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Registration Dossier
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EC number: 265-025-3 | CAS number: 64704-23-0
Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Description of key information
In a study published in 1986, cystine was tested for its ability to revert lacZ53 cells to Lac+. It did not have a significant effect on Lac reversion in a uvrB mumC E.coli strain but it did have a significant anti-mutagenic effect on the isogenic uvrB strain.
In an Ames assay (published in 1983) that tested up to 40 mM of cysteine, the postmitochondrial supernatant from rat liver and kidney homogenates induced test substance cysteine to revert Salmonella typhimurium TA100 to histidine independence. Cysteine exhibited mutagenic properties in the presence of S9 liver and kidney metabolic activation.
Link to relevant study records
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1983
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Principles of method if other than guideline:
- - Principle of test:
Ames test (Salmonella typhimurium reverse mutation assay) with histidine-dependent strain.
- Short description of test conditions: Postmitochondrial supernatant was prepared from homogenates of kidney and lvier from untreated adult male Sprague-Dawley rats. Histidine-dependent bacteria of Salmonella typhimurium TA100, the subcellular fraction from 100 mg of tissue with or without an NADPH-generating system, a neutralized solution of the test compound in water, and histidine-poor soft agar were mixed and added to culture plates containing minimal agar. The colonies that reverted to histidine independence were counted after 2 days' incubation in the dark.
- Parameters analysed / observed: Number of revertants per plate - GLP compliance:
- not specified
- Type of assay:
- bacterial reverse mutation assay
- Specific details on test material used for the study:
- Cysteine sourced from three different manufacturers: Boehringer, Sigma and Merck
- Target gene:
- Histidine
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Species / strain / cell type:
- S. typhimurium TA 1538
- Metabolic activation:
- with and without
- Metabolic activation system:
- liver or kidney S9 (postmitochondrial supernatant)
- Test concentrations with justification for top dose:
- 0, 5, 10, 20, 40 mM (according to figure)
- Vehicle / solvent:
- not specified
- Untreated negative controls:
- yes
- Remarks:
- Hydrogen peroxide
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in agar
DURATION
- Preincubation period: not specified
- Exposure duration: 2 days
- Expression time (cells in growth medium): not specified
- Selection time (if incubation with a selection agent): 2 days
NUMBER OF REPLICATIONS: 3 - Rationale for test conditions:
- Followed the Ames test procedure.
- Evaluation criteria:
- Counted the number of histidine revertants.
- Statistics:
- Not specified
- Key result
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with
- Genotoxicity:
- positive
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- valid
- Remarks:
- Hydrogen peroxide
- Positive controls validity:
- not specified
- Key result
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- valid
- Remarks:
- hydrogen peroxide
- Positive controls validity:
- not specified
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- valid
- Remarks:
- hydrogen peroxide
- Positive controls validity:
- not specified
- Key result
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- valid
- Remarks:
- hydrogen perioxide
- Positive controls validity:
- not specified
- Key result
- Species / strain:
- S. typhimurium 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:
- valid
- Remarks:
- hydrogen perioxide
- Positive controls validity:
- not specified
- Key result
- Species / strain:
- S. typhimurium TA 1538
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- valid
- Remarks:
- hydrogen perioxide
- Positive controls validity:
- not specified
- Additional information on results:
- S. typhimurium TA 98, TA 1535, TA 1539, TA 1538: negative, with and without metabolic activation
S. typhimurium TA100:
In the absence of S9, cysteine did not increase the number of revertants.
With the addition of liver S9, cysteine increased the number of revertants
With the addition of kidney S9, cysteine increased the number of revertants severalfold above the spontaneous level.
Different batches from different manufacturers (Boehringer, Sigma, Merk) did not show any quantitative differences. - Conclusions:
- In the presence of liver or kidney S9, cysteine increased the number of histidine revertants in S typhimurium TA 100. Without S9, no increase was observed.
In S. typhimurium TA 98, TA 1535, TA 1539, TA 1538, in increase in the number of histidine revertants was reported, with or without metabolic activation. - Executive summary:
In an Ames assay testing up to 40 mM of cysteine, the postmitochondrial supernatant from rat liver and kidney homogenates induced test substance cysteine to revert Salmonella typhimurium TA100 to histidine independence. Cysteine exhibited mutagenic properties in the presence of S9 liver and kidney metabolic activation in Salmonella typhimurium TA100. In S. typhimurium TA 98, TA 1535, TA 1539, TA 1538, in increase in the number of histidine revertants was reported, with or without metabolic activation.
The increased number of mutants in the presence of relatively high concentration of physiological compounds could be the result not of mutagenicity but of nutritional interactions between these compounds and histidine because the histidine-dependent strains TA1537, TA1538, TA98 and TA1535 which differ from TA100 in the mutation leading to histidine dependence or in the DNA repair system, showed either no revertants or very low numbers of revertants in response to glutathione and cysteine compared with the number induced in strain TA100.
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1983
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Justification for type of information:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The structurally similar read across candidates for Disodium L-cystinate are: Cystine (EC# 200-296-3 / CAS# 56-89-3) and L- Cysteine (EC # 200-158-2/CAS# 52-90-4) which contain the same constituents as the target substance and as such, provide excellent structural surrogates for read-across purposes.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See attached read-across justification document.
3. ANALOGUE APPROACH JUSTIFICATION
The physical-chemical properties are very similar between the Target and Source substances (i.e., melting point, density, particle size, partition coefficient). In addition, the source substance is more soluble than the target substance, making the source (read across) substance a conservative read across substance in terms of increased bioavailability. Based on the chemical structure and the available supporting data for the Source (read across) substances, the Target substance is expected to rapidly biodegrade in the environment. The Source (read across) substances are more soluble than the target substance, making the source substance a conservative read across substance in terms of increased bioavailability. Upon ingestion, the target Disodium L-cystinate is metabolized to form the source Cystine. Therefore the Cystine values are predictive of the acute and repeat dose oral toxicity endpoints. The source (read across) substance is more soluble than the target substance, making the source substance a conservative read across substance in terms of increased bioavailability.
4. DATA MATRIX
See attached read-across justification document. - Reason / purpose for cross-reference:
- read-across source
- Key result
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with
- Genotoxicity:
- positive
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- valid
- Remarks:
- Hydrogen peroxide
- Positive controls validity:
- not specified
- Key result
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- valid
- Remarks:
- Hydrogen peroxide
- Positive controls validity:
- not specified
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- valid
- Remarks:
- hydrogen perioxide
- Positive controls validity:
- not specified
- Key result
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- valid
- Remarks:
- hydrogen perioxide
- Positive controls validity:
- other:
- Key result
- Species / strain:
- S. typhimurium 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:
- valid
- Remarks:
- hydrogen perioxide
- Positive controls validity:
- not specified
- Key result
- Species / strain:
- S. typhimurium TA 1538
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- valid
- Remarks:
- hydrogen perioxide
- Positive controls validity:
- not specified
- Additional information on results:
- S. typhimurium TA 98, TA 1535, TA 1539, TA 1538: negative, with and without metabolic activation
S. typhimurium TA100:
In the absence of S9, cysteine did not increase the number of revertants.
With the addition of liver S9, cysteine increased the number of revertants
With the addition of kidney S9, cysteine increased the number of revertants severalfold above the spontaneous level.
Different batches from different manufacturers (Boehringer, Sigma, Merk) did not show any quantitative differences. - Conclusions:
- In the presence of liver or kidney S9, cysteine increased the number of histidine revertants in S typhimurium TA 100. Without S9, no increase was observed.
In S. typhimurium TA 98, TA 1535, TA 1539, TA 1538, in increase in the number of histidine revertants was reported, with or without metabolic activation. - Executive summary:
In an Ames assay testing up to 40 mM of cysteine, the postmitochondrial supernatant from rat liver and kidney homogenates induced test substance cysteine to revert Salmonella typhimurium TA100 to histidine independence. Cysteine exhibited mutagenic properties in the presence of S9 liver and kidney metabolic activation in Salmonella typhimurium TA100. In S. typhimurium TA 98, TA 1535, TA 1539, TA 1538, in increase in the number of histidine revertants was reported, with or without metabolic activation.
The increased number of mutants in the presence of relatively high concentration of physiological compounds could be the result not of mutagenicity but of nutritional interactions between these compounds and histidine because the histidine-dependent strains TA1537, TA1538, TA98 and TA1535 which differ from TA100 in the mutation leading to histidine dependence or in the DNA repair system, showed either no revertants or very low numbers of revertants in response to glutathione and cysteine compared with the number induced in strain TA100.
This information is used in a read-across approach in the assessment of the target substance.
For justification of read-across please refer to the attached read-across report.
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1986
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Principle of test:
To test Disodium L-cystinate for mutagenicity with the goal of finding a type of mutagenesis that is regulated by DNA repair genes
- Short description of test conditions: The test substance is tested for its ability to revert lacZ53 cells to Lac+ in E. coli uvrB and uvrB umuC strains.
- Parameters analysed / observed: Relative Lac+ mutagenesis in the presence of test substance at 2 mM in two different E. coli strains. - GLP compliance:
- not specified
- Type of assay:
- bacterial forward mutation assay
- Specific details on test material used for the study:
- L-cystine (0.1 M in 0.3 N HCl)
- Target gene:
- Lac
- Species / strain / cell type:
- E. coli, other: uvrB and uvrB umuC
- Details on mammalian cell type (if applicable):
- CELLS USED
- Source of cells: not reported
MEDIA USED
- Type and identity of media including CO2 concentration if applicable:
- all plates except for rifampicin plates: SMM1, PB, Glu-0, Glu-600, YENB plates, R-top and R-plates
- rifampicin plates: YENB plates containing rifampicin (Sigma) at 100 ug/mL and 1% (v/v) DMSO and M-top agar 0.8% NaCl and 1.8% Bacto agar (Difco).
- Properly maintained: not specified
- Periodically checked for Mycoplasma contamination: not specified
- Periodically checked for karyotype stability: not specified
- Periodically 'cleansed' against high spontaneous background: not specified - Test concentrations with justification for top dose:
- 2 mM
- Vehicle / solvent:
- - Vehicle(s)/solvent used: none described
- Untreated negative controls:
- yes
- Remarks:
- Glu-0 and Glu-600
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in agar (plate incorporation)
- Cell density at seeding (if applicable): 0.1 mL of 1.5 x 10E8 CFU/mL
DURATION
- Preincubation period: none
- Exposure duration: 3 days at 37°C
- Expression time (cells in growth medium): none
- Fixation time (start of exposure up to fixation or harvest of cells): 3 days at 37°C
SELECTION AGENT (mutation assays): glucose
- OTHER: - Evaluation criteria:
- To determine the relative mutagenesis, the mean number of pre-existing mutants on 5 Glu-0 plates was subtracted from the mean number of plate mutants on 10 Glu-600 plates and from the mean number of plate plus induced mutants on 5 Glu-600 plates containing the test compound. The ratio test:control was determined.
- Statistics:
- None reported
- Key result
- Species / strain:
- E. coli, other: uvrB
- 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:
- valid
- Key result
- Species / strain:
- E. coli, other: uvrB umuC
- Metabolic activation:
- not specified
- Genotoxicity:
- not specified
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- not specified
- Positive controls validity:
- valid
- Remarks on result:
- other: not mutagenic under the test conditions
- Conclusions:
- Cystine was tested for its ability to revert lacZ53 cells to Lac+. It did not have a significant effect on Lac reversion in a uvrB mumC E.coli strain but it did have a significant anti-mutagenic effect on the isogenic uvrB strain.
- Executive summary:
In a study published in 1986, cystine was tested for its ability to revert lacZ53 cells to Lac+. It did not have a significant effect on Lac reversion in a uvrB mumC E.coli strain but it did have a significant anti-mutagenic effect on the isogenic uvrB strain.
- 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:
- REPORTING FORMAT FOR THE ANALOGUE APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The structurally similar read across candidates for Disodium L-cystinate are: Cystine (EC# 200-296-3 / CAS# 56-89-3) and L- Cysteine (EC # 200-158-2/CAS# 52-90-4) which contain the same constituents as the target substance and as such, provide excellent structural surrogates for read-across purposes.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See attached read-across justification document.
3. ANALOGUE APPROACH JUSTIFICATION
The physical-chemical properties are very similar between the Target and Source substances (i.e., melting point, density, particle size, partition coefficient). In addition, the source substance is more soluble than the target substance, making the source (read across) substance a conservative read across substance in terms of increased bioavailability. Based on the chemical structure and the available supporting data for the Source (read across) substances, the Target substance is expected to rapidly biodegrade in the environment. The Source (read across) substances are more soluble than the target substance, making the source substance a conservative read across substance in terms of increased bioavailability. Upon ingestion, the target Disodium L-cystinate is metabolized to form the source Cystine. Therefore the Cystine values are predictive of the acute and repeat dose oral toxicity endpoints. The source (read across) substance is more soluble than the target substance, making the source substance a conservative read across substance in terms of increased bioavailability.
4. DATA MATRIX
See attached read-across justification document. - Reason / purpose for cross-reference:
- read-across source
- Key result
- Species / strain:
- E. coli, other: uvrB
- 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:
- valid
- Key result
- Species / strain:
- E. coli, other: uvrB umuC
- Metabolic activation:
- not specified
- Genotoxicity:
- not specified
- Cytotoxicity / choice of top concentrations:
- not specified
- Vehicle controls validity:
- not specified
- Untreated negative controls validity:
- not specified
- Positive controls validity:
- valid
- Remarks on result:
- other: not mutagenic under the test conditions
Referenceopen allclose all
Relative Lac+ mutagenesis in the presence of Cystine at 2 mM, by E. coli strain
| uvrB | uvrB umuC |
| 0.34* | 0.88 |
*Value indicates significant effects on mutagenesis by either the mean mutant frequency ±1 SD (range) for the cystine-supplemented plates did not overlap the range for the control plates, and the mean relative (test/control) range for the uvrB strain did not overlap the mean relative range for the uvrB umuC strain.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (positive)
Additional information
Justification for classification or non-classification
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
