Registration Dossier

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Bacterial reverse mutation assay (Ames test, OECD TG 471): negative with and without metabolic activation

In vitro mutation study in mammalian cells (HPRT assay, OECD TG 476): negative with and without metabolic activation

Link to relevant study records

Referenceopen allclose all

Endpoint:
in vitro gene mutation study in bacteria
Type of information:
experimental study
Adequacy of study:
key study
Study period:
01 Aug 2001 - 29 Nov 2001 (experimental)
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
GLP compliance:
yes (incl. QA statement)
Type of assay:
bacterial reverse mutation assay
Specific details on test material used for the study:
- Name of test material (as cited in study report): Tert.-Butylacrylat
- Physical state: colorless liquid
- Analytical purity: 99.6%
- Purity test date: 2001-07-16
- Lot/batch No.: Tank B 601
- Stability under test conditions: verified by reanalysis
- Storage condition of test material: Refrigerator, protected from light
Target gene:
his- (S. typhimurium), trp- (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:
Aroclor 1254 induced rat liver S-9 mix
Test concentrations with justification for top dose:
20, 100, 500, 2500 and 5000 µg/plate both, in the standard plate test (SPT) and in the preincubation test (PIT)
Vehicle / solvent:
DMSO
Untreated negative controls:
yes
Remarks:
sterility control
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
4-nitroquinoline-N-oxide
9-aminoacridine
other: N-methyl-N'-nitro-N-nitrosoguanidine (4-MNNG), 4-nitrophenylenediamine (4-NPD), 2-aminoanthracene (2-AA)
Details on test system and experimental conditions:
STANDARD PLATE TEST
Test tubes containing 2 ml soft agar kept in a water bath at 45°C, and remaining components added in the following order:
0.1 mL test solution or vehicle
0.1 mL bacterial suspension
0.5 mL S-9 mix (in tests with metabolic activation) or 0.5 mL phosphate buffer (in tests without metabolic activation).
After mixing, the samples are poured onto Vogel-Bonner agar plates (S. typhimurium) or minimal agar plates (E.coli)

PREINCUBATION TEST
0.1 mL test solution or vehicle, 0.1 mL bacterial suspension and 0.5 mL S-9 mix are incubated at 37°C for the duration of 20 minutes. Subsequently, 2 mL of soft agar is added and, after mixing, the samples are poured onto the agar plates.

BOTH TESTS
In each experiment 3 test plates per dose or per control used; after incubation at 37°C for 48 hours in the dark, the bacterial colonies ( his+/trp+ revertants) are counted. The titer was determined and in regularly measurements the strain characteristics were checked. Sterility control was performed.
Evaluation criteria:
POSITIVE RESULTS
- A dose-related and reproducible increase in the number of revertant colonies, i.e. about doubling of the spontaneous mutation rate in at least one tester strain either without S-9 mix or after adding a metabolizing system.
- A test substance is generally considered nonmutagenic in this test if: the number of revertants for all tester strains were within the historical negative control range under all experimental conditions in two experiments carried out independently of each other.

ACCEPTANCE CRITERIA
- The number of revertant colonies in the negative controls was within the normal range of the historical control data for each tester strain.
- The sterility controls revealed no indication of bacterial contamination.
- The positive control articles both with and without S-9 mix induced a significant increase in the number of revertant colonies within the range of the historical control data.
- The titer of viable bacteria was >= E+08/mL
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:
cytotoxicity
Remarks:
A slight decrease in the number of revertants was occasionally observed in the standard plate test. In the preincubation test bacteriotoxicity was found from about 500 µg/plate onward.
Vehicle controls validity:
valid
Untreated negative controls validity:
valid
Positive controls validity:
valid
Key result
Species / strain:
E. coli WP2 uvr A
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Remarks:
A slight decrease in the number of revertants was occasionally observed in the standard plate test. In the preincubation test bacteriotoxicity was found from about 500 µg/plate onward.
Vehicle controls validity:
valid
Untreated negative controls validity:
valid
Positive controls validity:
valid
Additional information on results:
No test substance precipitation was found.

Genotoxicity

Standard plate test (20 - 5000 µg/plate)

Strain

Metabolic activation system

Replicates

maximum revertant factor*

dose dependency

Assessment

TA 98

no

3

0.9

no

negative

 

yes

3

0.7

no

negative

TA 100

no

3

1.0

no

negative

 

yes

3

1.0

no

negative

TA 1535

no

3

0.9

no

negative

 

yes

3

1.0

no

negative

TA 1537

no

3

1.0

no

negative

 

yes

3

1.0

no

negative

WP2 uvr A

no

3

1.0

no

negative

 

yes

3

0.8

no

negative

Preincubation test (20 - 5000 µg/plate)

Strain

Metabolic activation system

Replicates

maximum revertant factor*

dose dependency

Assessment

TA 98

no

3

0.9

no

negative

 

yes

3

0.9

no

negative

TA 100

no

3

1.0

no

negative

 

yes

3

0.9

no

negative

TA 1535

no

3

1.0

no

negative

 

yes

3

1.0

no

negative

TA 1537

no

3

1.0

no

negative

 

yes

3

0.9

no

negative

WP2 uvr A

no

3

1.0

no

negative

 

yes

3

1.3

no

negative

* in non-toxic doses

Endpoint:
in vitro gene mutation study in mammalian cells
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 476 (In Vitro Mammalian Cell Gene Mutation Test)
GLP compliance:
yes (incl. QA statement)
Type of assay:
other: mammalian cell gene mutation assay
Specific details on test material used for the study:
- Name of test material (as cited in study report): tert.-Butylacrylate
- Physical state: liquid, colourless, clear
- Analytical purity: 99.83%
- Lot/batch No.: 011631eda0
Target gene:
hypoxanthine-guanine phosphoribosyl transferase (HPRT)
Species / strain / cell type:
Chinese hamster lung fibroblasts (V79)
Details on mammalian cell type (if applicable):
- Type and identity of media: MEM (minimal essential medium)
- Properly maintained: yes
- Periodically checked for Mycoplasma contamination: yes
- Periodically checked for karyotype stability: yes
Metabolic activation:
with and without
Metabolic activation system:
rat liver S9 mix (Phenobarbital/β-naphthoflavone induced)
Test concentrations with justification for top dose:
pre test: 10 - 1280 µg/mL (with and without S9-mix)
The dose range of the main experiments was set according to the data generated in the preexperiment. The individual concentrations were generally spaced by a factor of 2.0. Narrower spacing was used at higher concentrations.

experiment 1: 160, 320, 640, 960, 1280 µg/mL (with and without S9 mix)
experiment 2: 320, 640, 800, 960, 1120 µg/mL (without S9 mix); 640, 800, 960, 1120, 1280 µg/mL (with S9 mix)
Vehicle / solvent:
- Vehicle(s)/solvent(s) used: DMSO
- Justification for choice of solvent/vehicle: The final concentration of DMSO in the culture medium was 0.5% (v/v). The solvent was chosen to its solubility properties and its relative non-toxicity to the cell cultures.
Untreated negative controls:
yes
Negative solvent / vehicle controls:
yes
True negative controls:
no
Positive controls:
yes
Positive control substance:
7,12-dimethylbenzanthracene
ethylmethanesulphonate
Details on test system and experimental conditions:
METHOD OF APPLICATION: in medium

DURATION
- Preincubation period: 24 h
- Exposure duration: 4 h
- Expression time (cells in growth medium): 7 days
- Selection time (if incubation with a selection agent): 8 days

SELECTION AGENT (mutation assays): 6-thioguanine (11 μg/mL)
Evaluation criteria:
- A test item is classified as mutagenic if it reproducibly induces a mutation frequency that is three times above the spontaneous mutation frequency at least at one of the concentrations in the experiment.
- The test item is classified as mutagenic if there is a reproducible concentration-related increase of the mutation frequency. Such evaluation may be considered also in the case that a threefold increase of the mutant frequency is not observed.
Statistics:
A linear regression (least squares) was performed to assess a possible dose dependent increase of mutant frequencies. The number of mutant colonies obtained for the groups treated with the test item was compared to the solvent control groups. A trend is judged as significant whenever the p-value (probability value) is below 0.05. However, both, biological and statistical significance was considered together.
Key result
Species / strain:
Chinese hamster lung fibroblasts (V79)
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
not examined
Positive controls validity:
valid
Additional information on results:
ADDITIONAL INFORMATION ON CYTOTOXICITY:
Relevant cytotoxic effects indicated by a relative cloning efficiency I or cell density below 50% occurred in experiment I at 640 μg/mL and above without metabolic activation and at 960 μg/mL and above with metabolic activation. In experiment II relevant cytotoxic effects were noted at 640 μg/mL and above without metabolic activation. Cytotoxicity was more severe and the maximum concentration without metabolic activation was not analyzable. The relative cloning efficiency I was still acceptable with 16.3% and 17.0% but the cell density at the first subcultivation after treatment was too low to proceed. In the presence of metabolic activation cytotoxicity as described above was noted at 800 μg/mL and above. The recommended cytotoxic range of approximately 10%-20% relative cloning efficiency or relative cell density was covered with and without metabolic activation.

- No relevant and reproducible increase in mutant colony numbers/106 cells was observed in the main experiments up to the maximum concentration. The mutant frequency remained well within the historical range of solvent controls.

-The induction factor exceeded the threshold of three times the corresponding solvent control in the first culture of the first experiment at 960 μg/mL without metabolic activation. This effect however, was judged as biologically irrelevant, since it was based upon the rather low solvent control of 4.9 mutant colonies/106 cells and was not reproduced in the parallel culture under identical conditions.

-In both experiments of this study (with and without S9 mix) the range of the solvent controls was from 4.9 up to 19.0 mutants per 106 cells; the range of the groups treated with the test item was from 4.5 up to 31.3 mutants per 106 cells.

-The viability (cloning efficiency II) of the solvent control of culture I of the first experiment with metabolic activation and of culture I of the second experiment with metabolic activation reached but did not exceed the lower limit of 50%. The data are valid however, as the solvent control of the parallel culture exceeded this limit.

-EMS (150 μg/mL) and DMBA (1.1 μg/mL in experiment I, 2.2 μg/mL in experiment II) were used as positive controls and showed a distinct increase in induced mutant colonies.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

In vivo micronucleus test (OECD TG 474): non-clastogenic and non-aneugenic

Link to relevant study records
Reference
Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13 Aug 2001 - 05 Nov 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of assay:
other: micronucleus assay
Specific details on test material used for the study:
- Name of test material (as cited in study report): Tert.-Butylacrylat
- Physical state: liquid
- Lot/batch No.: Tank B 601
- Analytical purity: 99.69 % (Stability of the test substance in olive oil was determined analytically.)
- Stability under test conditions: Storage stability of the test substance covering the period of the study was determined by the sponsor by recharacterisation after completion of the experimental phase of the study.
- Storage condition of test material: Refrigerator, protected from light
Species:
mouse
Strain:
NMRI
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd., Fuellinsdorf, CH
- Age at study initiation: 7-10 weeks
- Weight at study initiation: males 46.7±3.0 g; females 32.2 ± 4.9g
- Assigned to test groups randomly: yes
- Housing: individually
- Diet: standard diet, ad libitum (ALTROMIN 1324, D-32791 Lage/Lippe )
- Water: ad libitum, (Gemeindewerke, D-64380 Rossdorf)
- Acclimation period: minimum 5 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 4
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
intraperitoneal
Vehicle:
- Vehicle(s)/solvent(s) used: olive oil
- Justification for choice of solvent/vehicle: The vehicle was chosen to its relative non-toxicity for the animals
Details on exposure:
- i.p. injection of 10 mL/kg bw
Duration of treatment / exposure:
single treatment
Frequency of treatment:
single treatment
Post exposure period:
24 or 48 h
Dose / conc.:
100 other: mg/kg bw
Remarks:
males
Dose / conc.:
200 other: mg/kg bw
Remarks:
males
Dose / conc.:
400 other: mg/kg bw
Remarks:
males
Dose / conc.:
125 other: mg/kg bw
Remarks:
females
Dose / conc.:
250 other: mg/kg bw
Remarks:
females
Dose / conc.:
500 other: mg/kg bw
Remarks:
females
No. of animals per sex per dose:
- Pre-tests: 2 + 5 per sex and per dose
- Main-test: 12 per sex in the high dose and 6 per sex in the mid and low dose, each
Control animals:
yes, concurrent vehicle
Positive control(s):
Cyclophosphamide, dissolved in water
- Route of administration: i.p.
- Dose: 40 mg/kg bw
Tissues and cell types examined:
Bone marrow cells were used. At least 2000 PCEs per animal were scored for micronuclei.
Details of tissue and slide preparation:
CRITERIA FOR DOSE SELECTION:
It is generally recommended to use the maximum tolerated dose or the highest dose that can be formulated and administered reproducibly or 2000 mg/kg as the upper limit for non-toxic test substances.
The maximum tolerated dose level is determined to be the dose that causes toxic reactions without having major effects on survival.
The maximum tolerated dose was therefore determined in extensive pre-tests in which doses of 400 to 1000 mg/kg were administered intraperitoneal to male and female mice.

Results of the pre-tests:
In a first pretest male mice (2 animals/dose) were administered i.p. 400, 500 and 1000 mg/kg. Both animals of the 1000 mg/kg dose died, also 1/2 animals of the 500 mg/kg dose. Clinical signs described were reduction of the spontaneous activity, abdominal position eyelid closure and apathy. To confirm the results 5 animals per dose were administered 400 and 500 mg/kg i.p.. Two of the animals in the 500 mg/kg dose died. All animals of both groups showed a reduction of the spontaneous activity and apathy, further clinical signs were abdominal position, and eyelid closure.
Based on this results a clear systemic availability of the test substance was proved in male mice.

Also in female mice the systemic availability and the maximum tolerated dose was determined in pre-tests.
Again in a first pretest 2 mice per dose received 500, 600, 750 and 1000 mg/kg i.p. The animals of the 750 and 1000 mg/kg dose died. Clinical signs in all groups were reduction of the spontaneous activity, apathy and eyelid closure. In confirming prestudies 5 female mice per group were administered i.p. 500 and 600 mg/kg. 4/5 mice in the 600 mg/kg dose died. All animals showed reduction of spontaneous activity, further clinical signs observed were abdominal position, eyelid closure and apathy.

The volume to be administered should be compatible with physiological space available. Three adequate spaced dose levels spaced by a factor of 2 were applied at the central sampling interval 24 h after treatment. For the highest dose level an additional sample was taken at 48 h after treatment.

TREATMENT AND SAMPLING TIMES (in addition to information in specific fields):
Males:
Negative control and 400 mg/kg bw: sampling after 24 and 48 h
Positive control, 100 and 200 mg/kg bw: sampling after 24 h
Females:
Negative control and 500 mg/kg bw: sampling after 24 and 48 h
Positive control, 125 and 250 mg/kg bw: sampling after 24 h

DETAILS OF SLIDE PREPARATION:
The cell suspension was centrifuged at 1500 rpm (390 x g) for 10 minutes and the supernatant was discarded. A small drop of the resuspended cell pellet was spread on a slide. The smear was air-dried and then stained with May-Grünwald (MERCK, D-64293 Darmstadt)/Giemsa (Gurr, BDH Limited Poole, Great Britain). Cover slips were mounted with EUKITT (KINDLER, D-79110 Freiburg). At least one slide was made from each bone marrow sample.

OTHER:
To describe a cytotoxic effect due to the treatment with the test substance the ratio between polychromatic (PCE) and normochromatic erythrocytes (NCE) was determined in the sample and reported as number of NCEs per 2000 PCEs.
After treatment with the test substance the number of NCEs was not substantially changed as compared to the mean value of NCEs of the vehicle control thus indicating that tert-butyl acrylate had no cytotoxic effectiveness in the bone marrow.
Evaluation criteria:
A test substance is classified as mutagenic if it induces either a dose-related increase in the number of micronucleated polychromatic erythrocytes, which clearly exceeds the negative control range or a relevant positive response for at least one of the test points. Statistical methods (nonparametric Mann-Whitney test) can be used as an aid in evaluating the results. However, the primary point of consideration is the biological relevance of the results.
A test substance producing neither a dose-related increase in the number of micronucleated polychromatic erythrocytes nor a positive response at any of the test points is considered non-mutagenic in this system.

Acceptance Criteria
The study was considered valid as the following criteria were met:
- the negative controls are in the range of the laboratory's historical control data (0.30 - 1.5 per thousand; mean = 0.86 ± 0.27 per thousand PCEs with micronuclei).
- the positive controls are in the range of the laboratory's historical control data (10.0 - 27.1 per thousand; mean = 16.53 ± 4.09 per thousand PCEs with micronuclei).
- at least 80 % of animals are evaluable
- the test was performed up to the maximum tolerated dose, clear signs of systemic toxicity demonstrated systemic availablity of the test material
Key result
Sex:
male/female
Genotoxicity:
negative
Toxicity:
yes
Remarks:
at the highest dose level
Vehicle controls validity:
valid
Negative controls validity:
not applicable
Positive controls validity:
valid
Additional information on results:
Systemic availablity as well as the maximum tolerated dose were determined in pre-studies. Both was also shown by the clinical effects in the main study, all animals of the highest dose groups showed reduction of the spontaneous activity, eyelid closure, apathy and abdominal position after the application. There was no significant cytotoxic effect on the PCE/NCE ratio in the bone marrow for tBA as well as for the significantly micronuclei inducing positive control.

males
test group  dose      sampling  PCEs with    PCE / NCE
            mg/kg bw  time (h)  micronuclei 
                                (percentile)
vehicle     0          24        0.50         2000 / 1821
tBA         100       24        0.60         2000 / 1855
tBA         200       24        0.60         2000 / 1760
tBA         400       24        0.70         2000 / 1878
positiv 
control     40         24      19.80         2000 / 1719
vehicle     0          48        0.10         2000 / 1886
tBA         400       48        0.20         2000 / 1886

females
test group  dose      sampling  PCEs with    PCE / NCE
            mg/kg bw  time (h)  micronuclei 
                                (percentile)
vehicle     0          24        0.70         2000 / 1509
tBA         125       24        0.10         2000 / 1542
tBA         250       24        0.90         2000 / 1714
tBA         500       24        0.20         2000 / 1573
positiv 
control     40         24       13.70        2000 / 1627
vehicle     0          48        0.20         2000 / 1752
tBA         500       48        0.40         2000 / 1674

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

In-vitro studies: Bacterial systems

Tert-butyl acrylate was tested in the Ames Assay according to OECD-guideline 471 with Salmonella typhimurium TA98, TA100, TA1535, TA1537 and E.coli WP2 uvrA at concentrations from 20 to 5000 μg/plate with and without metabolic activation. No increase in the number of revertants was observed in the standard plate test or in the preincubation test either without S-9 mix or after addition of a metabolizing system (BASF 2002).

In-vitro studies: Mammalian cell gene mutation test

A study was performed to investigate the potential of tert.-Butylacrylate to induce gene mutations at the HPRT locus in V79 cells of the Chinese hamster. The assay was performed in two independent experiments, using two parallel cultures each. The main experiments were performed with and without liver microsomal activation and a treatment period of 4 hours. The maximum concentration of 1280 μg/mL was equal to approximately 10 mM. The test item was dissolved in DMSO. No substantial and reproducible dose dependent increase of the mutation frequency was observed up to the maximum concentration with and without metabolic activation. Appropriate reference mutagens (EMS and DMBA), used as positive controls, induced a distinct increase in mutant colonies and thus, showed the sensitivity of the test system and the activity of the metabolic activation system. In conclusion it can be stated that under the experimental conditions reported the test item did not induce gene mutations at the HPRT locus in V79 cells. Therefore, tert.-Butylacrylate is considered to be non-mutagenic in this HPRT assay.

The structural-related n-Butyl Acrylate (n-BA) was tested for its ability to induce gene mutations at the thymidine kinase (TK) locus or structural chromosome aberrations at chromosome 11 in L5178Y TK+/- mouse lymphoma cells in vitro with the microwell method. The test substance did not cause any biologically relevant increase in the mutant frequencies either without S9 mix or after adding a metabolizing system in three experiments performed independently of each other. Thus, under the experimental conditions described, n-butyl acrylate did not induce forward mutations or structural chromosome aberrations in vitro in the mouse lymphoma assay with L5178Y TK+/- cells in the absence and the presence of metabolic activation. (BASF 2016)

 

In addition there are older publications, in which the structurally-related acrylate esters ethyl acrylate and methyl acrylate were tested in both the HPRT assay and the Mouse Lymphoma TK assay.

The HPRT assays were all negative without metabolic activation (Moore et al. 1989, 1991). In contrast, both acrylate esters were positive in the Mouse Lymphoma TK+/- mutation assay using L5178Y cells with and without metabolic activation at clearly cytotoxic concentrations (Rohm & Haas 1980, Moore 1988, 1989). The majority of the mutant colonies were small colonies, suggesting that ethyl and methyl acrylate did act via a clastogenic mechanism (Moore 1988, 1989, Amtower 1986). More recent studies have indicated that there is an association between chromosomal aberrations and cytotoxicity at exposure concentrations which reduce cell growth to less than 50% of the control value (Galloway, 2000 and references cited therein). These data suggest that the increase in mutagenicity reported in the TK assays with ethyl and methyl acrylate may be an artifact of the experimental method.

In-vitro studies: Genotoxicity tests

There are no in vitro micronucleus assays or chromosome aberration tests available for tert-butyl acrylate. In accordance with column 2 of REACH Annex VIII, no study has to be conducted since adequate data from an in vivo cytogenicity test are available.

In vivo studies

In a mouse micronucleus test in accordance to OECD guideline 474, NMRI mice were dosed intraperitoneally with tert-butyl acrylate up to 400 mg/kg bw (males) and 500 mg/kg bw (females), which were shown in pre-tests to be the maximum tolerated doses. The test substance did not induce micronuclei in bone marrow at any dose level or harvesting time used in this study (24 and 48 hours after administration). Tert-butyl acrylate was considered to be non-clastogenic and non-aneugenic in this assay. The clinical effects in the main study clearly demonstrate systemic availability of the tBA. All animals of the highest dose group showed reduction of the spontaneous activity , eyelid closure, apathy and abdominal position after the application. There was no significant cytotoxic effect to the bone marrow, indicated in a change of the PCE/NCE ratio for tBA as well as for the positive control (which significantly induced micronuclei). (BASF 2001).


Justification for classification or non-classification

The substance was not mutagenic in the Ames test and the HPRT assay in V79 cells, and it was not clastogenic in vivo in the mouse micronucleus test. Therefore, based on the available data, classification for genetic toxicity is not warranted in accordance with EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation No. 1272/2008 and GHS classification (GHS UN rev.6, 2015).