normochromatic erythrocytes of bone marrow
- Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION:
In a pretest for the determination of the acute intraperitoneal toxicity, deaths were observed down to a dose of 150 mg/kg body weight. 100 mg/kg body weight were survived by all animals but led to evident signs of toxicity such as piloerection, squatting posture, and the general state of the animals was poor, however, showing no distinct symptomatic differences between the male and female animals.
Thus, only male animals were used for the cytogenetic investigations.
Therefore, a dose of 100 mg/kg body weight was selected as the highest dose in the present cytogenetic study. 50 mg/kg and 25 mg/kg body weight were administered as further doses.
TREATMENT AND SAMPLING TIMES ( in addition to information in specific fields):
The animals were treated once and samples of bone marrow were taken 24 hours and 48 hours after the treatment
- The low dose group was given 25 mg test substance/kg body weight or 4 ml/kg body weight of a solution with a concentration of 0.625 g/100 ml.
- The intermediate dose group was given 50 mg test substance/kg body weight or 4 ml/kg body weight of a solution with a concentration of 1.25 g/100 ml.
- The top dos~: groups were given 100 mg test substance/kg body weight or 4 ml/kg body weight of a solution with a concentration of 2.5 g/100 ml
DETAILS OF SLIDE PREPARATION:
The bone marrow was prepared according to the method described by SCHMID (1976):
- The two femora were prepared by dissection and removing all soft tissues.
After cutting off the epiphyses, the bone marrow was flushed out of the diaphysis into a centrifuge tube using a cannula filled with fetal calf serum which was at 37°C (about 2 ml/femur). The suspension was mixed thoroughly with a pipette, centrifuged at 300 x g for 5 minutes, the supernatant was removed and the precipitate was resuspended in about 50 pl fresh FCS. 1 drop of this suspension was dropped onto clean microscopic slides, using a Pasteur pipette. Smears were prepared using slides with ground edges, the preparations were dried in the air and subsequently stained.
METHOD OF ANALYSIS:
In general, 2000 polychromatic erythrocytes (PCE) from each of the male animals of every test group are evaluated and investigated for micronuclei (MN). The normochromatic erythrocytes (NCE) which occur are also scored. - Evaluation criteria:
- The test chemical is to be considered positive in this assay if the following criteria are met:
- A dose-relatod and significant increase in the number of micronucleated polychromatic erythrocytes at any of the intervals.
- The proportion of cells containing micronuclei exceeded both the values of the concurrent negative control range and the negative historical control range.
A test substance is generally considered negative in this test system if:
- There was no significant increase in the number of micronucleated polychromatic erythrocytes at any dose above concurrent control frequencies and at any time.
- The frequencies of cells containing micronuclei were within the historical control range. - Statistics:
- The statistical evaluation of the data was carried out using the program system MUKERN (BASF Aktiengesellschaft) .
The number of micronuclei in polychromatic erythrocytes was analyzed. A comparison of the dose group with the vehicle control was carried out using the Wilcoxon test for the hypothesis of equal medians. Here, the relative frequencies of cells with micronuclei of each animal were used. If the results of this test were significant, labels (* for p <= 0.05, ** for p >= 0.01) were printed with the group means in the tables.
This test was performed one-sided. - Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- yes
- Remarks:
- squatting, poor general state, piloerection
- Vehicle controls validity:
- valid
- Negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Additional information on results:
- RESULTS OF RANGE-FINDING STUDY
- Dose range: 150, 100 mg/kg bw
- Clinical signs of toxicity in test animals: piloerection, squatting posture, and the general state of the animals was poor - Conclusions:
- Interpretation of results: negative
The test substance had no chromosome-damaging (clastogenic) effect, and there were no indications of any impairment of chromosome distribution in the course of mitosis (aneugenic activity) in bone marrow cells in vivo. - Executive summary:
In this in vivo micronucleus test (according to OECD Guideline 474, GLP), 5 male mice (strain: NMRI) were dosed intraperitoneally with the test item isovaleraldehyde. Test doses were 0, 25, 50, 100 mg/kg bw. The top dose was selected based on a pretest were mortality was observed down to a dose of 150 mg/kg bw and 100 mg/kg bw was survived by all animals but led to signs of toxicity. The animals were treated once and samples of bone marrow were taken 24 hours and 48 hours after the treatment. In general, 2000 polychromatic erythrocytes (PCE) from each of the male animals of every test group are evaluated and investigated for micronuclei (MN). The normochromatic erythrocytes (NCE) which occur were also scored.
There was no increase in the number of polychromatic erythrocytes containing either small or large micronuclei. The rate of microneuclei was nearly the range of the concurrent negative control in all dose groups and within the range of the historical control data. No inhibition of erythropoiesis, determined from the ratio of polychromatic to normochromatic erythrocytes, was detected.
The result for the negative control was within the historical control range. According to this study, the test item is considered to be not chromosome-damaging (clastogenic) effect, and does not lead to any impairment of chromosome distribution in the course of mitosis (aneugenic activity).
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- For details on endpoint specific justification please see read-across justification report attached to this endpoint study record.
- Reason / purpose for cross-reference:
- read-across source
- Sex:
- male
- Genotoxicity:
- negative
- Toxicity:
- yes
- Remarks:
- squatting, poor general state, piloerection
- Vehicle controls validity:
- valid
- Negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Conclusions:
- Interpretation of results: negative
The test substance had no chromosome-damaging (clastogenic) effect, and there were no indications of any impairment of chromosome distribution in the course of mitosis (aneugenic activity) in bone marrow cells in vivo. - Executive summary:
The study used as source investigated the effect of isovaleraldehyde on genotoxicity. The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (structural analogue) is outlined in the read-across report in section 13 or find a link in cross reference “assessment report”.
Referenceopen allclose all
The administration of the test substance led to evident signs of toxicity:
- 25 mg/kg bw:
1, 2 and 4 h: squatting posture; 1 d: no symptoms
- 50 mg/kg bw:
1 h: squatting posture; 2 and 4 h: squatting posture and poor general state; 1 d: no symptoms
- 100 mg/kg bw:
1 h: squatting posture and poor general state, 2 and 4 h:
squatting posture, poor general state and piloerection;
1 d: poor general state and piloerection
Results:
Test group | Interval: 24 h | Interval: 48 h | ||||||
Polychromatic erythrocytes | Normocytes / total amount polychromatic erythrocytes | Cells with micronuclei (%) | Polychromatic erythrocytes | Normocytes / total amount polychromatic erythrocytes | Cells with micronuclei (%) | |||
Dose (mg/kg bw) | polychromatic | normochromatic | polychromatic | normochromatic | ||||
vehicle control | 10000 | 3396 | 1.3 | 0.3 | 100000 | 2974 | 1.7 | 1.0 |
25 | 10000 | 3997 | 1.3 | 1.5 | ||||
50 | 10000 | 3764 | 2.2 | 2.9 | ||||
100 | 10000 | 3769 | 1.9 | 1.6 | 10000 | 4193 | 0.9 | 1.0 |
20, cyclophosphamide | 10000 | 3092 | 21.5** | 3.6 | ||||
0.15, vincristine | 10000 | 4859 | 49.7** | 2.3 |
* p<=0.05; ** p<= 0.01
There was no increase in the number of polychromatic erythrocytes containing either small or large micronuclei.
The rate of microneuclei was nearly the range of the concurrent negative control in all dose groups and within the range of the historical control data.
No inhibition of erythropoiesis, determined from the ratio of polychromatic to normochromatic erythrocytes, was detected.
The result for the negative control was within the historical control range.
Both of the positive control chemicals, i.e. cyclophosphamide for clastogenic effects and vincristine for induction of spindle poison effects, induced the expected increases in the rate of polychromatic erythrocytes containing small or large micronuclei.
The administration of the test substance led to evident signs of toxicity:
- 25 mg/kg bw:
1, 2 and 4 h: squatting posture; 1 d: no symptoms
- 50 mg/kg bw:
1 h: squatting posture; 2 and 4 h: squatting posture and poor general state; 1 d: no symptoms
- 100 mg/kg bw:
1 h: squatting posture and poor general state, 2 and 4 h:
squatting posture, poor general state and piloerection;
1 d: poor general state and piloerection
Results:
Test group | Interval: 24 h | Interval: 48 h | ||||||
Polychromatic erythrocytes | Normocytes / total amount polychromatic erythrocytes | Cells with micronuclei (%) | Polychromatic erythrocytes | Normocytes / total amount polychromatic erythrocytes | Cells with micronuclei (%) | |||
Dose (mg/kg bw) | polychromatic | normochromatic | polychromatic | normochromatic | ||||
vehicle control | 10000 | 3396 | 1.3 | 0.3 | 100000 | 2974 | 1.7 | 1.0 |
25 | 10000 | 3997 | 1.3 | 1.5 | ||||
50 | 10000 | 3764 | 2.2 | 2.9 | ||||
100 | 10000 | 3769 | 1.9 | 1.6 | 10000 | 4193 | 0.9 | 1.0 |
20, cyclophosphamide | 10000 | 3092 | 21.5** | 3.6 | ||||
0.15, vincristine | 10000 | 4859 | 49.7** | 2.3 |
* p<=0.05; ** p<= 0.01
There was no increase in the number of polychromatic erythrocytes containing either small or large micronuclei.
The rate of microneuclei was nearly the range of the concurrent negative control in all dose groups and within the range of the historical control data.
No inhibition of erythropoiesis, determined from the ratio of polychromatic to normochromatic erythrocytes, was detected.
The result for the negative control was within the historical control range.
Both of the positive control chemicals, i.e. cyclophosphamide for clastogenic effects and vincristine for induction of spindle poison effects, induced the expected increases in the rate of polychromatic erythrocytes containing small or large micronuclei.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Mode of Action Analysis / Human Relevance Framework
In the absence of information on a species specific mode of action the available information is regarded as relevant for humans.
Additional information
The genotoxic potential of valeraldehyde was tested in vitro with bacterial and mammalian cells (see table below). In vivo genotoxicity studies could not be identified. However, anin vivo test results is available for the closely related isovaleraldehyde (structural isomer with a branched carbon chain) which can be used for read across.
The following table summarises the available studies used in the genetic toxicity assessment of valeraldehyde:
Study | Substance | Reliability | GLP | Test type/ | Guideline | Results | Remarks |
In vitro tests; | |||||||
NTP | Valeraldehyde | 2 | no data | Ames | similar | negative | tested up to 2000 µg/plate with and without metab. activ. |
In vitro tests, | |||||||
Brambilla | Valeraldehyde | 2 | no | HPRT | similar | positive | V79 cells; |
Martelli 1994 | Valeraldehyde | 2 | no | Gen. Tox. | similar | positive | primary hepatocytes; |
Marinari | Valeraldehyde | 2 | no | DNA damage | no TG | positive | single strand breaks, |
In vivo tests; | |||||||
BASF AG | Read across; | 1 | yes | MNT | Similar to | negative | Read across; 3 concentrations up to |
The Ames test is negative.
Results of in vitro tests with mammalian cell systems are predominantly positiv.
In vivo genotoxicity studies for valeraldehyde are not available, but data from the closely related iso-valeraldehydes can be used for read across.
Isovaleraldehyde was tested by BASF in an in vivo mammalian erythrocyte micronucleus test. The result was negative (no increase in polychromatic erythrocytes containing neither small nor large micronuclei). The study satisfies the requirements of OECD TG 474.
Based on the above, it is concluded that valeraldehyde does not induce cytogenic effects. But the positive results in the mammalian cells require further clarification.
Justification for classification or non-classification
Based on the available information it is concluded that valeraldehyde does not meet classification criteria according to Regulation (EC) No 1272/2008 for germ cell mutagenicity.
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