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EC number: 218-336-3
CAS number: 2123-24-2
The substance (and the decomposition products) do not show any relevant
mutagenic or cytotoxic effects.
Data obtained by experimental results with sodium caprolactamate, as
defined in section 1.2:
The test item didn't show mutagenic effects in both experiments. The
number of revertant colonies was not increased in comparison with the
spontaneous revertants (solvent only).
Cytotoxity of the test item was not detected. The background lawn was
visible and the number of revertants was not significantly decreased.
Therefore it can be stated, that under the test conditions, the test
item is not mutagenic in the Bacteria Reverse Mutation Test using
Salmonella typhimurium, strains TA 97a, TA 98, TA 100, TA 102, and TA
Data obtained by Read-Across from Caprolactam:
Genetic toxicity in vitro
A number of studies are available where Caprolactam (CAP) was tested for
its mutagenic potential in-vitro.
Weight of evidence in vitro gene mutation in bacteria:
1) Allied Chemical Corp. (ACC), In Vitro Mutagenicity and Cell
Transformation Screening of Caprolactam, MA-03-77-4, 1979.
2) Mueller W. et al. (1993), Environ. Health Persp. Suppl. 101, 33-36.
CAP was not mutagenic in the Ames test with and without metabolic
activation. 5 different Salmonella strains were tested negative but no
test was performed with E.coli (ACC, 1979). In order to detect oxidizing
mutagens or cross-linking agent S. typhimurium strain TA 102 was used in
a separate assay (Mueller et al., 1993).
Weight of evidence in vitro cytogenicity in mammalian cells:
1) Chromosomal aberration in CHO-cells,
Gulati, D.K. et al. (1989), Environm. Molec. Mutag. 13, 133-193.
2) in vitro micronucleus assay in CHO-cells,
Douglas, G.R. et al. (1985), Prog. Mutat. Res. 5, 359-366.
3) Unscheduled DNA synthesis assay in rat hepatocytes,
Probst, G.S. & Hill, L.E. (1985), Prog. Mutat. Res. 5, 381-386.
4) Sister chromatid exchange assay in CHO-cells,
No signs of a genotoxic potential were identified in a chromosomal
aberration test with CHO cells at doses of 16-5000 µg/ml (Gulati et al.,
1989) and a UDS test with primary rat hepatocytes at doses of 0.056-1130
µg/ml (Probst et al., 1985). Additionally, CAP was observed to be
negative in the micronucleus assay with CHO cells at 566-11300 µg/ml
(Douglas et al. 1985) and the SCE assay with CHO cells at doses of
16-5000 µg/ml (Gulati 1985). All assays were performed according to
current guidelines in the absence and presence of a metabolic activation
Weight of evidence in vitro gene mutation in mammalian cells
1) HGPRT assay in V79-cells,
Fox, M. & Delow, G.F. (1985), Prog. Mutat. Res. 5, 517-523.
2) In vitro gene mutation assay in mouse lymphoma L5178Y cells,
Myhr, B. et al. (1985), Prog. Mutat. Res. 5, 555-568.
No signs of a mutagenic activity were detected in the HPRT Test with V79
cells at doses of 300-4000 µg/ml (Fox et al., 1985) and the mouse
lymphoma test at doses of 500-5000 µg/ml (Myhr et al., 1985). Both
assays were performed with and without the presence of a metabolic
As part of an interlaboratory survey, many in-vitro tests were performed
with CAP. Most of these gave negative results. Although, few experiments
with human lymphocytes yielded inconsistent results. At high cytotoxic
concentrations (higher than the 10 mM recommended in the guideline)
chromosomal aberrations were described (Norppa et al., 1989).
A very small but significant increase in the frequency of chromosomal
aberrations was described at the highest tested CAP dose-levels
(5.5mg/ml, Sheldon et al., 1989; 7.5mg/l, Kristiansen et al., 1989). A
likewise small but dose dependent increase in chromosomal aberrations in
human lymphocytes was described by Howard et al. (1985) at doses of
270-2750 µg/ml with and without auxiliary metabolic activation.
Summarizing the vast amount of negative in vitro assays and comparing
them to the exclusive findings in human primary lymphocytes at high
cytotoxic concentrations, by means of a weight of evidence it can be
anticipated that caprolactam is not genotoxic in vitro.
For a comprehensive overview, the large amount of additional
genotoxicity studies was partly combined by assay read out (e.g.
chromosomal aberration, gene mutation, SCE) in the IUCLID5 file. All of
them supported the above mentioned results.
Genetic toxicity in vivo
Weight of evidence:
1) Chromosomal aberration assay in bone marrow cells of mice, gavage
Adler, I.D. & Ingwersen,(1989), Mutat. Res. 224, 343-345.
2) Chromosomal aberration assay in bone marrow cells of mice,
McFee, A.F. & Lowe, K.W. (1989), Mutat. Res. 224, 347-350.
3) Mouse micronucleus assay in bone marrow cells, gavage application.
Sheldon, T. (1989), Mutat. Res. 224, 351-355.
4) Mouse micronucleus assay in bone marrow cells, 3 subsequent
Shelby et al. (1993), Environm. Molec. Mutagenesis 21, 160-179.
5) SCE-assay in bone marrow cells of mice, intraperitoneal application.
6) Assay for unscheduled DNA synthesis (UDS) and DNA strand breaks (SB)
in hepatocytes of rats, gavage application.
Bermudez, E. et al. (1989), Mutat. Res. 224, 361-364.
No chromosomal aberrations were induced in bone marrow cells of mice
treated with caprolactam orally via gavage in dose levels up to 1000
mg/kg bw (Adler and Ingwersen, 1989) or intraperitoneally in dose levels
up to 700 mg/kg bw (McFee and Lowe, 1989).
Simillarly, no micronuclei were induced in bone marrow cells of mice
treated with caprolactam orally via gavage in dose levels up to 700
mg/kg bw (Sheldon, 1989) or 3 times intraperitoneally in dose levels up
to ca. 500 mg/kg bw (Shelby et al., 1993).
Finally, no induction of DNA strand breaks or unscheduled DNA synthesis
was observed in hepatocytes of rats gavaged with CAP (750 mg/kg bw,
Bermudez et al., 1989) and no induction of SCE was observed in bone
marrow cells of mice intraperitoneally dosed with CAP (up to 700 mg/kg
bw, McFee and Lowe, 1989).
The results of two mouse spot test performed in two independent
laboratories with two different mouse strains were ambiguous.
In one experiment treatment of heterozygous pigment precursor cells in
embryos with up to 500 mg/kg bw resulted in a slight increase in the
frequency of colored spots in adult animals (Fahrig, 1989). Statistical
significance was only obtained in 1 of 3 experimental groups. Similar
results were obtained in the second laboratory with maximal dose levels
of 700 mg/kg bw (Neuhäuser-Klaus & Lehmacher, 1989). Again slight
increase in the frequency of colored spots was observed only gaining
statistical significance in 1 of 5 replicates and exhibiting no signs of
The nature of these spots in both experiments suggested that they may
have been the result of the induction of mitotic recombination and not
as a result of mutagenicity. Induction of mitotic recombination is
presumably secondary to the high, dose dependent toxicity of caprolactam
observed under the conditions of the assay (mortality, loss of litter).
Therefore the relevance of this effect remains unclear.
Combining all results, CAP showed neither mutagenic nor clastogenic
potential with respect to most of the different genetic endpoints
tested. Few in-vitro and in-vivo tests show induction of mitotic
recombination; however these effects remain unclear, especially taking
into account the negative results in rats and mice carcinogenicity
bioassays (NTP, 1982).
Data obtained by Read-Across from sodium hydroxide:
In vivo Studies
Valid in vivo genotoxicity studies are not available.
A mouse bone marrow micronucleus test using 15 mM NaOH at a dose of 10
mg/kg bw revealed no significant increase of nuclei (Aaron et al.,
1989). The test compound was administered as a single i.p. dose to
treatment groups (5 males and 5 females) at 30, 48 and 72h. Mouse
oocytes of the Swiss strain were used to determine possible
aneuploidy-inducing effects (Brook et al., 1985). Mice were injected
intraperitoneally with 0.3-0.4 ml of 0.01 M NaOH and chromosome spreads
were made 12 h after injection. NaOH was used as control substance. No
evidence of non-disjunction was found in control groups up to the age of
40 weeks tested.
Both the in vitro and the in vivo genetic toxicity test indicated no
evidence for a mutagenic activity. Furthermore NaOH is not expected to
be systemically available in the body under normal handling and use
conditions and for this reason additional testing is considered
unnecessary (see section 3.1).
In vitro Studies
NaOH was assayed in the Ames reversion test with S. typhimurium strains
TA1535, TA1537, TA1538, TA98, TA100 and in a DNA-repair test with E.
coli strains WP2, WP67 and CM871 (De Flora et al., 1984). Based on the
results of these tests NaOH was classified as non genotoxic.
The clastogenic activity of NaOH was studied in an in vitro chromosomal
aberration test using Chinese hamster ovary (CHO) K1 cells (Morita et
al., 1989). No clastogenic activity was found at NaOH concentrations of
0, 4, 8 and 16 mM NaOH, which corresponded with initial pH values of
7.4, 9.1, 9.7 and 10.6, respectively. Incubation of CHO-K1 cells with
NaOH in the presence of rat liver S9 increased the clastogenic activity
of S9, or induced new clastogens by breakdown of the S9. Therefore,
testing at non-physiological pH might give false-positive responses,
which means that the effect of sodium hydroxide is of a methodical kind
and not valid to asses the genotoxicity under realistic conditions.
Justification for selection of genetic toxicity endpoint
Since sodium caprolactamate hydrolyses under physiological
conditions with the formation of epsilon-Caprolactam and sodium
hydroxide, cross-reading from toxicological studies of
epsilon-Caprolactam is justified. For the substance’s endpoint
assessment also the impact of sodium hydroxideis taken into
consideration, however avaiable literature indicated that there is no
contribution to be expected.
No indication for a genotoxic potential in vitro and in vivo was found.
Therefore there is no indication for a genetic toxicity classification.
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