Disulfiram

Bioaccumulation: aquatic / sediment

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

bioaccumulation in aquatic species: fish

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
EPI Suite v4.11 Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11. US EPA, United States Environmental Protection Agency, Washington, DC, USA.

2. MODEL (incl. version number)
BCFBAF v3.02, regression-based method

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables"

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.

Principles of method if other than guideline:

- Software tool(s) used including version: EPI Suite v4.11
- Model(s) used: BCFBAF v3.02
Full reference and details of the used formulas can be found in:
1. Meylan, W.M., Howard, P.H, Aronson, D., Printup, H. and S. Gouchie.  1997.  "Improved Method for Estimating Bioconcentration Factor (BCF) from Octanol-Water Partition Coefficient", SRC TR-97-006 (2nd Update), July 22, 1997; prepared for: Robert S. Boethling, EPA-OPPT, Washington, DC; Contract No. 68-D5-0012; prepared by: ; Syracuse Research Corp., Environmental Science Center, 6225 Running Ridge Road, North Syracuse, NY 13212.
2. Meylan,WM, Howard,PH, Boethling,RS et al. 1999.  Improved Method for Estimating Bioconcentration / Bioaccumulation Factor from Octanol/Water Partition Coefficient.Environ. Toxicol. Chem. 18(4): 664-672 (1999).
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on Material and methods'
- Justification of QSAR prediction: see field 'Justific ation for type of information', 'Attached justification' and/or 'overall remarks'

GLP compliance:

no

Test organisms (species):

other: Fish

Route of exposure:

aqueous

Test type:

other: calculation

Water / sediment media type:

natural water: freshwater

Details on estimation of bioconcentration:

BASIS FOR CALCULATION OF BCF
- Estimation software: BCFBAF v3.02
- Result based on measured log Kow of: 3.6

Type:

BCF

Value:

110 L/kg

Basis:

whole body w.w.

Type:

other: Log BCF

Value:

2.04 dimensionless

Basis:

whole body w.w.

For detailed information on the results please refer to the attached report.

Reference 2

Endpoint:

bioaccumulation in aquatic species: fish

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
EPI Suite v4.11 Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11. US EPA, United States Environmental Protection Agency, Washington, DC, USA.

2. MODEL (incl. version number)
BCFBAF v3.02, Arnot-Gobas method

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached information on the model provided by the developer. Further information on the OECD criteria as outlined by the applicant is provided below under "Any other information of materials and methods incl. tables"

5. APPLICABILITY DOMAIN
See attached information and information as provided in "Any other information on results incl. tables".

6. ADEQUACY OF THE RESULT
See assessment of adequacy as outlined in the "Overall remarks, attachments" section.

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSARs R.6

Principles of method if other than guideline:

- Software tool(s) used including version: EPI Suite v4.11
- Model(s) used: BCFBAF v3.02
Full reference and details of the used formulas can be found in:
1. Arnot JA, Gobas FAPC. 2003. A generic QSAR for assessing the bioaccumulation potential of organic chemicals in aquatic food webs. QSAR and Combinatorial Science 22: 337-345.
- Model description: see field 'Justification for non-standard information', 'Attached justification' and 'any other information on material and methods'
- Justification of QSAR prediction: see field 'Justific ation for type of information', 'Attached justification' and/or 'overall remarks'

GLP compliance:

no

Vehicle:

no

Test organisms (species):

other: Fish

Route of exposure:

other: aqueous and dietary

Test type:

other: calculation

Water / sediment media type:

natural water: freshwater

Details on estimation of bioconcentration:

BASIS FOR CALCULATION OF BCF
- Estimation software: EPI Suite v4.11, BCFBAF v3.02
- Result based on measured log Pow of: 3.6

Type:

BCF

Value:

182.8 L/kg

Basis:

whole body w.w.

Remarks on result:

other: including biotransformation, upper trophic

Type:

other: log BCF

Value:

2.26 dimensionless

Basis:

whole body w.w.

Remarks on result:

other: including biotransformation, upper trophic

For detailed information on the results please refer to the attached report.

Reference 3

Endpoint:

bioaccumulation in aquatic species: fish

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication which meets basic scientific principles.

Principles of method if other than guideline:

A short-term static bioaccumulation test was conducted with disulfiram (tetraethylthiuram disulfide) using Rainbow trout (Salmo gairdneri) as test organism.

GLP compliance:

no

Radiolabelling:

yes

Vehicle:

yes

Test organisms (species):

Oncorhynchus mykiss (previous name: Salmo gairdneri)

Details on test organisms:

TEST ORGANISM
- Common name: Rainbow trout
- Source: Fijge Trout Farm at Vassen (The Netherlands)
- Weight at study initiation: 3.4 ± 0.4 g
- Feeding during test: during acclimatization and elimination, trout were fed with Trouvit pellets (Trouw & Co. N.V., The Netherlands)

Route of exposure:

aqueous

Test type:

static

Water / sediment media type:

natural water: freshwater

Total exposure / uptake duration:

96 h

Hardness:

50 mg/L as CaCO3

Test temperature:

10 ± 1

pH:

8.0 ± 0.1 °C

Dissolved oxygen:

No data, nevertheless, test solutions were aerated continuously

Details on test conditions:

TEST SYSTEM
- Test vessel: 25 L all-glass fish tanks
- Aeration: continuous
- Biomass loading rate: 4 g/L

OTHER TEST CONDITIONS
- Photoperiod: 12-h light/dark cycle

Nominal and measured concentrations:

Nominal concentration: Sub-lethal concentration

Details on estimation of bioconcentration:

- BCF for tissues and organs were calculated from the mean total 14C-concentrations in fish and water, respectively. The rate constants were estimated from a kinetic model for static bioaccumulation experiments, which also comprised biotransformation processes. The degradation process is assumed to be first order in the concentration of the parent compound in the organism. For compounds which metabolize slowly, k3 approximates 0. In that case, the steady-state bioconcentration factor equals k1/k2.

Type:

BCF

Value:

225 dimensionless

Basis:

whole body w.w.

Calculation basis:

other: Measured radioactivity levels fish/water

Details on results:

- The levels of radioactivity present in early juvenile trout exposed to disulfiram showed that no steady-state conditions were reached during the testing period, i.e. the total 14C-activity in water initially decreased and subsequently increased again, whereas the total radioactivity levels in fish showed a reversed pattern of behaviour. This hindered the calculation of a steady-state BCF value. The best fit to these experimental data was obtained by introducing three biotransformation-related constants:
k3 was 0.08 ± 0.02
k1 was 40.4 ± 58.8
k2 was 0.88 ± 1.6
The resulting BCF value of 225 indicate that the bioaccumulation potential of the substance is low.

Description of key information

The potential for bioaccumulation of disulfiram is expected to be low based on all available data.

Additional information

The experimental partition coefficient value of disulfiram (CAS No. 97-77-8), reported to be 3.6 suggests low potential of the substance to bioaccumulate.

 

Experimental data

One study evaluating the bioaccumulation potential of disulfiram (CAS No. 97-77-8) is available (van Leeuwen, 1986). In this test, the bioaccumulation of radio-labeled disulfiram was evaluated in Rainbow trout (Oncorhynchus mykiss) after an exposure of 96 hours, within a static water regime. The results of the study shows that no steady-state conditions were reached for fish exposed to the test substance, and therefore the BCF value in steady-state could not be determined. In order to determine the BCF value, three biotransformation constants were introduced in the equation, leading to an estimated BCF value of 225. According to Regulation (EC) No. 1907/2006, Annex XIII, 1.1.2, a substance only fulfills the bioaccumulation criterion (B) when BCF values are > 2000 L/kg. Since the BCF value obtained for disulfiram is well below the trigger value of 2000 L/kg, this substance is considered to have a low bioaccumulation potential.

 

QSAR data

Additional information on the bioaccumulation of disulfiram in fish species is available. Estimated bioconcentration (BCF) and bioaccumulation (BAF) factors were calculated using the regression and Arnot-Gobas methods (BCFBAF v3.02 program, Estimation Programs Interface Suite™ for Microsoft® Windows v 4.11., US EPA). The resulting BCF/BAF values are in the same order of magnitude than the one from the experimental study (110-182.8 L/kg), thus supporting the assumption of the expected low bioaccumulation potential of disulfiram.

Intrinsic properties and environmental fate

Regarding the relation between partition coefficient and bioaccumulation potential, the Guidance on information requirements and chemical safety assessment, Chapter R.11 (PBT Assessment; ECHA, 2017) states that substances with a log Kow ≤ 4.5 can be considered not to be bioaccumulative (B) or very bioaccumulative (vB). Furthermore, tetraethylthiuram disulfide does not meet either the bioaccumulation criteria set in the Guidance on the application of the CLP criteria (ECHA, 2017), since the available BCF values for the substance are well below 500 L/kg and the partition coefficient value is below 4.

Tetraethylthiuram disulfide is expected to be rapidly degraded in water/sediment systems considering its potential for hydrolysis (especially under neutral and alkaline conditions, with half-lives of 3.5 days and 6.9 hours, respectively; Norris, 1991) and photolysis in water (half-life < 10 hours; Norris, 1990, Knoch, 1994). According to the Guidance on information requirements and chemical safety assessment, Chapter R7.C (ECHA, 2017), the likelihood of bioaccumulation is greatly reduced for hydrolytically unstable substances, since the rate of hydrolysis is expected to be greater than that of the uptake of exposed organisms. In most cases, hydrolysis products are more hydrophilic than the parent substance, and as a consequence their bioaccumulation potential is expected to be even lower than for tetraethylthiuram disulfide. This is the case for the main metabolites (based on chemical structure) of tetraethylthiuram disulfide: diethyldithiocarbamate (DDTC) and carbon disulfide (CS2). Estimated log Kow values for these two substances are calculated with the KOWWIN v1.68 program (Estimation Programs Interface Suite™ for Microsoft® Windows v 4.10., US EPA). The resulting values of 1.67 and 1.94 for DDTC and CS2 (respectively) show that indeed the bioaccumulation potential of the metabolites is lower than that of the parent substance.

Metabolism

The available information on mammalian toxicokinetics (IUCLID section 7.1) also indicate that tetraethylthiuram disulfide (CAS No. 97-77-8) has a low bioaccumulation potential in mammals, since its main by-products, diethyldithiocarbamate (DDTC) and carbon disulfide (CS2) are rapidly and effectively excreted (in humans, after 3 days in the form of DDC and other minor metabolites in the case of DDTC, and through respiration in the case of CS2; Peachey, 1981).

Conclusion

In conclusion, all information above provides strong evidence supporting the statement that tetraethythiuram disulfide (CAS No. 97-77-8) has low potential for bioaccumulation in biota.

References

European Chemicals Agency (ECHA, 2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

European Chemicals Agency (ECHA, 2017). Guidance on information requirements and chemical safety assessment, Chapter R.11: PBT Assessment.

European Chemicals Agency (ECHA, 2017). Guidance on application of the CLP criteria.

Knoch, E. (1994). Determination of the direct phototransformation of 14C-Thiram in a buffered medium at pH 7. Unpublished study. Report No. 449600. Taminco BVBA.

Norris, K.J. (1991). Determination of the hydrolysis of 14C-Thiram. Unpublished study. Report No. 1156. Taminco BVBA.

Norris, K.J. (1990). Determination of the aqueous degradation of 14C-Thiram. Unpublished study. Report No. 1157. Taminco BVBA.

Peachey, J.E. et al. (1981). A comparative review of the pharmacological and toxicological properties of disulfiram and calcium carbimide. Journal of Clinical Psychopharmacoly, 1(1):21-6.

Van Leeuwen, C.J. (1986). Ecotoxicological aspects of dithiocarbamates: Chapter 9. Uptake, distribution and retention of zineb and ziram in rainbow trout (Salmo gairdneri). Report No. 44/1986. Rijkswaterstaat/University of Utrecht.