Registration Dossier
Registration Dossier
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EC number: 203-931-2 | CAS number: 112-05-0
Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Description of key information
In-vivo micronucleus test and all in-vitro tests on the various genotoxicity endpoints (mutagenicity in bacterial and mammlian cells; chromosome aberration) were negative.
Link to relevant study records
- 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:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- bacterial reverse mutation assay
- Target gene:
- histidine operon (Salmonella typhimurium))
tryptophan operon (E. coli) - Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Species / strain / cell type:
- E. coli WP2 uvr A
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9-mix; contains 9000 g rat liver supernatant from Aroclor 1254 induced Wistar rats
- Test concentrations with justification for top dose:
- 100, 333, 1000, 3330, and 5000 µg/plate
- Vehicle / solvent:
- - Vehicle/solvent used: DMSO
- Justification for choice of solvent/vehicle: low water solubility of the test substance - Untreated negative controls:
- yes
- Remarks:
- historical controls
- Negative solvent / vehicle controls:
- yes
- Positive controls:
- yes
- Positive control substance:
- other: Without metabolic activation: sodium azide; 9-aminoacridine; daunomycine; methylmethanesulfonate; 4-nitroquinoline N-oxide. With metabolic activation: 2-aminoanthracene.
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in agar (plate incorporation)
DURATION
- Exposure duration: 48 hours
- Expression time (cells in growth medium): 48 hours
- Selection time (if incubation with a selection agent): 48 hours
SELECTION AGENT (mutation assays): hisitidine (S. typhimurium); tryptophan (E. coli)
NUMBER OF REPLICATIONS: 3
NUMBER OF CELLS EVALUATED: all colonies
DETERMINATION OF CYTOTOXICITY
- Method: cloning efficiency; relative total growth - Evaluation criteria:
- Inter alia, at least doubling of vehicle control number of revertants in at least one strain, and reproducibility
- Statistics:
- Calculation of means and standard deviation
- Species / strain:
- S. typhimurium TA 1535
- 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
- Species / strain:
- S. typhimurium TA 1537
- 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
- Species / strain:
- S. typhimurium TA 98
- 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
- Species / strain:
- S. typhimurium TA 100
- 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
- Species / strain:
- E. coli WP2 uvr A
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity, but tested up to precipitating concentrations
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Precipitation: noted at 5000 µg/plate
RANGE-FINDING/SCREENING STUDIES: yes
COMPARISON WITH HISTORICAL CONTROL DATA: yes
ADDITIONAL INFORMATION ON CYTOTOXICITY: strain-dependent reduction of treh number of revertant colonies was not from 1000 µg/plate onwards (cf. below) - Conclusions:
- Interpretation of results:
negative
Pelargonic acid was not genotoxic in bacteria. - Executive summary:
Pelargonic acid was not mutagenic in the Ames test (OECD guideline No. 471) using Salmonella typhimurium (strains TA98, TA100, TA1535, and TA1537) and E. coli (WP2uvrA) when tested up 5000 µg/mL with and without metabolic activation under GLP conditions. Precipitation was seen at 5000 µg/mL. Strain specific cytotoxicity was seen, as evidenced by reduced bacterial background lawn and/or reduction of the number of revertant colonies with increasing doses. Solvent control and positive controls performed as expected. Thus, pelargonic acid was not genotoxic in bacteria (NOTOX, 2001).
- Endpoint:
- in vitro cytogenicity / chromosome aberration study in mammalian cells
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.10 (Mutagenicity - In Vitro Mammalian Chromosome Aberration Test)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- in vitro mammalian chromosome aberration test
- Species / strain / cell type:
- lymphocytes: cultured peripheral human
- Details on mammalian cell type (if applicable):
- - Type and identity of media: F10 complete culture medium
- Properly maintained: yes
- Periodically checked for Mycoplasma contamination: not required. Cell cultures were started within 4 hours after blood collection.
- Periodically checked for karyotype stability: not required. Cell cultures were started within 4 hours after blood collection.
- Periodically "cleansed" against high spontaneous background: not required. Cell cultures were started within 4 hours after blood collection. - Metabolic activation:
- with and without
- Metabolic activation system:
- 9000g supernatanet (S9) from Aroclor 1254 induced rat liver
- Test concentrations with justification for top dose:
- 1st experiment, w/wo metabolic activation: 100, 333, 420, 480, 520*, 750* µg/mL
2nd experiment:
wo metabol activation: 10, 33, 100, 240, 300 µg/mL
with metabol activation: 333, 420, 480, 520* µg/mL
* = precipitation - Vehicle / solvent:
- - Vehicle/solvent used: DMSO
- Justification for choice of solvent/vehicle: low solubility of pelargonic acid - Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- Positive controls:
- yes
- Positive control substance:
- cyclophosphamide
- Remarks:
- both mitomycin C and cyclophosphamide were used Migrated to IUCLID6: mitomycin C
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in medium
DURATION
- Preincubation period: 48 hours
- Exposure duration:
First experiment: with S9: 3 hours. Without S9: 3, 24, and 48 hours.
Second experiment: with S9: 3 hours. Without S9: 24 and 48 hours.
- Expression time (cells in growth medium): 48 hours
- Fixation time (start of exposure up to fixation or harvest of cells): 51- 96 hours
SPINDLE INHIBITOR (cytogenetic assays): colchicine
NUMBER OF REPLICATIONS: 2
NUMBER OF CELLS EVALUATED: 200/dose level/experiment
DETERMINATION OF CYTOTOXICITY
- Method: mitotic index
OTHER EXAMINATIONS:
- Determination of polyploidy: yes
- Determination of endoreplication: yes - Evaluation criteria:
- A result was considered positive if a statistically significant (p<0.05) increase of the number of cells with chromosome aberrations was seen.
- Statistics:
- Chi-square test
- Key result
- Species / strain:
- lymphocytes: cultured peripheral human
- 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
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Effects of pH: at 480 µg/mL the pH was lowered to 7.34, compared to pH=7.48 of the solvent control; p. 12)
- Effects of osmolality: no
- Precipitation: yes; at 520 and 750 µg/mL in the First and Second experiment
RANGE-FINDING/SCREENING STUDIES: yes
COMPARISON WITH HISTORICAL CONTROL DATA: yes
ADDITIONAL INFORMATION ON CYTOTOXICITY: yes - Conclusions:
- Interpretation of results:
negative
Pelargonic acid did not induce chromosomal aberrations and was not clastogenic in human lymphocytes with and without metabolic activation - Executive summary:
Pelargonic acid was tested for its ability to induce chromosomal aberrations in cultured human peripheral lymphocytes in a study conducted according to OECD test guideline No. 473 and under GLP conditions. Following a range finding pre-test, two independent experiments were conducted, both with and without metabolic activation (S9 mix; contained 9000g supernatant from Aroclor 1254 induced male Wistar rat liver). The test concentrations in the definitive test ranged from 100 to 750 µg/mL.
Precipitation was seen at 520 and 750 µg/mL. The pH at the highest non-precipitating dose level was of 480 µg/mL was lowered to 7.34, compared to pH=7.48 of the solvent control. Low mitotic index below 50% of the control indicated cytotoxicity at 750 µg/mL in the first experiment and at 240 µg/mL and above in the second.
A statistically significantly increased number of cells with chromosome aberrations was only seen at the toxic concentration of 750 µg/mL (mitotic index 38%, with and without metabolic activation), which was ruled out as being not biologically relevant. The solvent and positive controls performed as expected.
Therefore, it was concluded that pelargonic acid did not induce chromosomal aberrations and was not clastogenic in human lymphocytes with and without metabolic activation (NOTOX, 2001).
- Endpoint:
- in vitro gene mutation study in bacteria
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1989-06-15 through 1989-08-29
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study
- Remarks:
- no information on genotoxicity in S. typhimurium TA 102 or E. coli WP2 uvrA
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Deviations:
- no
- Principles of method if other than guideline:
- Salmonella/mammalian-microsome plate incorporation test
- GLP compliance:
- yes
- Type of assay:
- bacterial reverse mutation assay
- Target gene:
- Histidine operon
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Species / strain / cell type:
- S. typhimurium TA 1538
- Metabolic activation:
- with and without
- Metabolic activation system:
- microsomal enzymes from Aroclor 1254-induced rat liver
- Test concentrations with justification for top dose:
- 667-10000 µg/plate
- Vehicle / solvent:
- - Vehicle/solvent used: DMSO
- Justification for choice of solvent/vehicle: the test substance was first tested without DMSO in experiment B2 (result: negative). It was then decided to reexamine pelargoniuc acid with DMSO as vehicle in experiment B3. - Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- yes
- Positive controls:
- yes
- Positive control substance:
- other: 2-aminoanthracene, 2-nitrofluorene, sodium azide, ICR-191
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in agar (plate incorporation)
DURATION
- Exposure duration: 48 hours
- Expression time (cells in growth medium): 48 hours
SELECTION AGENT (mutation assays): histidine independence
NUMBER OF REPLICATIONS: 3
DETERMINATION OF CYTOTOXICITY
- Method: number of revertants per plate and background lawn condition
- Strain: TA100
Activation: with and without
Doses tested: 10, 33, 67, 100, 333, 667, 1000, 3333, 6667, 10000 µg/plate
- Evaluation criteria:
- 1) test validity criteria: tester strain integrity; tester strain titers; no. of spontaneous revertants within defined ranges; mean positive control values at least 3-fold over the respective vehicle control.
2) evaluation of test result as positive: at least doubling of mean number of revertants in at least one tester strain, accompanied by a dose response - Statistics:
- - Calculation of means +/- standard deviation
- Key result
- Species / strain:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1538
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
ADDITIONAL INFORMATION ON CYTOTOXICITY: there was no pronounced cytotoxicity noted in a rangefinding test using TA100 w/wo metabolic activation at up to 10000 µg pelargonic acid/plate- Conclusions:
- Pelargonic was not mutagenic under the conditions of this study.
- Executive summary:
Pelargonic acid was examined in the Ames-test according to OECD TG 471 under GLP conditions using the Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 both in the absence and presence of metabolic activation (S9 from male Aroclor 254 induced rat liver). The test substance concentrations were 667, 1000, 3333, 6667, and 10000 µg/plate in the definitive experiment, because cytotoxicity was not pronounced at 6667 and 10000 µg/plate in the range finding test with TA100.
In the definitive test, the vehicle control (DMSO) and the positive controls performed as expected, while pelargonic acid did not increase the number of revertants in any strain at any dose, with or without metabolic activation. The same result was obtained in another experiment where water served as vehicle. Thus, pelargoic was not mutagenic.
This study is classified as reliable without restrictions. It was performed in accordance with OECD test guideline 471 and GLP (Hoechst-Celanese/MBA, 1985).
Referenceopen allclose all
Results of experiment 1 (empty cells: strains not examined)
Concentration [µg/plate] |
Metabol activation1 |
Revertants/plate [mean of 3 plates] |
||||
TA 98 |
TA 100 |
TA 1535 |
TA 1537 |
E. coli |
||
DMSO |
- |
16±2 |
n.d. |
13±2 |
6±2 |
n.d. |
100 |
- |
18±7 |
n.d. |
11±2 |
7±1 |
n.d. |
333 |
- |
15±2 |
n.d. |
12±4 |
6±2 |
n.d. |
1000 |
- |
13±1 |
n.d. |
11±1 |
5±1 |
n.d. |
3333 |
- |
9±2 |
n.d. |
11±5 |
2±1 |
n.d. |
5000 |
- |
7±2 |
n.d. |
12±6 |
MC ³ |
n.d. |
Pos. control |
- |
239±71 |
n.d. |
138±5 |
174±10 |
n.d. |
|
||||||
DMSO |
+ |
23±4 |
n.d. |
13±1 |
5±1 |
n.d. |
100 |
+ |
20±5 |
n.d. |
12±1 |
6±2 |
n.d. |
333 |
+ |
25±6 |
n.d. |
9±2 |
6±3 |
n.d. |
1000 |
+ |
15±3 |
n.d. |
10±2 |
4±15 |
n.d. |
3333 |
+ |
16±1 |
n.d. |
7±1 |
1±1 |
n.d. |
5000 |
+ |
11±3 |
n.d. |
11±3 |
MC ³ |
n.d. |
Pos. control |
+ |
419±25 |
n.d. |
138±5 |
418±57 |
n.d. |
MC Microcolonies
1 the S9-mix contained 5% S9 fraction
² background lawn slightly reduced
³ background lawn extremely reduced
n.d. not determined
Results of experiment 2
Concentration [µg/plate] |
Metabol activation1 |
Revertants/plate [mean of 3 plates] |
||||
TA 98 |
TA 100 |
TA 1535 |
TA 1537 |
E. coli |
||
DMSO |
- |
18±1 |
99±10 |
11±2 |
8±3 |
15±5 |
100 |
- |
17±2 |
90±12 |
13±4 |
9±4 |
13±4 |
333 |
- |
18±6 |
81±3 |
13±4 |
6±4 |
10±1 |
1000 |
- |
17±5 |
70±13 |
6±1 |
6±3 |
12±5 |
3333 |
- |
8±4 |
55±5 |
9±3 |
1±2 |
9±4 |
5000 |
- |
5±1 |
5±1 SP |
6±2 ² |
0±0 |
9±2 |
Pos. control |
- |
422±69 |
25±6 ² |
461±24 |
449±58 |
1019±49 |
|
||||||
DMSO |
+ |
23±1 |
79±12 |
14±2 |
7±2 |
15±5 |
100 |
+ |
29±8 |
61±7 |
13±5 |
6±1 |
13±4 |
333 |
+ |
20±2 |
49±13 |
10±1 |
8±3 |
10±1 |
1000 |
+ |
18±5 |
29±2 ² |
13±8 |
6±4 |
12±5 |
3333 |
+ |
14±2 |
13± 2 SP |
7±0 |
2±1 ² |
9±4 |
5000 |
+ |
10±2 |
5±1 SP |
8±3 |
1±1 ² |
9±2 |
Pos. control |
+ |
198±15 |
9±4 ² |
125±28 |
86±18 |
1019±49 |
SP slight precipitate
1 the S9-mix contained 10% S9 fraction
² background lawn slightly reduced
n.d. not determined
Results of experiment 3 (empty cells: strains not examined)
Concentration [µg/plate] |
Metabol activation1 |
Revertants/plate [mean of 3 plates] |
||||
TA 98 |
TA 100 |
TA 1535 |
TA 1537 |
E. coli |
||
DMSO |
- |
27±2 |
n.d. |
15±5 |
5±2 |
12±1 |
1000 |
- |
23±7 |
n.d. |
10±2 |
7±3 |
12±6 |
3333 |
- |
9±3 |
n.d. |
10±6 |
1±1 |
9±5 |
5000 |
- |
9±4SP |
n.d. |
10±3SP |
0±0SP |
7±1SP |
Pos. control |
- |
597±51 |
n.d. |
247±23 |
170±27 |
997±97 |
|
||||||
DMSO |
+ |
38±6 |
n.d. |
13±1 |
7±3 |
13±2 |
1000 |
+ |
26±4 |
n.d. |
9±1 |
7±2 |
10±3 |
3333 |
+ |
16±5 |
n.d. |
12±2 |
1±2 |
15±3 |
5000 |
+ |
14±1SP |
n.d. |
15±8SP |
1±1SP |
12±2SP |
Pos. control |
+ |
306±14 |
n.d. |
116±3 |
148±3 |
286±49 |
SP light precipitate
1 the S9-mix contained 10% S9 fraction
n.d. not determined
1) Range-finding test using TA100, with and without metabolic activation:
Cytotoxicity was not observed up to and including 10000 µ/plate, the highest concentration tested.
2) Experiments conducted:
Experiment B1: a weighing error occured, the experiment was therefore repeated (B2).
Experiment B2: pelargonic acid was tested in all tester strains with and without metabolic activation. Vehicle: water.
The substance was not mutagenic. The results are contained in teh study report but not included in this Robust Study Summary.
Experiment B3: pelargonic acid was tested in all tester strains with and without metabolic activation. Vehicle: DMSO. The substance was also not mutagenic. The results of this experiment are tabulated below.
3) Results of experiment B3
Table:
Gene mutation assay (plate incorporation) results
Average revertants per plate in tester strains TA98, TA 100, TA 1535,
TA1537 and TA 1538 with and without S9-mix
Concentration [µg/plate] |
S9 |
Revertants/plate [mean of 3 plates] |
||||
TA98 |
TA100 |
TA1535 |
TA1537 |
TA1538 |
||
DMSO |
- |
21 |
95 |
8 |
9 |
10 |
667 |
- |
19 |
82 |
11 |
7 |
7 |
1000 |
- |
16 |
79 |
12 |
7 |
6 |
3333 |
- |
13 |
69 |
4 |
5 |
3 |
6667 |
- |
9 |
58 |
5 |
1 |
0 |
10000 |
- |
7 |
12 |
2 |
0 |
0 |
Positive control |
|
255 |
612 |
498 |
287 |
529 |
|
||||||
DMSO |
+ |
24 |
118 |
12 |
7 |
11 |
667 |
+ |
19 |
117 |
10 |
6 |
12 |
1000 |
+ |
19 |
115 |
12 |
8 |
14 |
3333 |
+ |
22 |
117 |
13 |
4 |
7 |
6667 |
+ |
13 |
93 |
6 |
1 |
2 |
10000 |
+ |
11 |
50 |
6 |
0 |
0 |
Positive control |
|
377 |
513 |
40 |
27 |
449 |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Genetic toxicity in vivo
Description of key information
Pelargonic acid lacks genotoxicity. Pelargonic acid was not mutagenic in valid Ames tests conducted in accordance with OECD TG 471 and GLP, with and without metabolic activation. Regarding mammalian cells, pelargonic acid (w/wo metabolic activation) did not induce chromosomal aberrations in human lymphocytes, and was not mutagenic in mouse lymphoma TK+/- cells. Pelargonic was negative in a valid in vivo mouse micronucleus test.
Link to relevant study records
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- secondary literature
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 475 (Mammalian Bone Marrow Chromosome Aberration Test)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- micronucleus assay
- Species:
- mouse
- Strain:
- ICR
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Harlan Sprague Dawley, Inc., Frederick, MD, USA
- Age at study initiation: 8 weeks
- Weight at study initiation: males 21.5-37.6 g; females 21.4-31.0 g - Route of administration:
- oral: gavage
- Vehicle:
- - Vehicle/solvent used:corn oil
- Justification for choice of solvent/vehicle: low water solubility of the test substance
- Concentration of test material in vehicle: approx. 12.5, 25, and 50%
- Amount of vehicle: dose volume was 10 mL/kg bw - Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Pelargonic acid was suspended in corn oil. - Duration of treatment / exposure:
- single dose
- Frequency of treatment:
- single dose
- Post exposure period:
- sampling at 24, 48, and 72 hours post dosing
- Remarks:
- Doses / Concentrations:
1250, 2500, and 5000 mg/kg bw
Basis:
actual ingested - No. of animals per sex per dose:
- 15
- Control animals:
- yes, concurrent no treatment
- Positive control(s):
- - Positive control substance: cyclophosphamide
- Route of administration: oral gavage
- Doses / concentrations: 80 mg/kg bw - Tissues and cell types examined:
- Erythrocytes
- Details of tissue and slide preparation:
- TREATMENT AND SAMPLING TIMES: sampling at 24, 48, and 72 hours after single treatment
DETAILS OF SLIDE PREPARATION: At 24, 48, and 72 hours after administration of the test material or the vehicle, the appropriate groups of animals were sacrificed by CO2 asphyxiation. Sacrifice time for the vehicle and positive control groups was 24 hours. Bone marrow cells were flushed from both femurs of each animal with fetal calf serum and centrifuged. Supernatants were discarded; pellets were resuspended in residual supernatant, spread onto slides and air dried. The slides were fixed in methanol. stained with May-Grunwald and Giemsa solutions. cover slipped, coded and scored.
METHOD OF ANALYSIS: 1000 cells per animal were examined for the occurrence of micronuclei.
- Evaluation criteria:
- The test material was considered positive for micronuclei induction if a significant increase (p ≤ 0.05) in micronucleated polychromatic erythrocytes at any test dose compared to the vehicle control was seen.
- Statistics:
- The results were evaluated for statistical significance using an analysis of variance on the square root arcsine transformation, performed on the proportion of cells with micronuclei/animal. Tukey's Studentized range test with adjustment for multiple comparisons was used at each harvest time to determine which dose groups, if any, were significantly different (p ≤ 0.05) from the vehicle control. Analyses were performed separately for each harvest time and sex, and also at each harvest time for the sexes combined.
- Key result
- Sex:
- male/female
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
-
RESULTS OF DEFINITIVE STUDY
- Induction of micronuclei (for Micronucleus assay): no
- Ratio of PCE/NCE (for Micronucleus assay): unchanged - Conclusions:
- Interpretation of results: negative
Pelargonic acid was negative in a mouse micronucleus test. - Executive summary:
Pelargonic acid (in corn oil) was examined in a mouse micronucleus test equivalent to OECD test guideline No. 475 for its genotoxicity in vivo. 15 male and female mice were used per dose level (0, 1250, 2500, 5000 mg/kg bw; single oral gavage). At 24, 48, and 72 hours after administration of the test material or the vehicle, bone marrow cells were harvested from both femurs, washed and stained. 1000 cells per animal were examined for chromosomal changes.
There was no statistically significant increase (p > 0.05) in micronucleated polychromatic erythrocytes at any test dose or any time after dosing compared to the vehicle control. The vehicle control and the positive control (cyclophosphamide, harvest at 24 hours) performed as expected.
The study is not yet available. The findings are available in a second source publication (reliability 4) and are used as a Weight of Evidence approach (EPA OPPT, 1995). In conclusion, pelargonic was negative in this adequately conducted in vivo micronucleus test.
Reference
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 effect the data are regarded as relevant for humans.
Additional information
Additional information from genetic toxicity in vivo:
Genetic toxicity in vitro:
Bacterial cells
Pelargonic acid was not mutagenic in the Ames test (OECD guideline No. 471) using Salmonella typhimurium (strains TA98, TA100, TA1535, and TA1537) and E. coli (WP2uvrA) when tested up 5000 µg/mL with and without metabolic activation under GLP conditions. Precipitation was seen at 5000 µg/mL. Strain specific cytotoxicity was seen, as evidenced by reduced bacterial background lawn and/or reduction of the number of revertant colonies with increasing doses. Solvent control and positive controls performed as expected. Thus, pelargonic acid was not genotoxic in bacteria (NOTOX, 2001).
In a second test, pelargonic acid was examined in the Ames-test according to OECD TG 471 under GLP conditions using the Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 both in the absence and presence of metabolic activation (S9 from male Aroclor 254 induced rat liver). The test substance concentrations were 667, 1000, 3333, 6667, and 10000 µg/plate in the definitive experiment, because cytotoxicity was not pronounced at 6667 and 10000 µg/plate in the range finding test with TA100.
In the definitive test, the vehicle control (DMSO) and the positive controls performed as expected, while pelargonic acid did not increase the number of revertants in any strain at any dose, with or without metabolic activation. The same result was obtained in another experiment where water served as vehicle. Thus, pelargonic was not mutagenic (Hoechst-Celanese/MBA, 1985).
Chromosome aberration in vitro:
Pelargonic acid was tested for its ability to induce chromosomal aberrations in cultured human peripheral lymphocytes in a study conducted according to OECD test guideline No. 473 and under GLP conditions. Following a range finding pre-test, two independent experiments were conducted, both with and without metabolic activation (S9 mix; contained 9000g supernatant from Aroclor 1254 induced male Wistar rat liver). The test concentrations in the definitive test ranged from 100 to 750 µg/mL.
Precipitation was seen at 520 and 750 µg/mL. The pH at the highest non-precipitating dose level was of 480 µg/mL was lowered to 7.34, compared to pH=7.48 of the solvent control. Low mitotic index below 50% of the control indicated cytotoxicity at 750 µg/mL in the first experiment and at 240 µg/mL and above in the second.
A statistically significantly increased number of cells with chromosome aberrations was only seen at the toxic concentration of 750 µg/mL (mitotic index 38%, with and without metabolic activation), which was ruled out as being not biologically relevant. The solvent and positive controls performed as expected.
Therefore, it was concluded that pelargonic acid did not induce chromosomal aberrations and was not clastogenic in human lymphocytes with and without metabolic activation (NOTOX, 2001).
Mammalian cells:
The genotoxic potential of pelargonic acid was examined in mammalian cells (mouse lymphoma L5178Y TK +/- cells, equivalent to OECD test guideline No. 476) under GLP conditions. The test concentrations were 150, 200, 300, 600, 800, 1000, 1200, and 1600 µg/mL without metabolic activation, and 37.5, 50, 75, 100, 150, 200, 300, 500, and 600 µg/mL with metabolic activation (S9 mix, from livers of Aroclor 1254 induced male Sprague Dawley rats).
Cytotoxicity was more pronounced in the presence of S9 mix. In the absence of S9 the relative suspension growth generally decreased with increased doses to 9.6% at 1200 µg/mL; no cytotoxicity was seen < 600 µg/mL. With S9, the relative suspension growth generally decreased with increased doses to approx. 11% at 600 µg/mL. No increased mutation frequencies were not without metabolic activation. With metabolic activation, mutation frequencies doubled at >300 µg/mL. Colony sizing revealed a bimodal distribution in small and large colonies, which could indicate the induction of chromosome deletions.
Overall, pelargonic acid, in the presence of S9 metabolic activation, induced a weak mutagenic response in mouse TK+/-lymphoma cells. This occurred in the presence of increasing cytotoxicity, however, and may indicate damage to the chromosome carrying the TK locus, rather than actual mutagenicity at that locus. The observed weak positive result in the presence of metabolic activation is therefore considered to be ambiguous. The study is not yet available. The findings are avilable in a second source publication (reliability 4) and are used as a Weight of Evidence approach (EPA OPPT, 1995).
Genetic toxicity in vivo:
Pelargonic acid (in corn oil) was examined in a mouse micronucleus test equivalent to OECD test guideline No. 475 for its genotoxicity in vivo. 15 male and female mice were used per dose level (0, 1250, 2500, 5000 mg/kg bw; single oral gavage). At 24, 48, and 72 hours after administration of the test material or the vehicle, bone marrow cells were harvested from both femurs, washed and stained. 1000 cells per animal were examined for chromosomal changes.
There was no statistically significant increase (p > 0.05) in micronucleated polychromatic erythrocytes at any test dose or any time after dosing compared to the vehicle control. The vehicle control and the positive control (cyclophosphamide, harvest at 24 hours) performed as expected.
The study is not yet available. The findings are available in a second source publication (reliability 4) and are used as a Weight of Evidence approach (EPA OPPT, 1995). In conclusion, pelargonic was negative in this adequately conducted in vivo micronucleus test.
Justification for classification or non-classification
No classification required according to Regulation EC 1272/2008.
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