Registration Dossier

Administrative data

Endpoint:
in vivo mammalian cell study: DNA damage and/or repair
Remarks:
Comet assay / OECD 489
Type of information:
experimental study planned
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS

In accordance with REACH Regulation (1907/2006) Annex VIII column 2 point 8.4 "appropriate in vivo mutagenicity studies shall be considered in case of a positive result in any of the genotoxicity studies in Annex VII or VIII". Since hexanal was positive in mammalian gene mutation and cytogenicity assays (non GLP, Klimisch 2), an in vivo Comet assay conducted according to OECD 489 is considered appropriate to fulfil data requirements of Annex VIII of the REACH Regulation.

NON-CONFIDENTIAL NAME OF SUBSTANCE:
Hexanal

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:

- Available GLP studies :
In-vitro Gene Mutation Study in Bacteria/OECD 471, in-vitro Chromosome Aberration/OECD 473.

- Available non-GLP studies :
Umu assay (Ono 1991), gene mutation in mammalian cells (Brambilla 1989), UDS in mammalian cells (Martelli 1994), DNA damage in mammalian cells (Marinari 1984), all Klimisch 2

- Historical human data :
no data

- (Q)SAR :
Profiling with OECD QSAR Toolbox v4.2: positive alerts for Ames and micronucleus mutagenicity due to aldehyde group (explanation: "All compounds carrying an aldehydic group can potentially undergo Schiff base formation with a primary amine. They are to be considered potentially genotoxic, as demonstrated in vivo ability to react with nucleobases, without metabolic activation, forming adducts, interbase cross-links (both intra- and inter-strand), and DNA-protein crosslinks. The length of carbon chain for aliphatic aldehydes, and in general molecular size, can strongly modulate the formation of every type of cross-link and even the accessibility of the DNA nucleobases. DNA-protein crosslinks have been reported as the primary DNA damage induced by the related substance formaldehyde (Speit et al. 2007)).

- In vitro methods :
in vitro assays conducted under GLP conditions: In-vitro gene mutation study in bacteria/OECD 471, in-Vitro Chromosome Aberration/OECD 473

- Weight of evidence :
A weight-of-evidence approach was performed using in vitro data from different publications (Ono 1991, Brambilla 1989, Martelli 1994, Marinari 1984) and the availble Ames test (Andres 2018) and Chromosomal aberration test (Beres 2018). The results were ambiguous. While hexanal was negative on bacterial strains in Ames test (GLP study) and did not induce chromosomal aberrations in V79 chinese hamster fibroblasts (GLP study), it was tested positive in umu assay (Ono 1991, Klimisch 2). In addition, results of in vitro assays indicate cytogenic and genotoxic potential of hexanal in rat hepatocytes and Chinese hamster cells (Martelli 1994b, Marinari 1984, Brambilla 1989, all Klimisch 2). Cytogenicity testing (UDS) in human hepatocytes, on the other hand, was negative (Martelli 1994a)

- Grouping and read-across :
Heptanal was negative in in vitro chromosomal aberration and gene mutation in mammalian cells. Pentanal, on the other hand, was tested positive in in vitro gene mutation assay and DNA repair studies in mammalian cells (ECHA registration dossiers). Due to these ambiguous results, a grouping approach was not considered appropriate to address this endpoint.

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
The following adaptations are possible according to REACH Regulation (1907/2006) Annex VIII column 2
8.4.2. The study does not usually need to be conducted
– if adequate data from an in vivo cytogenicity test are available or
– the substance is known to be carcinogenic category 1 or 2 or mutagenic category 1, 2 or 3.
8.4.3. The study does not usually need to be conducted if adequate data from a reliable in vivo mammalian gene mutation test are available.
The above mentioned adaptations are not applicable, hence a further in vivo Comet assay conducted according to OECD 489 is considered appropriate to fulfil data requirements of Annex VIII of the REACH Regulation.

Data source

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 489 (In vivo Mammalian Alkaline Comet Assay)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

Results and discussion

Applicant's summary and conclusion