Registration Dossier
Registration Dossier
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EC number: 255-255-2 | CAS number: 41198-08-7
Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Link to relevant study records
- Endpoint:
- in vitro gene mutation study in bacteria
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 13 November 1990 to 11 January 1991
- Reliability:
- 1 (reliable without restriction)
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OTS 798.5265 (The Salmonella typhimurium Bacterial Reverse Mutation Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: MHW Japan Part 1, notification no 118
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- bacterial reverse mutation assay
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Additional strain / cell type characteristics:
- not specified
- Species / strain / cell type:
- E. coli WP2 uvr A
- Additional strain / cell type characteristics:
- not specified
- Metabolic activation:
- with and without
- Metabolic activation system:
- Aroclor 1254 induced
- Test concentrations with justification for top dose:
- Toxicity test: 0, 20.6, 61.7, 185.2, 555.6, 1666.7, 5000 ug/mL Mutation assay: 0, 312.5, 625, 1250, 2500, 5000 ug/mL
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO for all strains
- Positive controls:
- yes
- Remarks:
- -S9
- Positive control substance:
- sodium azide
- Remarks:
- Migrated to IUCLID6: 5 ug/plate. TA100; TA1535
- Positive controls:
- yes
- Remarks:
- -S9
- Positive control substance:
- 4-nitroquinoline-N-oxide
- Remarks:
- Migrated to IUCLID6: 2 ug/plate. E coli
- Positive controls:
- yes
- Remarks:
- -S9
- Positive control substance:
- 2-nitrofluorene
- Remarks:
- -S9Migrated to IUCLID6: 20 ug/plate. TA98
- Positive controls:
- yes
- Remarks:
- -S9
- Positive control substance:
- 9-aminoacridine
- Remarks:
- Migrated to IUCLID6: 150 ug/plate. TA1537
- Positive controls:
- yes
- Remarks:
- +S9
- Positive control substance:
- other: 2-aminoanthracene. 2.5 ug/plate (TA100; TA98; TA1537) or 50 ug/plate (E coli)
- Positive controls:
- yes
- Remarks:
- +S9
- Positive control substance:
- cyclophosphamide
- Remarks:
- Migrated to IUCLID6: 400 ug/plate. TA1535
- 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
- Vehicle controls validity:
- valid
- 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:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Remarks on result:
- other: all strains/cell types tested
- Remarks:
- Migrated from field 'Test system'.
- Conclusions:
- Interpretation of results (migrated information):negative with metabolic activationnegative without metabolic activationBased on the results from this study, profenofos was not mutagenic in the bacterial strains tested, either in the presence or absence of metabolic activation when tested up 5000 mg/plate (the maximum dose in accordance with regulatory guidelines).
- Executive summary:
In a reverse gene mutation assay in bacteria,Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and Escherichia coli strain WP2uvrA were exposed to CGA15324 tech formulated in DMSO. The assay was performed in two phases, using the plate incorporation method.
Following a preliminary toxicity-mutation assay, dose levels of 312, 625, 1250, 2500 and 5000 ug/plate in the presence and absence of S9 activation were assessed in an initial and confirmatory mutagenicity assay. Owing to a growth-inhibiting effect of the test material in experiments without and with S9 activation, a reduction in the colony numbers by more than 50% was occasionally observed with strains TA1537 and WP2uvrA at the upper concentrations. No precipitate was observed.
Based on the results from this study, profenofos was not mutagenic in the bacterial strains tested, either in the presence or absence of metabolic activation when tested up 5000 ug/plate (the maximum dose in accordance with regulatory guidelines).
- Endpoint:
- in vitro cytogenicity / chromosome aberration study in mammalian cells
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 26 October 1989 to 18 January 1990
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Insufficient level of toxicity induced for the +S9 condition
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 473 (In Vitro Mammalian Chromosome Aberration Test)
- Version / remarks:
- 1983
- Deviations:
- yes
- Remarks:
- Insufficient level of toxicity induced in +S9 condition
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.10 (Mutagenicity - In Vitro Mammalian Chromosome Aberration Test)
- Version / remarks:
- 1984
- Deviations:
- yes
- Remarks:
- Insufficient level of toxicity induced in +S9 condition
- Qualifier:
- according to guideline
- Guideline:
- EPA OTS 798.5375 (In Vitro Mammalian Chromosome Aberration)
- Version / remarks:
- 1987
- Deviations:
- yes
- Remarks:
- Insufficient level of toxicity induced in +S9 condition
- GLP compliance:
- yes
- Type of assay:
- in vitro mammalian chromosome aberration test
- Species / strain / cell type:
- Chinese hamster Ovary (CHO)
- Additional strain / cell type characteristics:
- not applicable
- Metabolic activation:
- with and without
- Metabolic activation system:
- Aroclor 1254
- Test concentrations with justification for top dose:
- 4.69, 9.38, 18.75, 37.5, 75, 150, 300, 600, 1200, 2400 ug/plate Doses scored for chromosome aberrations: 3hr -S9: 18.75,37.5, 75 ug/mL; 3hr +S9: 4.69, 9.38, 18.75 ug/mL; 24hr -S9: 9.38, 18.75, 37.5 ug/mL;
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO
- True negative controls:
- no
- Positive controls:
- yes
- Remarks:
- +S9
- Positive control substance:
- cyclophosphamide
- Remarks:
- Migrated to IUCLID6: 40 ug/mL
- Positive controls:
- yes
- Remarks:
- -S9
- Positive control substance:
- mitomycin C
- Remarks:
- Migrated to IUCLID6: 3hr 0.8 ug/mL, 24hr 0.1 ug/mL
- Species / strain:
- Chinese hamster Ovary (CHO)
- Metabolic activation:
- without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- MI reduced to 29.6%
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Species / strain:
- Chinese hamster Ovary (CHO)
- Metabolic activation:
- with
- Genotoxicity:
- negative
- Remarks:
- see below
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Remarks:
- Insufficient level of toxicity induced (MI 109.3%)
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Species / strain:
- Chinese hamster Ovary (CHO)
- Metabolic activation:
- without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- MI reduced to 28.7%
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Remarks on result:
- other: all strains/cell types tested
- Remarks:
- Migrated from field 'Test system'. Remarks: 3hr -S9
- Conclusions:
- Interpretation of results (migrated information):negative without metabolic activationambiguous with metabolic activation Insufficient level of cytotoxicty not obtainedBased on the results on this assay, CGA 15324 did not induced chromosome aberrations in the in vitro chromosome aberration study using CHO cells following sampling at 3 (–S9) and 24 (-S9) hours, when tested up to cytotoxic concentrations. For the 3hr +S9 treatment whilst no increased in chromsome aberrations were observed, the level of toxicity induced was insufficient.
- Executive summary:
In a mammalian chromosomal aberration assay, Chinese hamster ovary cells cultured in vitro were exposed to CGA15'324 using DMSO as the solvent in either the presence of metabolic activation (+S9, 3 hours) or absence of metabolic activation (-S9, 3 and 24 hours).
No preliminary toxicity test was undertaken, instead all treatments were treated with a concentration range of 4.69 to 2400 ug/mL. Prior to examination of cells for aberrations the MI was scored with the intention of reduction the MI to 20 - 50% of the vehicle control (as per OECD 4473, 1983).
For the 3 hour treatment –S9, doses selected for chromosome aberration assessment were 18.75, 37.5 and 77 ug/mL. At 75 ug/mL, MI was reduced to 29.6%. No increased in in structural aberrations were observed at any treatment dose compared to the concurrent control.
For the 3 hour treatment +S9, doses selected for chromosome aberration assessment were 4.69, 9.38, 18.75 and 37.5 ug/mL. At 37.5 ug/mL, MI was reduced to 47.2%, however potential aberrant cells could not be scored due to the quality of metaphases available, There, a 18.75 ug/mL becomae the highest available dose scored, where no toxicity was observed. Of the doses scored for aberrantions, all doses were comparable to the concurrent control. However, as indicated, a sufficeint level of toxicity was not achieved.
For the 24 hour treatment -S9, doses selected for chromosome aberration assessment were 9.38, 18.75 and 37.5 ug/mL. At 37.5 ug/mL, MI was reduced to 28.7%.
No increased in in structural aberrations were observed at any treatment dose compared to the concurrent control.
No measure of polyploidy was undertaken. Positive controls induced the appropriate response.
Based on the results on this assay, CGA 15'324 did not induced chromosome aberrations in the in vitro chromosome aberration study using CHO cells following sampling at 3 (–S9) and 24 (-S9) hours, when tested up to cytotoxic concentrations. For the 3hr +S9 treatment whilst no increased in chromsome aberrations were observed, the level of toxicity induced was insufficient.
- Endpoint:
- in vitro gene mutation study in mammalian cells
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Dates not given, however study reported in 1982
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Non GLP. Result not confirmed in a independent assay
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 476 (In Vitro Mammalian Cell Gene Mutation Test)
- GLP compliance:
- no
- Type of assay:
- mammalian cell gene mutation assay
- Target gene:
- thymidine kinase (tk)
- Species / strain / cell type:
- mouse lymphoma L5178Y cells
- Details on mammalian cell type (if applicable):
- - Type and identity of media: Fischer's medium plus antibiotics and 10% horse serum- Properly maintained: insufficient information- Periodically checked for Mycoplasma contamination: not stated- Periodically checked for karyotype stability: insufficient informatin- Periodically "cleansed" against high spontaneous background: yes
- Additional strain / cell type characteristics:
- not applicable
- Metabolic activation:
- with and without
- Metabolic activation system:
- Aroclor 1254
- Test concentrations with justification for top dose:
- Preliminary toxicity test: 0.156 to 10.0 ug/mLMutation test: 0.078, 0.156, 0.313, 0.625 ug/mL
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO
- True negative controls:
- yes
- Positive controls:
- yes
- Positive control substance:
- ethylmethanesulphonate
- Remarks:
- -S9Migrated to IUCLID6: 0.5 uL/mL
- Positive controls:
- yes
- Positive control substance:
- N-dimethylnitrosamine
- Remarks:
- +S9Migrated to IUCLID6: 0.5 ug/mL
- Key result
- Species / strain:
- mouse lymphoma L5178Y cells
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not determined
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Conclusions:
- Interpretation of results (migrated information):negative with metabolic activationnegative without metabolic activationBased on the results of this assay, CGA15’324 was concluded to be negative up to a concentration of 0.625 ug/mL in the absence and presence of S9 activation, with the maximum dose limited by toxicity in both test conditions.
- Executive summary:
In a mammalian cell gene mutation assay, mouse lymphoma cell cultures were exposed to CGA15’324, using DMSO as a solvent. Forward mutation at the thymidine kinase (tk) gene locus was measured, using the soft agar method. A preliminary toxicity test was undertaken using CGA15’324 tested at concentrations ranging from 0.156 to 10.0 ug/mL in the absence and presence of S9 using a 4 hour exposure. Relative suspension growth resulting from this preliminary test were not reported, but the results of the test dictated the maximum dose tested in the mutation assay.
In the mutation assay in theabsence of S9, RTG was reduced to 12% at a concentration of 0.625 ug/mL, where mutant frequency was determined. In the presence of S9 RTG was reduced to 8% at a concentration of0.625 ug/mL where mutant frequency was determined.
Based on the results of this assay, CGA15’324 was concluded to be negative up to a concentration of 0.625 ug/mL in the absence and presence of S9 activation, with the maximum dose limited by toxicity in both test conditions.
- Endpoint:
- in vitro gene mutation study in bacteria
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 16 August 1994 tp 12 September 1994
- Reliability:
- 1 (reliable without restriction)
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OTS 798.5265 (The Salmonella typhimurium Bacterial Reverse Mutation Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: MHW Japan Part 1, notification no 118
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- bacterial reverse mutation assay
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Additional strain / cell type characteristics:
- not specified
- Species / strain / cell type:
- E. coli WP2 uvr A
- Additional strain / cell type characteristics:
- not specified
- Species / strain / cell type:
- S. typhimurium TA 102
- Additional strain / cell type characteristics:
- not specified
- Metabolic activation:
- with and without
- Metabolic activation system:
- Aroclor 1254 induced
- Test concentrations with justification for top dose:
- Toxicity test: 0, 20.58, 61.73, 185.19, 555.56, 1666.67, 5000 ug/plate Initial mutation assay: All strains: 0, 156.25, 312.5, 625, 1250, 2500 ug/plate Confirmatory mutation assay: +S9: TA100, TA1535, TA98, WP2uvrA, TA1537: 0, 156.25, 312.5, 625, 1250, 2500 ug/plate +S9: TA102: 0, 312.5, 625, 1250, 2500, 5000 ug/plate -S9: TA100, TA1535, TA1537: 0, 39.06, 78.13, 156.25, 312.5, 625 ug/plate -S9 WP2uvrA, TA98: 0, 156.25, 312.5, 625, 1250, 2500 ug/plate -S9: TA102: 0, 312.5, 625, 1250, 2500, 5000 ug/plate
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO for all strains
- Positive controls:
- yes
- Remarks:
- -S9
- Positive control substance:
- sodium azide
- Remarks:
- Migrated to IUCLID6: 5 ug/plate. TA100; TA1535
- Positive controls:
- yes
- Remarks:
- -S9
- Positive control substance:
- 4-nitroquinoline-N-oxide
- Remarks:
- Migrated to IUCLID6: 2 ug/plate. E coli
- Positive controls:
- yes
- Remarks:
- -S9
- Positive control substance:
- 2-nitrofluorene
- Remarks:
- -S9Migrated to IUCLID6: 20 ug/plate. TA98
- Positive controls:
- yes
- Remarks:
- -S9
- Positive control substance:
- 9-aminoacridine
- Remarks:
- Migrated to IUCLID6: 150 ug/plate. TA1537
- Positive controls:
- yes
- Remarks:
- +S9
- Positive control substance:
- other: 2-aminoanthracene. 2.5 ug/plate (TA100; TA98; TA1537), 20 ug/plate (TA102) or 50 ug/plate (E coli)
- Positive controls:
- yes
- Remarks:
- +S9
- Positive control substance:
- cyclophosphamide
- Remarks:
- Migrated to IUCLID6: 400 ug/plate. TA1535
- 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:
- or tested up to the max. recommended limit
- Vehicle controls validity:
- valid
- 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:
- cytotoxicity
- Remarks:
- or tested up to the max. recommended limit
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Species / strain:
- S. typhimurium TA 102
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- or tested up to the max. recommended limit
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Remarks on result:
- other: all strains/cell types tested
- Remarks:
- Migrated from field 'Test system'.
- Conclusions:
- Interpretation of results (migrated information):negative with metabolic activationnegative without metabolic activationBased on the results from this study, CGA15324/lambda-cyhalothrin EC620 (A-9431 A) was not mutagenic in the bacterial strains tested, either in the presence or absence of metabolic activation when tested up 5000 ug/plate (the maximum dose in accordance with regulatory guidelines) or up to cytotoxic levels.
- Executive summary:
In a reverse gene mutation assay in bacteria,Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and Escherichia coli strain WP2uvrA were exposed to CGA15324 tech formulated in DMSO. The assay was performed in two phases, using the plate incorporation method.
Following a preliminary toxicity-mutation assay, dose levels ranging from 39.06 to 5000 ug/plate in the presence and absence of S9 activatio were assessed in an initial and confirmatory mutagenicity assay.
Based on the results from this study, CGA15324/lambda-cyhalothrin EC620 (A-9431 A) was not mutagenic in the bacterial strains tested, either in the presence or absence of metabolic activation when tested up 5000 ug/plate (the maximum dose in accordance with regulatory guidelines) or up to cytotoxic levels.
- Endpoint:
- in vitro DNA damage and/or repair study
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- Dates not given, however study reported in 1982
- Reliability:
- 3 (not reliable)
- Rationale for reliability incl. deficiencies:
- other: Non GLP. No concurrent measure of cyotoxicity
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 482 (Genetic Toxicology: DNA Damage and Repair, Unscheduled DNA Synthesis in Mammalian Cells In Vitro)
- Deviations:
- yes
- Remarks:
- No concurrent measure of cytotoxicity undertaken
- GLP compliance:
- no
- Type of assay:
- DNA damage and repair assay, unscheduled DNA synthesis in mammalian cells in vitro
- Species / strain / cell type:
- other: Human fibroblasts
- Details on mammalian cell type (if applicable):
- - Type and identity of media: Dulbecco's minimal essential medium (10% FBS).- Properly maintained: yes- Periodically checked for Mycoplasma contamination: insufficient information- Periodically checked for karyotype stability: insufficient information- Periodically "cleansed" against high spontaneous background: not applicable
- Additional strain / cell type characteristics:
- not applicable
- Metabolic activation:
- without
- Test concentrations with justification for top dose:
- Cytotoxicity test: 0.32 to 40 nL/mL UDS repair test: 0.32, 1.6, 8, 40 nl/mL
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- yes
- Positive controls:
- yes
- Positive control substance:
- 4-nitroquinoline-N-oxide
- Remarks:
- Migrated to IUCLID6: 5uM
- Species / strain:
- other: Human fibroblasts
- Metabolic activation:
- with
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- but concurrently determined in the UDS test
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- other: strain/cell type: fibroblasts
- Remarks:
- Migrated from field 'Test system'.
- Conclusions:
- Interpretation of results (migrated information):negativeBased on the results of this study, no evidence of induction of DNA damage by CGA' 15324 tech was observed.
- Executive summary:
CGA-15324 was tested for DNA damaging effect on human fibroblasts in vitro. The investigations were performed with concentrations of 0.32, 1.6, 8 and 40 nL/mL. The maximum dose tested was determined froma toxicity assay, where the viability of cells were reduced to 25%. Of note, no concurrent measure of cytotoxicity was performed in the main UDS assay.
In the experiment performed, comparison of the mean number of silver grains/nucleus in the negative controls and in the cultures treated with the various concentrations of CGA 15324 revealed no marked deviations. The positive control, 4NQO yielded a mean value of 50.8 silver grains/nucleus respectively. This value differed greatly from the negative control by a factor of 63.5.
Based on the results of this study, no evidence of induction of DNA damage by CGA' 15324 tech was observed.
- Endpoint:
- in vitro DNA damage and/or repair study
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 13 November 1981 to 14 January 1982
- Reliability:
- 3 (not reliable)
- Rationale for reliability incl. deficiencies:
- other: Non GLP. No concurrent measure of cyotoxicity
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 482 (Genetic Toxicology: DNA Damage and Repair, Unscheduled DNA Synthesis in Mammalian Cells In Vitro)
- Deviations:
- yes
- Remarks:
- No concurrent measure of cytotoxicity undertaken
- GLP compliance:
- no
- Remarks:
- However, the supplementary report was conducted in accordance with GLP
- Type of assay:
- DNA damage and repair assay, unscheduled DNA synthesis in mammalian cells in vitro
- Species / strain / cell type:
- hepatocytes: rat
- Details on mammalian cell type (if applicable):
- - Type and identity of media: Williams' Medium E, 10% FBS, 100 U/mL penicllin, 100 ug/mL streptomycin and 2.5% ug/mL amphotericin- Properly maintained: yes- Periodically checked for Mycoplasma contamination: not applicable as a primary cell culture- Periodically checked for karyotype stability: not applicable as a primary cell culture- Periodically "cleansed" against high spontaneous background: not applicable as a primary cell culture
- Additional strain / cell type characteristics:
- not applicable
- Metabolic activation:
- not applicable
- Metabolic activation system:
- not applicable
- Test concentrations with justification for top dose:
- Cytotoxicity test: 0.0073, 0.0146, 0.0728, 0.15, 0.29, 2.91, 29.1 ug/mL UDS repair test: 0.02, 0.12, 2.91 ug/mL
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- yes
- Positive controls:
- yes
- Positive control substance:
- 4-nitroquinoline-N-oxide
- Remarks:
- Migrated to IUCLID6: 2uM
- Positive controls:
- yes
- Positive control substance:
- N-dimethylnitrosamine
- Remarks:
- Migrated to IUCLID6: 100uM
- Species / strain:
- hepatocytes: Male rat Tif.RAIf strain
- Metabolic activation:
- not applicable
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- but concurrently determined in the UDS test
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- other: other: primary cell culture
- Remarks:
- Migrated from field 'Test system'.
- Conclusions:
- Interpretation of results (migrated information):negativeBased on the results of this study, no evidence of induction of DNA damage by CGA' 15324 tech was observed.
- Executive summary:
CGA-15324 was tested for DNA damaging effect on rat hepatocytes in vitro. The investigations were performed with concentrations of 0.016, 0.08, 0.4 and 2 nL/mL. The maximum dose tested was determined froma toxicity assay, where the viability of cells were reduced to 25%. Of note, no concurrent measure of cytotoxicity was performed in the main UDS assay.
In the experiment performed, comparison of the mean number of silver grains/nucleus in the negative controls and in the cultures treated with the various concentrations of CGA 15324 revealed no marked deviations. The positive control, DMN and 4NQO yield mean values of 24.3 and 16.5 silver grains/nucleus respectively. These values differed greatly from the negative controls by factors of 7.5 and 5.1 respectively.
Based on the results of this study, no evidence of induction of DNA damage by CGA' 15324 tech was observed.
Referenceopen allclose all
INITIAL TOXICITY-MUTATION ASSAY:
Six doses of the test material ranging from 20.6 to 5000 ug/plate±S9 were evaluated in the overlay toxicity test using T100 WP2urA strains. No precipitation was observed up to the limit dose, 5000 ug/plate. Based on the qualitative data generated, cytotoxicity (as indicated by decreased revertants/plate) was evident at the highest dose tested (HDT) with most test conditions. Hence, 5000 ug/plate (the maximum recommended dose in accordance with guidelines) ± S9 was chosen as the HDT for mutagenicity testing using the overlay method.
CONFIRMATORY MUTAGENICITY ASSAY:
Reproducible cytotoxic effects were seen in the confirmatory mutation test in the majority of strains at 5000 mg/plate±S9. Revertant counts in profenofos treated pre-incubation tests did not differ from the negative (DMSO) control data.Owing to a growth-inhibiting effect of the test material in experiments without and with S9 activation, a reduction in the colony numbers by more than 50% was occasionally observed with strains TA1537 and WP2uvrA at the upper concentrations. No precipitate was observed. In contrast, positive controls responded appropriately with at least a three-fold increase in the number of revertants over the mean value of the respective vehicle control.
Table 7.6.1 -1: Bacterial mutation assay, summary of results
Dose (ug/plate) |
0 |
312.5 |
625 |
1250 |
2500 |
5000 |
Positive control |
REVERTANTS/PLATE ± STANDARD DEVIATION |
|||||||
INITIAL MUTATION ASSAY |
|||||||
TA98 -S9 |
24.7±6.1 |
19.7±6.1 |
10.7±6.4 |
16.3±0.6 |
19.3±7.5 |
15.3±3.5 |
616.3±68.3 |
TA98 +S9 |
31.0±8.7 |
21.7±7.0 |
24.7±7.0 |
22.3±8.7 |
22.0±6.2 |
20.0±3.5 |
1582.0±92.5 |
TA100 -S9 |
111.7±1.5 |
104.7±19.5 |
113.3±5.9 |
106.7±12.2 |
112.0±9.2 |
109.3±10.5 |
757.3±78.5 |
TA100 +S9 |
118.0±14.5 |
104.7±7.2 |
101.0±9.0 |
100.7±23.1 |
117.3±8.5 |
119.0±5.0 |
1266.0±412.0 |
TA1535 -S9 |
10.3±3.8 |
14.7±0.6 |
14.7±0.6 |
12.3±3.5 |
11.3. ±3.1 |
13.7±2.1 |
558.3±49.6 |
TA1535 +S9 |
9.7±2.1 |
11.0±4.6 |
7.3±4.5 |
6.0±2.6 |
4.3±3.2 |
8.7±2.3 |
213.3±9.1 |
TA1537 -S9 |
8.7±1.5 |
4.7±2.1 |
5.3±0.6 |
3.3±1.5 |
4.3±1.2 |
3.3±0.6 |
1465.0±229.4 |
TA1537 +S9 |
5.3±2.9 |
3.7±0.6 |
6.7±1.5 |
6.7±1.5 |
2.3±1.2 |
1.7±1.5 |
98.7±12.1 |
WP2uvrA –S9 |
22.3±3.8 |
19.0±1.0 |
17.3±3.1 |
21.7±5.9 |
16.0±4.4 |
18.0±6.0 |
837.7±169.2 |
WP2uvrA +S9 |
28.3±10.1 |
22.0±3.6 |
22.7±3.2 |
14.7±2.5 |
24.3±6.5 |
10.0±2.0 |
1233.7±149.9 |
CONFIRMATORY ASSAY |
|||||||
TA98 -S9 |
36.0±3.6 |
26.7±2.5 |
28.0±4.4 |
42.7±4.6 |
23.7±5.5 |
34.3±2.3 |
850.7±57.7 |
TA98 +S9 |
46.0±3.6 |
40.0±12.5 |
46.3±5.5 |
28.0±3.5 |
37.7±5.1 |
24.0±5.0 |
2590.3±319.9 |
TA100 -S9 |
81.0±4.0 |
77.7±26.3 |
81.7±3.5 |
96.0±8.2 |
92.7±11.0 |
87.3±20.6 |
373.0±24.3 |
TA100 +S9 |
93.3±10.8 |
83.3±18.1 |
77.3±9.7 |
80.3±10.8 |
5.7±1.2 |
53.3±2.9 |
1678.7±56.1 |
TA1535 -S9 |
19.3±2.1 |
16.7±2.1 |
21.0±4.4 |
20.3±4.0 |
19.0±2.6 |
14.0±2.6 |
1337.7±67.3 |
TA1535 +S9 |
10.3±4.7 |
11. 3±4.7 |
12.7±0.6 |
12.7±5.9 |
14.3±0.6 |
9.0±5.3 |
335.3±10.0 |
TA1537 -S9 |
4.7±2.1 |
7.5±0.7 |
6.7±0.6 |
5.7±0.3 |
3.0±1.0 |
3.0±2.0 |
1454.0±234.2 |
TA1537 +S9 |
11.0±5.3 |
7.7±1.5 |
10.0±4.6 |
7.7±1.5 |
4.7±2.1 |
4.7±0.6 |
81.3±11.2 |
WP2uvrA –S9 |
37.3±4.2 |
37.0±1.0 |
36.0±5.6 |
27.0±8.2 |
24.0±4.4 |
17.0±3.6 |
1507.0±103.6 |
WP2uvrA +S9 |
48.7±3.5 |
45.0±7.8 |
38.0±7.2 |
30.7±5.7 |
16.3±3.8 |
12.0±7.8 |
1728.7±103.1 |
CYTOGENETIC ASSAYS
The following concentrations were treated in all treatments: 4.69, 9.38, 18.75, 75, 150, 300, 600, 1200, 2400 ug/mL.
In the 3hr –S9 treatment the highest concentration selected for analysis was 75 ug/mL, where mitotic index (MI) was reduced to 29.6% (70.4% suppression). With reduction in MI to an acceptable level, no increase in chromosomal aberrations were observed.
In the presence of S9, MI was reduced to 47.2% (52.8% suppression) at 37.5 ug/mL. However, due to poor metaphase quality, this dose level could not be scored for chromosome aberrations. The next available concentration available for analysis was 18.75 ug/mL, where MI was 109.3% (i.e. no evidence of toxicity). At the highest concentration available for analysis (18.75 ug.mL), no increase in chromosomal aberrant cells was observed, however as stated the level of toxicity observed was insufficient.
In the second experiment, 24hr treatment –S9, MI was reduced t 28.7% (71.3% suppression) at a dose of 37.5 ug/mL. Up to this dose, no increase in aberrant cells was observed.
Positive controls induced the appropriate response.
Table 7.6.1 -2: Chromosome aberrations in human lymphocytes, 3h, without S9: Cells fixed 21h after initiation of treatment
metaphases with specific aberrations |
metaphases with unspecific aberrations |
Toxicity determination |
|||||||||||
|
Cells scored |
% |
ctb |
Cte |
ctf |
% |
Gap |
Chrd |
Chrc |
Total scored |
Mitosis |
%MI |
Relative |
CONTROLS |
|||||||||||||
DMSO |
100 |
0 |
0 |
0 |
0 |
2 |
2 |
0 |
0 |
2000 |
108 |
5.4 |
100 |
|
|||||||||||||
MMC |
50 |
22 |
5 |
6 |
4 |
16 |
7 |
1 |
0 |
NR |
NR |
NR |
NR |
CGA 15’324 (ug/mL) |
|||||||||||||
9.38 |
NS |
NS |
NS |
NS |
0 |
0 |
0 |
0 |
0 |
2000 |
101 |
2.05 |
93.5 |
18.75 |
100 |
3 |
0 |
2 |
1 |
10 |
10 |
0 |
0 |
2000 |
94 |
4.7 |
87.0 |
37.5 |
100 |
4 |
0 |
1 |
3 |
2 |
2 |
0 |
0 |
2000 |
95 |
4.75 |
88.0 |
75 |
100 |
3 |
1 |
1 |
2 |
5 |
5 |
0 |
0 |
2000 |
32 |
1.6 |
29.6 |
NR – not reported
NS – not scored
Table 7.6.2 -3: Chromosome aberrations in human lymphocytes, 3h, with S9: Cells fixed 21h after initiation of treatment
metaphases with specific aberrations |
metaphases with unspecific aberrations |
Toxicity determination |
|||||||||||
|
Cells scored |
% |
ctb |
Cte |
ctf |
% |
Gap |
Chrd |
Chrc |
Total scored |
Mitosis |
%MI |
Relative |
CONTROLS |
|||||||||||||
DMSO |
100 |
3 |
0 |
0 |
3 |
1 |
1 |
0 |
0 |
2000 |
108 |
5.4 |
100 |
|
|||||||||||||
CPA |
25 |
60 |
6 |
7 |
16 |
28 |
7 |
1 |
0 |
NR |
NR |
NR |
NR |
CGA 15’324 (ug/mL) |
|||||||||||||
4.69 |
100 |
0 |
0 |
0 |
0 |
2 |
2 |
0 |
0 |
2000 |
129 |
6.45 |
119.4 |
9.38 |
100 |
4 |
0 |
2 |
2 |
6 |
6 |
0 |
0 |
2000 |
120 |
6.0 |
111.1 |
18.75 |
100 |
4 |
1 |
1 |
2 |
4 |
4 |
0 |
0 |
2000 |
118 |
5.9 |
109.3 |
37.5 |
NS |
NS |
NS |
NS |
NS |
NS |
NS |
NS |
NS |
2000 |
51 |
2.55 |
47.2 |
NR – not reported
NS – not scored due to metaphase quality
Table 7.6.1 -4: Chromosome aberrations in human lymphocytes, 24h, without S9: Cells immediately post treatment
metaphases with specific aberrations |
metaphases with unspecific aberrations |
Toxicity determination |
|||||||||||
|
Cells scored |
% |
ctb |
Cte |
ctf |
% |
Gap |
Chrd |
Chrc |
Total scored |
Mitosis |
%MI |
Relative |
CONTROLS |
|||||||||||||
DMSO |
100 |
5 |
1 |
1 |
3 |
5 |
6 |
0 |
0 |
2000 |
108 |
5.4 |
100 |
|
|||||||||||||
MMC |
25 |
44 |
6 |
7 |
3 |
16 |
4 |
0 |
0 |
NR |
NR |
NR |
NR |
CGA 15’324 (ug/mL) |
|||||||||||||
4.69 |
100 |
NS |
NS |
NS |
NS |
NS |
NS |
NS |
NS |
2000 |
31 |
1.55 |
28.7 |
9.38 |
100 |
6 |
3 |
1 |
2 |
5 |
5 |
0 |
0 |
2000 |
114 |
5.7 |
105.8 |
18.75 |
100 |
3 |
1 |
2 |
0 |
5 |
5 |
0 |
0 |
2000 |
98 |
4.9 |
90.7 |
37.5 |
NS |
1 |
0 |
0 |
1 |
6 |
6 |
0 |
0 |
2000 |
103 |
5.15 |
95.4 |
NR – not reported
NS - not scored
TEST PERFORMANCE
Cell treatment:
Cells were exposed to test material, solvent or positive controls for 4 hours (in the absence and presence of S9). At the end of treatment cultures were washed and cells cultured for an additional 3 days to allow phenotypic expression (via forward mutation) of the tk-/- gene. At the end of the expression period, for mutant selection as well as viability assessment, cultures were set up in semi solid agar, containing cloning medium. For mutant selection, 8 tubes containing 4x105cells/tube in cloning medium with BUdR at a final concentration of 0.005% were established. For viability assessment, 4 tubes containing 200 cells/tube in cloning medium without BUdR were established.
The incubation time was 14 days for mutant selection and 10 days for viability assessment. At the end of the incubation period the numbers of colonies in the mutagenicity test tubes and in the viability control cultures were determined
Statistics:
No statistical analysis was conducted.
Evaluation criteria:
A test material was considered to induce a positive response if the colony count exceeded that of the solvent control by a factor of 2.5 or more at any concentration.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Genetic toxicity in vivo
Link to relevant study records
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 11 July 1989 to 19 February 1990
- Reliability:
- 1 (reliable without restriction)
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 475 (Mammalian Bone Marrow Chromosome Aberration Test)
- Version / remarks:
- (1983)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)
- Version / remarks:
- (1984)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OTS 798.5395 (In Vivo Mammalian Cytogenics Tests: Erythrocyte Micronucleus Assay)
- Version / remarks:
- (1987)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- micronucleus assay
- Species:
- mouse
- Strain:
- other: TRif: MAGF, SPF
- Sex:
- male/female
- Route of administration:
- oral: gavage
- Duration of treatment / exposure:
- single admin
- Frequency of treatment:
- once
- Post exposure period:
- 16, 24, 48hr (16hr data discounted and not report due to insufficient sample time)
- Remarks:
- Doses / Concentrations:50, 100, 200 mg/kgBasis:nominal conc.
- No. of animals per sex per dose:
- 5 animals/sex/gp
- Control animals:
- yes, concurrent vehicle
- Tissues and cell types examined:
- Micronuclei within polychromatic erthyrocytes (PCE) analysed for endpoint assessment and PCE and normochromatic erthyrocyte cells analysed for toxicity assessment
- Sex:
- male/female
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Negative controls validity:
- not applicable
- Positive controls validity:
- valid
- Conclusions:
- Interpretation of results (migrated information): negativeBased on the results from this study CGA 15’324 tech did not exhibit in vivo mammalian genotoxicity in male or female mouse bone marrow cells when tested up to a dose of 200 mg/kg (considered to exceed the MTD).
- Executive summary:
In a bone marrow micronucleus assay usingTif: MAG., SPF mice, a single administered gavage dose of CGA 15'324 tech was administered to groups of male and female animals, employing a dose volume of 20 mL/kg. Doses were selected from a pilot toxicity study where four male mice were dosed at 160, 200, 1000 and 5000 mg/kg. The maximum tolerated dose was deemed to be 160 mg/kg, however, for an unexplained reason the maximum dose selected for the micronucleus assay was 200 mg/kg, with further doses of 50 and 100 mg/kg.
Negative control groups were treated with vehicle only (0.5% CMC), and positive control groups were treated with cyclophosphamide (CPA, 64 mg/kg). Mouse bone marrow was sampled at 24 and 48 hours after dosing for the vehicle, positive control and the highest dose group and again at 48hrs for the vehicle, positive control and all dose groups. A further sample time of 16 hours was also utilised, however as this sample time is considered too early, data from this sample time point has not been reported. Slides of bone marrow cells were prepared from five animals/sex/time point (where available) for each group and scored for the occurrence of micronucleated polychromatic erythrocytes (MN PCE) and PCE/total erythrocyte ratios.
One female dosed at 200 mg/kg died within the 48 hour treatment period (2nd sample time) died prior to the scheduled necropsy. There were no marked decreases in mean PCE/total erythrocyte ratio observed for any of the CGA 15’324 tech treated groups compared to the vehicle control group for either time points.
Analysis of the mean MN PCE group data from the first experiment indicated that there was no statistically significant increases MN PCE frequency compared to concurrent control values for either sex. Individual animal and group mean MN PCE frequencies were consistent with both the concurrent vehicle control values and the historical control. Positive control treatment induced the appropriate response
In the second experiment, whilst a significant increase (p<0.05) in MN PCE was observed for both male and female animals dosed at 50 mg/kg, this was due MNPCE values in both control groups being particularly low, with the increases not deemed biologically relevant. Furthermore, the slight increases observed were not accompanied by a decrease in %PCE values Positive control treatment induced the appropriate response.
Based on the results from this study CGA 15’324 techdid not exhibit in vivo mammalian genotoxicity in male or female mouse bone marrow cells when tested up to a dose of 200 mg/kg (considered to exceed the MTD).
- Endpoint:
- in vivo mammalian germ cell study: cytogenicity / chromosome aberration
- Remarks:
- Type of genotoxicity: chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- Not stated, however report issued in 1974
- Reliability:
- 3 (not reliable)
- Rationale for reliability incl. deficiencies:
- other: Non GLP compliant, no justification for maximum dose used, insufficient dose levels, insufficient group size
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 478 (Genetic Toxicology: Rodent Dominant Lethal Test)
- GLP compliance:
- no
- Type of assay:
- rodent dominant lethal assay
- Species:
- mouse
- Strain:
- NMRI
- Sex:
- male/female
- Route of administration:
- oral: gavage
- Duration of treatment / exposure:
- Single dose. Male mice mated to untreated females over a 6 week period
- Frequency of treatment:
- Once
- Post exposure period:
- All females sacricied on day 14 of gestation
- Remarks:
- Doses / Concentrations:0, 35, 100 mg/kgBasis:nominal conc.
- No. of animals per sex per dose:
- Group sizes ranged from 21 to 34 female animals.
- Control animals:
- yes, concurrent vehicle
- Tissues and cell types examined:
- Embryos, implantations
- Sex:
- female
- Genotoxicity:
- negative
- Toxicity:
- not specified
- Vehicle controls validity:
- valid
- Negative controls validity:
- not applicable
- Positive controls validity:
- not specified
- Conclusions:
- Interpretation of results (migrated information): negativeBased on the results of this study, no evidence of dominant lethal effects were observed in the progeny of male mice treated with CGA 15324 TECHN.
- Executive summary:
CGA-15324 TECHN was administered as a oral single dose to male mice which were then mated to untreated females over a period of 6 weeks. At the end of each week the females were replaced by new ones. Doses of 35 and 100 mg/kg were given. The objectives of the experiment were to evaluate any cytotoxic or mutagenic effects on the male germinal cells as expressed by the loss of pre-implantation zygotes as well as by the rat of deaths of post-implantation stages of embryonic development.
The females mated to males which had been treated with CGA15324 TECHN did not differ significantly from the females mated to controls, neither in mating ratio nor in the number of implantations and embryonic deaths (resorptions).
Based on the results of this study, no evidence of dominant lethal effect was observed in the progeny of male mice treated with CGA 15324 TECHN.
Referenceopen allclose all
RANGE-FINDING TEST:
Four males were dosed at 160, 200, 1000 and 5000 mg/kg. Animals were sacrificed at 3 days post the end of dosing. The following deaths were observed 0/4, 1/4, 4/4 and 4/4 respectively. The MTD was determined to be 160 mg/kg, however, in spite of the death observed a maximum dose of 200 mg/kg was selected for the micronucleus assay.
MICRONUCLEUS ASSAY
Five animals/sex/group were dosed using a dose volume of 20 mL/kg. Vehicle was 0.5% CMC.
Clinical observations:
No data reported
PCE ratio:
No evidence of cytotoxicity was observed.
Micronucleated polychromatic erythrocytes (MN PCE):
Analysis of the mean MN PCE group data from the first experiment indicated that there was no statistically significant increases MN PCE frequency compared to concurrent control values for either sex. Individual animal and group mean MN PCE frequencies were consistent with both the concurrent vehicle control values and the historical control. Positive control treatment induced the appropriate response
In the second experiment, whilst a significant increase (p<0.05) in MN PCE was observed for both male and female animals dosed at 50 mg/kg, this was due MNPCE values in both control groups being particularly low, with the increases not deemed biologically relevant. Furthermore, the slight increases observed were not accompanied by a decrease in %PCE values.
Table 7.6.2 -1: Summary of micronucleus results in male and female mice (24 and 48hr sample)
Dose group |
Sex |
Harvest time (h) |
Mean %MN PCE/1,000 PCE |
Mean %PCE |
Vehicle |
male |
24 |
0.08 |
47 |
female |
24 |
0.14 |
45 |
|
Vehicle |
male |
48 |
0.08 |
46 |
female |
48 |
0.00 |
45 |
|
200 |
male |
24 |
0.12 |
48 |
female |
24 |
0.08 |
39 |
|
200 |
male |
48 |
0.06 |
40 |
female |
48 |
0.16 |
38 |
|
CPA |
male |
24 |
1.80 |
44 |
female |
24 |
2.48 |
42 |
Table 7.6.2 -2: Summary of micronucleus results in male and female mice (48hr sample)
Dose group |
Sex |
Harvest time (h) |
Mean %MN PCE/1,000 PCE |
Mean %PCE |
Vehicle |
male |
48 |
0.02 |
45 |
female |
48 |
0.06 |
44 |
|
50 |
male |
48 |
0.12* |
49 |
female |
48 |
0.16* |
46 |
|
100 |
male |
48 |
0.08 |
45 |
female |
48 |
0.08 |
44 |
|
200 |
male |
48 |
0.14 |
46 |
female |
48 |
0.08 |
47 |
|
CPA |
male |
24 |
1.54* |
48 |
female |
24 |
0.88* |
46 |
# Vehicle control,0.5% CMC(20 mL/kg body weight); positive control, cyclophosphamide (64 mg/kg)
* p<0.05
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Additional information
Gene mutation (bacterial)
Currently, existing Ames data in the form of two GLP conducted studies (key study, Ogorek, 1991 and supporting study, Hertner, 1994) are available. Under these studies Profenofos was tested up to 5 mg/plate (maximum recommended dose) and returned a negative result in the absence and presence of metabolic activation (S9). In the key study a purity of 90.5% Profenofos was tested, where as in the supporting study the purity value was quoted as 602 g/L Profenofos.
Mammalian chromosome aberration (in vitro)
The available in vitro mammalian CHO chromosomal aberration studies conducted on Profenofos returned a negative result. However, whilst both the 3hr and 24 treatments in the absence of S9 were tested up to cytotoxic concentrations, with no increases in aberrant frequency, the 3hr +S9 conditions was not assessed up to cytotoxic concentrations. Prior to selecting dose concentrations for aberration scoring, %MI was determined. A dose concentration of 37.5 ug/mL was found to have an MI of 47.2%, with the next highest dose of 18.75 ug/mL observing no toxicity (%MI 109.3). When chromosomes were scored for aberrations, dose level 37.5 ug/mL was deemed unsuitable for scoring due to poor quality of available metaphases. Therefore, dose level 18.75 ug/mL was selected as the next available dose; whilst no increase in chromosome aberrations were observed, the level of toxicity induced was insufficient.
Mammalian gene mutation (in vitro)
The mammalian gene mutation study conducted (Strasser, 1982) confirmed that Profenofos was negative in both the absence and presence of S9, following a 4 hour treatment when tested up to a concentration of 0.625 ug/mL. In both treatment conditions the maximum dose was limited by toxicity, with RTG being reduced to an acceptable level (i. e. 10 -20%). The result obtained from this study was not confirmed in an independent test. Therefore in order to address this deficiency, two in vitro UDS studies are available in which Profenofos was tested in rat primary hepatocyte cultures (Puri, 1982) or human fibroblasts (Puri, 1982). The maximum doses tested were determined from a cytotoxicity test; however no concurrent measure of cytotoxicity was undertaken in the UDS assay. In both cases the maximum dose was limited by toxicity (based on the cytotoxicity test). A negative result was returned in both assays. As the primary cell culture used rat hepatocytes, the use of S9 was not required, however the UDS assay conducted in human fibroblasts was only conducted in the absence of S9. These data would further support the negative result observed in thein vitromammalian gene mutation study.
In vivobone marrow micronucleus
The mouse bone marrow micronucleus study on Profenofos (Skripsky, 1990) involved a single administration of the test article with the bone marrow sampled at time points of 16, 24 and 48 hours post dosing. Data from the 16 hour sample time was not reported as such a time point is considered too early for any effects to be detected in the proliferating bone marrow. Data from the 24 and 48 hour sample time were in line with the guideline requirements. A negative result was obtained from this study, with the maximum dose exceeding the MTD.
A further in vivo study, examining male germinal cells confirmed no evidence of dominant lethal effects, mating ratio, implantations or embryonic deaths differed in females mated to treated males from those mated to control males. However there was no justification of the maximum dose tested.
Genetic Toxicology Summary
Whilst positive results were obtained in thein vitromammalian chromosome assay, the negativein vivodata confirms that in the in vitro result is not realised, imply thus that the in vitro positive result was not biologically relevant (possible resulting from a cell culture / in vitro artefact).
Under REACH for the registration of above 1000 tons/annum the minimum requirements for the genetic toxicology endpoint are bacterial gene mutation assay, in vitro mammalian gene mutation and chromosome aberration assays and in vivo assay. The available data, irrespective of the endpoint examined all returned negative results. The overall conclusion from these data confirm under the requirements of this registration the genetic endpoint has been adequately addressed and this chemicals which is devoid of genetic potential under the testing protocols used.
Short description of key information:
Section 7.6.1 (in vitro):
KS - Ames. Ogorek, 1991. KL.1 negative +/-S9;
SS - Ames. Hertner, 1994. KL.1 negative +/-S9;
KS - Chrom abs (CHO). Strasser, 1990. KL.2 negative-S9; +S9 insufficient
level of toxicity achieved
KS MLA (tk). Strasser, 1982. KL.2 negative +/-S9;
SS - UDS (rat hep) Puri, 1982. KL.3 negative;
SS - UDS (human fibro). Puri, 1982. KL.3 negative +/-S9;
Section 7.6.2 (in vivo):
KS - MNT (mouse). Skripsky, 1990. KL.1 negative;
SS - DLA (mouse). Fritz, 1974. KL.3 negative.
Endpoint Conclusion: No adverse effect observed (negative)
Justification for classification or non-classification
According to Regulation (EC) No 1272/2008 Profenofos is not classified for genetic toxicity.
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