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EC number: 948-040-6
CAS number: -
Reverse gene mutation assay; OECD 471; Dreher, D. (2018); Positive
Mammalian cell cytogeneticity assay; OECD 473; Lyoyd, M. (2018);
In vivo Micronucleus screen OECD 474 incorporated into OECD
442; N Barraclough (2018) - Negative
In vivo Comet assay in the rat OECD 489 (2021): study ongoing,
decision pending completion.
Based on the in vivo OECD 474 data, all measured parameters
produced negative results and as such the test item is not considered
clastogenic. However, data on mutagenicity is currently inconclusive and
as such the overall mode of action for genotoxicity and its relevance to
human cannot be confirmed. As such, an OECD489 in vivo Comet assay in
the rat is currently ongoing to provide further evidence.
in vitro genotoxicity data
OECD 471 (2018) - In a reverse gene mutation assay in
bacteria, strains TA98, TA100, TA1535, TA1537 and TA102 of S.
typhimuriumwere exposed to Reaction mass of
N,N,N’,N-tetrabutylmethylenediamine and dibutylamine in acetone at
concentrations of 5, 16, 50, 160, 500, 1600 and 5000 µg/plate a
screening experiment followed by concentrations of 31.25, 62.5, 125,
250, 500, 100 and 200 µg/plate (TA98 also tested at 400 and 750
µg/plate) in a secondary experiment. Both tests were conducted in the
presence and absence of S9 mix.
The test item was tested up to cytotoxic concentrations. The positive
controls induced the appropriate responses in the corresponding strains.
It was concluded that the test article induced mutation in
histidine-requiring strains TA98 and TA100, of Salmonella
typhimurium when tested under the conditions of this study.
This study is classified as acceptable. This study satisfies the
requirement for Test Guideline OECD 471 for in vitro mutagenicity
(bacterial reverse gene mutation) data.
OECD 473 (2018) - In a mammalian cell cytogenetics
assay (in vitro chromosome aberration, OECD 473), primary lymphocyte
cultures were exposed to Reaction mass of
N,N,N’,N’-tetrabutylmethylenediamine and dibutylamine at concentrations
of 0, 15, 20, 25, 30, 35, 45, 50, 70 and 90 µg/mL for 3 h with and
without metabolic activation. Additionally, a continuous exposure of 24
h was tested without metabolic activation at test item concentrations of
0, 5, 15, 27.5 and 35 µg/mL.
Reaction mass of N,N,N’,N’-tetrabutylmethylenediamine and dibutylamine
was tested up to precipitating and cytotoxic concentrations of 55.99 and
93.31 µg/mLfor the 3 h exposure, in the absence and presence f S9 mix,
respectively and 93.31 µg/mL for the 20 h exposure with S9 mix. Positive
controls induced the appropriate response.
There was evidence that the test item induced structural chromosome
aberrations in cultured human peripheral blood lymphocytes when tested
for 3+17 hours in the absence and presence of a rat liver metabolic
activation system (S-9) and for 20+0 hours in the absence of S-9 and is
therefore considered to have clastogenic potential in this chromosome
aberration test. Sporadic increases in the frequencies of cells with
numerical aberrations, particularly polyploidy, which marginally
exceeded the concurrent controls and the normal ranges, were observed
under all treatment conditions, but this assay is not specifically
designed for the quantitative evaluation of polyploidy.
This study is classified as acceptable. This study satisfies the
requirement for Test Guideline In vitro Mammalian Chromosome Aberration
Test (OECD 473) in human lymphocyte cells.
In vivo genotoxicity data
OECD 474 (incorporated into OECD 422 study design) -
The genotoxicity potential of the Reaction mass of
N,N,N',N'-tetrabutylmethylenediamine and dibutylamine was investigated
in an Oral (Gavage) Combined Repeated Dose Toxicity Study with the
Reproduction/Developmental Toxicity Screening Test in the Rat (OECD 422,
adopted 29 July 2016). Covance study 8359422. Four groups of 10 male and
10 female sexually mature Crl:WI(Han) rats were administered 0 (control
article [vehicle: corn oil]), 30, 50, or 100 mg/kg/day test item once a
day to male rats for 42 consecutive days and to female rats for up to 58
days (pre-pairing, throughout gestation, and during the first 2 weeks of
lactation). The control article (vehicle) was corn oil, and formulations
were administered at a dose volume of 5 mL/kg. The positive control
slides were prepared under the Covance Positive control Slide Bank Study
(Covance study 8360181) from animals that had received two daily oral
gavage doses of 10 mg/kg/day cyclophosphamide (dissolved in saline).
Sampling of these animals was on Day 3 (approximately 24 hours post the
last dose administration).
Animals treated with the test item at all doses exhibited group mean
%PCE values that were either similar to or slightly higher than the
value for the concurrent vehicle control group but which fell within the
historical vehicle control range. As such, there was no evidence of bone
marrow toxicity. Treatment with the test item exhibited group mean MN
PCE frequencies that were similar to and not significantly (p≤0.05)
higher than those observed in the concurrent vehicle control group for
all doses. Individual MN PCE values were consistent with historical
vehicle control distribution ranges and similar to values observed in
the concurrent vehicle control group.
Based on the conditions of the study, it can be stated that the test
item did not induce micronuclei in the polychromatic erythrocytes (PCE)
of the bone marrow of male and female Han-Wistar rats treated at doses
of 30, 50 or 100 mg/kg/day. The test item was considered non clastogenic
and does not meet the criteria for classification in accordance with GHS
and Regulation (EC) No 1272/2008 (CLP).
OECD 489 Comet assay in the rat - Reaction mass of
N,N,N',N'-tetrabutylmethylenediamine and dibutylamine was further
investigated via an OECD 489 study, commencing in January 2021. Due to
issues with bioanalysis and the requirement for additional
histopathological analysis in order to confirm outcome, this is
currently ongoing. Further information is provided within 7.6.2.
OECD 422 study design. The reproductive and developmental screening test
(OECD 422) incorporated with micronuclus screen OECD 474; the test item
was considered non-clastogenic and does not meet the criteria for
classification in accordance with Regulation (EC) No 1272/2008 (CLP).
However, data on mutagenicity is currently inconclusive based on the
positive in vitro gene mutation and as such the overall
classification on genotoxicity is also considered inconclusive. An OECD
489 Comet assay in vivo is ongoing in order to provide further
information to the weight-of-evidence analysis for clasification or
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