Registration Dossier

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Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

The test substance has no genotoxic potential in the in vitro gene mutation study in bacteria.

The test substance has no genotoxic potential in the in vitro cytogenicity / chromosome aberration test.

The test substance has no genotoxic potential in the in vitro mouse lymphoma assay.

The test substance has no genotoxic potential in the in vitro micronucleus assay.

Link to relevant study records

Referenceopen allclose all

Endpoint:
in vitro gene mutation study in bacteria
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Qualifier:
according to guideline
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
GLP compliance:
not specified
Remarks:
Not reported in this summary report
Type of assay:
bacterial reverse mutation assay
Specific details on test material used for the study:
- Name as used in study report: glucanase: Enzyme ZS
Target gene:
- S. typhimurium: his
- E. coli: trp
Species / strain / cell type:
S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
Species / strain / cell type:
E. coli WP2 uvr A
Metabolic activation:
with and without
Metabolic activation system:
S9 mix
Test concentrations with justification for top dose:
maximum concentration 5000 µg/plate
Untreated negative controls:
not specified
Negative solvent / vehicle controls:
not specified
True negative controls:
not specified
Positive controls:
yes
Positive control substance:
not specified
Details on test system and experimental conditions:
A bacterial reverse mutation test was carried out in a plate incorporation test and a pre-incubation test, with and without metabolic activation.
Species / strain:
S. typhimurium, other: TA 1535, 1537, 98, 100 and 102
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Species / strain:
E. coli WP2 uvr A
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Additional information on results:
These studies did not indicate a genotoxic potential.
Endpoint:
in vitro cytogenicity / chromosome aberration study in mammalian cells
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Qualifier:
according to guideline
Guideline:
OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
GLP compliance:
not specified
Remarks:
Not reported in this summary report
Type of assay:
other: in vitro mammalian chromosome aberration test
Specific details on test material used for the study:
- Name as used in study report: glucanase: Enzyme ZS
Species / strain / cell type:
lymphocytes: human
Metabolic activation:
with and without
Metabolic activation system:
S9 mix
Test concentrations with justification for top dose:
Up to 5000 µg/mL
Untreated negative controls:
not specified
Negative solvent / vehicle controls:
not specified
True negative controls:
not specified
Positive controls:
not specified
Details on test system and experimental conditions:
Chromosome aberrations were studied in vitro in human lymphocytes in two experiments, with and without metabolic activation (S9 mix).
Exposure was 4 or 22 hours, and cells were harvested 22 hours after start of the experiment.
Species / strain:
lymphocytes: human
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Additional information on results:
These studies did not indicate a genotoxic potential.
Endpoint:
in vitro gene mutation study in bacteria
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
Please refer to the read-across justification attached to section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Species / strain:
S. typhimurium, other: TA1535, TA1537, TA98, TA100 and TA102
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
valid
Species / strain:
S. typhimurium, other: TA 98, TA 100, TA 1535 and TA 1537
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
valid
Species / strain:
S. typhimurium, other: TA 98, TA 100, TA 102, TA 1535 and TA 1537
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
other: no, but tested up to maximum attainable concentration
Vehicle controls validity:
not specified
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
S. typhimurium, other: TA 98, TA 100, TA 1535 and TA 1537
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Vehicle controls validity:
not specified
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
E. coli WP2 uvr A
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Vehicle controls validity:
not specified
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
E. coli WP2 uvr A
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
valid
Species / strain:
S. typhimurium, other: TA 1535, TA 1537, TA 98 and TA 100
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Species / strain:
E. coli WP2 uvr A
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Species / strain:
S. typhimurium, other: TA 98, TA 100, TA 1535 and TA 1537
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
valid
Positive controls validity:
valid
Species / strain:
E. coli WP2 uvr A
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Vehicle controls validity:
valid
Untreated negative controls validity:
valid
Positive controls validity:
valid
Species / strain:
S. typhimurium, other: TA 1535, TA 1537, TA 1538, TA 98 and TA 100
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
valid
Species / strain:
S. typhimurium, other: TA98, TAI00, TA1535, TA 1537
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Species / strain:
E. coli WP2
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Additional information on results:
No genotoxicity was observed in any of the Ames tests.
Remarks on result:
other: Result read-across Amylofeed
Endpoint:
in vitro cytogenicity / chromosome aberration study in mammalian cells
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
Please refer to the read-across justification attached to section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Species / strain:
lymphocytes: human
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Species / strain:
lymphocytes: human peripheral
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Species / strain:
lymphocytes: human
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
lymphocytes: human
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
Vehicle controls validity:
valid
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Species / strain:
lymphocytes: human cells
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Species / strain:
Chinese hamster Ovary (CHO)
Metabolic activation:
with
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Species / strain:
Chinese hamster Ovary (CHO)
Metabolic activation:
without
Genotoxicity:
positive
Cytotoxicity / choice of top concentrations:
cytotoxicity
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Species / strain:
lymphocytes: human cells
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
valid
Species / strain:
lymphocytes: rat cells
Metabolic activation:
not specified
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Additional information on results:
No genotoxicity was observed in any of the chromosome aberration tests except in the case of Hostazym C (EFSA, 2013) where the enzyme induced structural aberrations only in the absence of S9 mix and only at the highest analysable dose (625 μg/mL), at which dose cytotoxicity was evident but not excessive (viable cell count > 50 %).
Remarks on result:
other: Result read-across Ultraflo
Endpoint:
in vitro gene mutation study in mammalian cells
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
Please refer to the read-across justification attached to section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Species / strain:
mouse lymphoma L5178Y cells
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Species / strain:
mouse lymphoma L5178Y cells
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Remarks on result:
other:
Remarks:
Based on result Read-across Cellulase (CAS 9012-54-8)_DYADIC
Endpoint:
in vitro cytogenicity / micronucleus study
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
Please refer to the read-across justification attached to section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Key result
Species / strain:
human lymphoblastoid cells (TK6)
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
valid
Species / strain:
lymphocytes: human cells
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
no cytotoxicity
Vehicle controls validity:
not specified
Untreated negative controls validity:
not applicable
Positive controls validity:
valid
Remarks on result:
other: Result read-across Amylofeed
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

The test substance has no genotoxic potential in the in vivo mouse micronucleus assay and comet assay.

Link to relevant study records

Referenceopen allclose all

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Qualifier:
according to guideline
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
GLP compliance:
not specified
Type of assay:
other: in vivo mouse micronucleus assay
Specific details on test material used for the study:
- Name as used in study report: glucanase: Enzyme ZS
Species:
mouse
Strain:
not specified
Sex:
not specified
Route of administration:
oral: gavage
Dose / conc.:
2 000 mg/kg bw/day (actual dose received)
Remarks:
maximum dose used
No. of animals per sex per dose:
not specified
Control animals:
not specified
Positive control(s):
not specified
Details of tissue and slide preparation:
immature erythrocytes from bone marrow
Sex:
not specified
Genotoxicity:
negative
Toxicity:
not specified
Vehicle controls validity:
not specified
Negative controls validity:
not specified
Positive controls validity:
not specified
Additional information on results:
No evidence for genotoxicity was observed in this test.
Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
Please refer to the read-across justification attached to section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Key result
Sex:
not specified
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
valid
Negative controls validity:
not applicable
Positive controls validity:
not specified
Remarks on result:
other: Result read-across beta-glucanase and xylanase
Sex:
male
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
not specified
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other:
Remarks:
Based on result Read-across Hostazym C
Sex:
male
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
valid
Negative controls validity:
not valid
Positive controls validity:
valid
Remarks on result:
other:
Remarks:
Based on result Read-across Natugrain TS
Sex:
male/female
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
not specified
Negative controls validity:
valid
Positive controls validity:
valid
Remarks on result:
other:
Remarks:
Based on result Read-across Hostazym C
Sex:
male
Genotoxicity:
negative
Toxicity:
not specified
Vehicle controls validity:
not specified
Negative controls validity:
not specified
Positive controls validity:
not specified
Remarks on result:
other:
Remarks:
Based on result Read-across BD5088_2003
Endpoint:
in vivo mammalian cell study: DNA damage and/or repair
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
Please refer to the read-across justification attached to section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Sex:
male
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
valid
Negative controls validity:
not specified
Positive controls validity:
valid
Remarks on result:
other: all three studies
Remarks:
Read across based on Hostazym C
Sex:
male
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
valid
Negative controls validity:
not specified
Positive controls validity:
not specified
Remarks on result:
other: As all data fall within the current vehicle historical control range, the statistical significance is not considered to be biologically relevant.
Remarks:
Based on read-across Hostazym C
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

IN VITRO STUDIES

Since only briefly described genetic toxicity studies are available for the test substance itself, read-across to very similar analogues is also performed.

 

A briefly reported in vitro gene mutation study in bacteria, performed in accordance to OECD TG 471, with and without metabolic activation up to the limit dose did not show any genotoxic potential (Efsa, 2011).

A briefly reported in vitro chromosome aberration study, performed with human lymphocytes with and without metabolic activation in accordance with OECD TG 473, did not show any genotoxic potential for the test substance (EFSA, 2011).

 

Several in vitro gene mutation studies in bacteria, in accordance with OECD TG 471, have been performed with very similar enzyme preparations, including some preparations in which endo-1,3-beta-glucanase (also called cellulase) (Dupont, 2015) and endo-1,4-beta-glucanase (DYADIC, 2009; EFSA, 2013) were used. Other tested enzymes include alpha-amylase, endo-1,4-beta-xylanase, endo-1,3-beta-glucanase and hemicellulase. In none of the tests, with and without metabolic activation, was a genotoxic potential observed (EFSA, 2013; Dupont, 2015a; Dupont, 2015b; DSM, 2013a; DSM, 2013b; Novozymes, 2006; BASFSE, 2006; Innovase, 2003).

 

Several in vitro chromosome aberration studies, in accordance with OECD TG 473, have also been performed with very similar enzyme preparations. These studies include the enzymes endo-1,4-beta-xylanase, endo-cellulase (or endo-1,4-beta-glucanase, which is the test substance) and endo-1,3-beta-glucanase. In almost all of the tests, with and without metabolic activation, was a genotoxic potential observed (Novozymes, 2006; DSM, 2013a; DSM, 2013b; Dupont, 2015a; Dupont, 2015b; DYADIC, 2009; Innovase, 2003). However, Hostazym C induced structural aberrations only in the absence of S9 mix and only at the highest analysable dose (625 μg/mL), at which dose cytotoxicity was evident but not excessive (viable cell count > 50 %) (EFSA, 2013).

 

Two in vitro micronucleus tests were performed, in accordance with OECD TG 487. The one with an enzyme preparation containing endo-1,3(4)-beta-glucanase, endo-1,4 -beta-xylanase and alpha-amylase and the other study with only endo-1,4-beta-glucanase. The two tests, using human lymphoblastoid cells (TK6) and human lymphosites with and without metabolic activation did not show a genotoxic potential of the preparation (EFSA, 2013, 2015).

BD5088 alpha-amylase has been tested to investigate its genotoxic potential in micronucleus test by using male CD-1 mice bone marrow (Innovase, 2003). The result of this study was negative for genotoxicity.

 

The cellulase enzyme, endo-1,4-beta-glucanase, was examined for its potential to induce gene mutations at the TK-locus of cultured mouse lymphoma L5178Y cells, in both the absence and presence of a metabolic activation system (S9-mix) (DYADIC, 2009). The test product (highest level tested was 5000 μg/mL) was not cytotoxic to the L5178Y cells, nor was an increase of the mutant frequency observed at any dose level in either the absence or presence of S9-mix. It was concluded that, under the conditions used in this study, the cellulase was not mutagenic at the TK-locus of mouse lymphoma L5178Y cells.

IN VIVO STUDIES

A briefly reported in vivo mouse micronucleus assay is available for the test substance itself (EFSA, 2011). This study, performed in accordance with OECD TG 474 up to a dose of 2000 mg/kg bw/day, did not show a genotoxic potential of the substance.

 

A number of in vivo mouse micronucleus assays are available. The one performed with an enzyme preparation with endo-1,3-beta-glucanase and endo-1,4 -beta-xylanase as major enzymatic activities (DSM, 2013b), two others with endo-1,4-beta-glucanase (EFSA, 2013; EFSA, 2015) and the fourth with endo-1,4-xylanase and endo-1,4-ß-glucanase (BASFSE, 2006). The studies were performed in accordance with OECD TG 474 up to a dose of 2000 mg/kg bw/day, and all did not show a genotoxic potential of the substance.

Hostazym C (endo-1,4 -beta-glucanase) concentrate was assessed in two in vivo alkaline single-cell gel electrophoresis analyses for its potential to induce primary DNA damage. In the one test the cells were prepared from the small intestine and stomach of treated rats (EFSA, 2015). Three in vivo comet assays were performed to ensure that the positive outcome reported in a previous in vivo comet assay study was an artefact due to residual test item in the analysed cells. The test item was dissolved in sterile water. Six male rats per group were treated twice orally with a dose of 500, 1000 and 2000 mg/kg bw (for the first & third experiment) or 125, 500 and 2000 mg/kg bw (for the second experiment) 24 and 4 hours prior to preparation of the cells. The volume administered orally was 10 mL/kg bw. At the end of the treatment period, the animals were sacrificed and cells were isolated by mincing of the small intestine tissue and scraping of the stomach tissue. At all tested dose levels, no signs of toxicity were observed. In all three in vivo comet assays, double oral administration of Hostazym C concentrate up to 2 x 2000 mg/kg bw did not induce any DNA damage in cells isolated from the small intestine or stomach of male rats. Therefore, Hostazym C concentrate was considered to be non-genotoxic in these three new in vivo alkaline single-cell gel electrophoresis assays.

In the other in vivo comet assay, provided upon request, the potential of Hostazym C concentrate (62650 CU/g) was assessed to induce of DNA strand breaks in the duodenum and stomach of Crl: CD(SD) rats (EFSA, 2013). Three parameters were evaluated: per cent tail intensity, tail length (μm) and tail moment. The animals were treated with Hostazym C concentrate orally by gavage on two occasions, the second dose being administered approximately 21 hours after the first dose and three hours before sampling.

On the basis of results from the preliminary toxicity test, dose levels of 12.5, 25, 50, 125 and 500 mg/kg bw per day were selected for the comet test. As no substantial differences in toxicity were observed between the sexes, in line with current guidelines, the main test was performed using male animals only. Statistically significant increases in the per cent tail intensity, tail length (μm) and tail moment (arbitrary) were observed in the duodenum of rats treated with Hostazym C concentrate at 125 or 500 mg/kg bw per day (P< 0.001) compared with vehicle-treated control rats. Statistically significant increases in the per cent tail intensity, tail length (μm) and tail moment (arbitrary) were observed in the glandular stomach of rats treated with Hostazym C concentrate at 50, 125 and 500 mg/kg bw per day compared with vehicle-treated control rats (P < 0.001). Furthermore, statistically significant increases in tail length (μm) and tail moment (arbitrary) were observed in the glandular stomach of rats treated with Hostazym C concentrate at 12.5 mg/kg bw per day compared with vehicle-treated control rats (P < 0.05). However, as all data fall within the current vehicle historical control range, the statistical significance is not considered to be biologically relevant. Significant increases in “hedgehog” or “ghost” comets were observed in the duodenum of all animals treated with Hostazym C concentrate at 125 or 500 mg/kg bw per day and in the stomach of all animals treated with Hostazym C concentrate at 50, 125 or 500 mg/kg bw per day, although histopathological examination revealed no treatment-related findings.

Justification for classification or non-classification

Based on the available information classification for genetic toxicity is not warranted in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation No. (EC) 1272/2008.