Dodecanal

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vivo

Description of key information

In the absence of data on the target substance, data was presented on analogue substances. Genotoxicity was assessed according to OECD guideline 471 with and without metabolic activation on the analogue substances 2-methylundecanal and undec-10-enal. Both analogue substances were found to be negative for mutagenicity both in the presence and absence of a metabolising system. Chromosome aberration, sister chromatid exchange and mouse lymphoma assays were presented on the analogue substance, Nonanal. A significant increase in SCEs was detected, but there was not significant change in chromosome aberrations. The mouse lymphoma showed that Nonanal was negative without metabolic activation, but positive with metabolic activation. An in vivo mouse micronucleus test performed according to OECD guideline 474 was presented on the analogue substance Undec-10-enal. The test substance was found to be negative for genetic toxicity in an in vivo mouse micronucleus test.

Link to relevant study records

Reference

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:

key study

Study period:

2007-02-05 to 2007-03-20

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

A valid study is available for the analogue substance, Undec-10-enal. It is a GLP compliant study conducted in compliance with agreed protocols, with no or minor deviations for the standard test. The read-across is considered to be suitable based on the structural and “mechanistic action” similarities between the target substance (Dodecanal) and source substance (Undec-10-enal) and their similar physico-chemical properties.

Qualifier:

according to guideline

Guideline:

OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)

Version / remarks:

Historical control data were updated; Age of the animals was 7 wks at start of experiment; neither of these affected the validity of the study.

Deviations:

yes

Remarks:

Historical control data were updated; Age of the animals was 7 wks at start of experiment; neither of these affected the validity of the study.

Qualifier:

according to guideline

Guideline:

EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)

Deviations:

yes

Remarks:

Historical control data were updated; Age of the animals was 7 wks at start of experiment; neither of these affected the validity of the study.

GLP compliance:

yes (incl. QA statement)

Type of assay:

micronucleus assay

Species:

mouse

Strain:

NMRI

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann GmbH, D-33178 Borchen, Germany
- Age at study initiation: 7 wks
- Weight at study initiation: Males mean 36.7 g (SD 1.8 g), females mean 28.2 g (SD 2.0 g)
- Assigned to test groups randomly
- Fasting period before study:
- Housing: Conventionally under standard laboratory conditions; Makrolon Type I cage with wire mesh top, granulated soft wood bedding
- Diet: Pelleted standard diet ad libitum
- Water: Tap water ad libitum
- Acclimation period: ≥ 5 d

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity: 30 % to 70 %
- Air changes (per hr): No data
- Photoperiod: 12 hrs dark / 12 hrs light

Route of administration:

oral: unspecified

Vehicle:

- Vehicle(s)/solvent(s) used: Corn oil
- Justification for choice of solvent/vehicle: Chosen for its relative non-toxicity to animals.
- Volume of vehicle: 10 mL/kg bw

Duration of treatment / exposure:

Single exposure

Frequency of treatment:

Single exposure

Post exposure period:

24 hrs (all dose levels) and 48 hrs (highest dose level only, i.e. 2000 mg/kg bw )

Remarks:

Doses / Concentrations:
500 mg/kg bw
Basis:
actual ingested

Remarks:

Doses / Concentrations:
1000 mg/kg bw
Basis:
actual ingested

Remarks:

Doses / Concentrations:
2000 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

6 males, 6 females, tested per dose group and sampling time.
5 males, 5 females, evaluated per dose group and sampling time.

Control animals:

yes, concurrent vehicle

yes, historical

Positive control(s):

- Positive control substance: Cyclophosphamide (CPA), dissolved in ionised water.
- Justification for choice of positive control: The stability of CPA at room temperature is sufficient. At 25 °C only 3.5 % of its potency is lost after 24 hrs.
- Route of administration: Orally, once
- Dose: 40 mg/kg bw
- Concentration: 10 mL/kg bw

Tissues and cell types examined:

Bone marrow

Details of tissue and slide preparation:

DETAILS OF SLIDE PREPARATION:
- The animals were sacrificed using CO₂ followed by bleeding.
- The femora were removed, the epiphyses were cut off and the marrow was flushed out with foetal calf serum using a syringe.
- The cell suspension was centrifuged at 1500 rpm (390 × g) for 10 mins and the supernatant was discarded.
- A small drop of resuspended cell pellet was spread on a slide. The smear was air dried and then smeared with May-Grünwald/Giemsa (both Merck, D-64293, Darmstadt, Germany).
- Cover slips were mounted with EUKITT (Kindler, D-79110, Freiburg, Germany).
- ≥ 1 slide was made from each bone marrow sample.

METHOD OF ANALYSIS:
- Evaluation of the cells was performed using Nikon microscopes with 100 × oil immersion objectives.
- ≥ 2000 polychromatic erythrocytes (PCEs) were analysed per animal for micronuclei.
- To describe a cytotoxic effect the ratio between polychromatic and normochromatic endpoints was determined in the same sample and expressed in PCEs per 2000 erythrocytes.
- The analysis was performed with coded slides.

Evaluation criteria:

A test item would have been classified as mutagenic if it induced either a dose-related increase or a clear increase in the number of micronucleated polychromatic erythrocytes in a single dose group. Statistical methods were used as an aid to evaluation of the results. However, the primary point of consideration was the biological relevance of the results. A test item that failed to produce a biologically relevant increase in the number of micronucleated polychromatic erythrocytes would have been considered non-mutagenic in this system.

Statistics:

Statistical significance at the 5 % level was evaluated by means of the non-parametric Mann-Whitney test.

Sex:

male/female

Genotoxicity:

negative

Toxicity:

no effects

Vehicle controls validity:

valid

Negative controls validity:

valid

Positive controls validity:

valid

Additional information on results:

RESULTS OF RANGE-FINDING STUDY
- Clinical signs of toxicity in test animals: No effects at 100 mg/kg bw or 1000 mg/kg bw. Ruffled fur in all 4 animals tested at 2000 mg/kg at 1-6 hr after treatment, but no effect at 24 hrs to 48 hrs after treatment.

RESULTS OF DEFINITIVE STUDY
- Clinical signs of toxicity: None, at all concentrations.
- For results summary see tables under "Any other information on results incl. tables" below.
- For full results please refer to the attached supporting information.
- Compared to vehicle controls there was no statistically significant or biologically relevant increase in the frequency of detected micronuclei at any preparation interval or dose level after administration of the test item. The mean values of micronuclei observed after treatment with the test material were below or near to the vehicle control group.
- Positive control showed a statistically significant increase in induced micronucleus frequency.

Summary of micronucleus test results

Test group	Dose mg/kg bw	Sampling time (hr)	PCEs with micronuclei (%)	Range	PCE per 2000 erythrocytes
Vehicle	0	24	0.105	0-5	1129
Test item	500	24	0.135	1-5	962
Test item	1000	24	0.160	1-6	1001
Test item	2000	24	0.110	0-4	1032
Positive control	40	24	2.700	40-79	1098
Test item	2000	48	0.100	0-5	1120

Historical control data

	Vehicle controls			Positive controls (CPA)
	Males	Females	Total	Males	Females	Total
Mean*, SD	0.086 ± 0.04	0.066 ± 0.036	0.077 ± 0.031	2.118 ± 0.71	1.568 ± 0.615	1.868 ± 0.618
Range**	0.01-0.23	0.00-0.19	0.01-0.16	0.70-4.19	0.49-3.68	0.77-3.68
No. of experiments	276	256	277	276	256	277

* Mean value (% micronucleated cells)

** Range of mean group values (% micronucleated cells)

Biometry

Vehicle control versus test group	Significance	p value
500 mg/kg bw test material at 24 hr	-	0.2223
1000 mg/kg bw test material at 24 hr	-	0.0784
2000 mg/kg bw test material at 24 hr	-	0.5000
40 mg/kg bw positive control at 24 hr	+	< 0.0001
2000 mg/kg bw test material at 48 hr	n.t.	-

n.t. = Not tested, as the mean micronucleus frequency was not above the vehicle control value.

Conclusions:

Interpretation of results (migrated information): negative
The test substance was assessed for gentoxicity in vivo according to OECD guideline 474. The test substance was found to be negative for genetic toxicity in the in vivo mouse micronucleus test.
A valid study is available for the analogue substance, Undec-10-enal. It is a GLP compliant study conducted in compliance with agreed protocols, with no or minor deviations for the standard test. The read-across is considered to be suitable based on the structural and “mechanistic action” similarities between the target substance (Dodecanal) and source substance (Undec-10-enal) and their similar physico-chemical properties.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vivo:

In the absence of data on the target substance, data was presented on analogue substances. Genotoxicity was assessed according to OECD guideline 471 with and without metabolic activation on the analogue substances 2-methylundecanal and undec-10-enal. Both analogue substances were found to be negative for mutagenicity both in the presence and absence of a metabolising system.

Chromosome aberration, sister chromatid exchange and mouse lymphoma assays were presented on the analogue substance, Nonanal. A significant increase in SCEs was detected, but there was no significant change in chromosome aberrations. Nonanal induced neither micronuclei nor chromosomal aberrations at any concentration tested. The mouse lymphoma showed that Nonanal was negative without metabolic activation, but positive with metabolic activation. Under conditions without metabolic activation cytotoicity was observed. A concentration approaching excessive lethality was closely approached without obtaining any evidence of mutagenic activity. When tested with metabolic activation, results indicated a weak mutagenic activity associated with high toxicity.

An in vivo mouse micronucleus test performed according to OECD guideline 474 was presented on the analogue substance Undec-10-enal. There was no statistically significant or biologically relevant increase in the frequency of detected micronuclei at any preparation interval or dose level after administration of the test item. The test substance was therefore found to be negative for genetic toxicity in an in vivo mouse micronucleus test.

The read-across is considered to be suitable based on the structural and “mechanistic action” similarities between the target substance (Dodecanal) and source substances (2-methylundecanal, Undec-10-enal and Nonanal) and their similar physico-chemical properties.

Justification for selection of genetic toxicity endpoint
An in vivo study performed according to OECD guideline 474.

Justification for classification or non-classification

The results of an in vivo mouse micronucleus test performed according to OECD guideline 474 on a structural analogue did not show any evidence of causing chromosome damage when administered orally.