Zinc isodecyl phosphorodithioate

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

For genetic toxicity endpoints, results are read across from the analogous ZDDP substances, CAS 4259 -15 -8, along with supporting information for zinc compounds and calcium dialkyldithiophosphate.

The weight of evidence suggests that the test substance is not expected to present a significant risk for mutagenicity or carcinogenicity in humans, therefore classification is not required in accordance with Directive 67/548/EEC and EU CLP (Regulation (EC) No. 1272/2008).

Link to relevant study records

Reference

Reference 1

Endpoint:

in vitro gene mutation study in bacteria

Remarks:

Type of genotoxicity: gene mutation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

GLP compliance:

yes

Type of assay:

bacterial reverse mutation assay

Target gene:

Histidine operon (hisG46, hisC3076, hisD3052); Lipopolysaccharide barrier (LPA); DNA excision repar (uvrB)

Species / strain / cell type:

S. typhimurium TA 1535, TA 1537, TA 98 and TA 100

Metabolic activation:

with and without

Metabolic activation system:

mammalian microsomal enzymes

Test concentrations with justification for top dose:

with s9 mix; 25, 50, 100, 250, 1000, and 5000 ug/plate
without s9 mix: 1, 5, 10, 25, 100, 500 ug/plate
Confirmatory assay:
with s9 mix; 50, 100, 250, 500, 1000, and 5000 ug/plate
without s9 mix: 5, 10, 25, 50, 100, 500 ug/plate

Vehicle / solvent:

- Vehicle(s)/solvent(s) used: ethanol
- Justification for choice of solvent/vehicle:

Negative solvent / vehicle controls:

yes

Positive controls:

yes

Positive control substance:

other: multiple postive controls (depending on strain and metabolic activation)

Details on test system and experimental conditions:

METHOD OF APPLICATION: in agar (plate incorporation)


DURATION
- Preincubation period:
- Exposure duration: 48 hours
- Expression time (cells in growth medium):
- Selection time (if incubation with a selection agent):
- Fixation time (start of exposure up to fixation or harvest of cells):


SELECTION AGENT (mutation assays):
SPINDLE INHIBITOR (cytogenetic assays):
STAIN (for cytogenetic assays):


NUMBER OF REPLICATIONS:


NUMBER OF CELLS EVALUATED:


DETERMINATION OF CYTOTOXICITY
- Method: growth inhibition


OTHER EXAMINATIONS:
- Determination of polyploidy:
- Determination of endoreplication:
- Other:


OTHER:

Evaluation criteria:

TA98, TA100, WP2uvrA: A postive result must produce at least a 2-fold increase the mean revertants per plate of at least one tester strain over the mean revertants per plate fo the control. A dose response in the mean number of revertants per plate must also occur.
TA1535 and TA1537: A postive result must produce at least a 3-fold increase the mean revertants per plate of at least one tester strain over the mean revertants per plate fo the control. A dose response in the mean number of revertants per plate must also occur.

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

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 activation
negative without metabolic activation

Reference 2

Endpoint:

in vitro gene mutation study in bacteria

Remarks:

Type of genotoxicity: gene mutation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH

A read-across analogue approach can be performed for this endpoint because the source substance (CAS 4259-15-8) is structurally similar to the target substance. Both substances consist of substituted phosphorodithioic acid structures complexed with zinc, with differing alkyl chain lengths. Based on the similarity of structure, both substances are expected to have similar toxicity, or lack of toxicity, in mammalian systems.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Source substance: Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS: 4259-15-8)
Target substance: Zinc, bis(O,O-diisodecyl phosphorodithioato.kappa.s,.kappa.s’) (CAS: 25103-54-2)
For full information on purity and impurities please see the attached read-across justification report.

3. ANALOGUE APPROACH JUSTIFICATION

Source and target substances are structurally similar, differing only due to the length of the alkyl chains and degree of branching. Physico-chemical properties of the source and target substances follow a predictable pattern based on molecular size. Based on the similarity of structure, both substances are expected to have similar toxicity, or lack of toxicity, in mammalian systems. For a full justification of the read across approach please see attached read across justification report.

4. DATA MATRIX

See attached read across justification.
 

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

GLP compliance:

yes

Type of assay:

bacterial reverse mutation assay

Target gene:

Histidine operon (hisG46, hisC3076, hisD3052); Lipopolysaccharide barrier (LPA); DNA excision repar (uvrB)

Species / strain / cell type:

S. typhimurium TA 1535, TA 1537, TA 98 and TA 100

Metabolic activation:

with and without

Metabolic activation system:

mammalian microsomal enzymes

Test concentrations with justification for top dose:

with s9 mix; 25, 50, 100, 250, 1000, and 5000 ug/plate
without s9 mix: 1, 5, 10, 25, 100, 500 ug/plate
Confirmatory assay:
with s9 mix; 50, 100, 250, 500, 1000, and 5000 ug/plate
without s9 mix: 5, 10, 25, 50, 100, 500 ug/plate

Vehicle / solvent:

- Vehicle(s)/solvent(s) used: ethanol
- Justification for choice of solvent/vehicle:

Negative solvent / vehicle controls:

yes

Positive controls:

yes

Positive control substance:

other: multiple postive controls (depending on strain and metabolic activation)

Details on test system and experimental conditions:

METHOD OF APPLICATION: in agar (plate incorporation)


DURATION
- Preincubation period:
- Exposure duration: 48 hours
- Expression time (cells in growth medium):
- Selection time (if incubation with a selection agent):
- Fixation time (start of exposure up to fixation or harvest of cells):


SELECTION AGENT (mutation assays):
SPINDLE INHIBITOR (cytogenetic assays):
STAIN (for cytogenetic assays):


NUMBER OF REPLICATIONS:


NUMBER OF CELLS EVALUATED:


DETERMINATION OF CYTOTOXICITY
- Method: growth inhibition


OTHER EXAMINATIONS:
- Determination of polyploidy:
- Determination of endoreplication:
- Other:


OTHER:

Evaluation criteria:

TA98, TA100, WP2uvrA: A postive result must produce at least a 2-fold increase the mean revertants per plate of at least one tester strain over the mean revertants per plate fo the control. A dose response in the mean number of revertants per plate must also occur.
TA1535 and TA1537: A postive result must produce at least a 3-fold increase the mean revertants per plate of at least one tester strain over the mean revertants per plate fo the control. A dose response in the mean number of revertants per plate must also occur.

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

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 activation
negative without metabolic activation

Genetic toxicity in vivo

Link to relevant study records

Reference

Reference 1

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:

1997

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)

GLP compliance:

yes

Type of assay:

micronucleus assay

Species:

mouse

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
- Age at study initiation: 8 weeks and 2 days
- Weight at study initiation: 29.8-37.8 g (male) and 23.3-28.8 g (female)
- Assigned to test groups randomly: yes
- Fasting period before study:
- Housing: five per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 55 +/- 15
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hours


IN-LIFE DATES: From: To:

Route of administration:

intraperitoneal

Vehicle:

- Vehicle(s)/solvent(s) used: Peanut oil
- Justification for choice of solvent/vehicle:
- Concentration of test material in vehicle:
- Amount of vehicle (if gavage or dermal): 10 mL
- Type and concentration of dispersant aid (if powder):
- Lot/batch no. (if required):
- Purity:

Duration of treatment / exposure:

24, 48, and 72 hours

Frequency of treatment:

Once

Remarks:

Doses / Concentrations:
6 mg/kg
Basis:

Remarks:

Doses / Concentrations:
12 mg/kg
Basis:

Remarks:

Doses / Concentrations:
24 mg/kg
Basis:

No. of animals per sex per dose:

5 males and 5 females per dose

Control animals:

yes, concurrent vehicle

Positive control(s):

cyclophosphamide
- Route of administration: sterile water
- Doses / concentrations: 60 mg/kg

Details of tissue and slide preparation:

CRITERIA FOR DOSE SELECTION:
Range finding study performed to find the maximum tolerated dose

TREATMENT AND SAMPLING TIMES ( in addition to information in specific fields):


DETAILS OF SLIDE PREPARATION:
Slides fixed with methanol and stained in May-Grunwald solution followed by Giemsa.

METHOD OF ANALYSIS:
Scored for micronuclei and the polychromatic erythrocyte (PCE) to normochromatic erythrocyte (NCE) cell ration.

OTHER:

Evaluation criteria:

Statistically sifnificant dose-related increase in micronucleated PCE's and the detection of a statictically sifnificant postive response for at least one dose level.

Statistics:

The frequency of micronucleated polychromatic erythrocytes between treated groups and vehicle controls were compared. Tests included Cochran-Armitage test for trend, a one-way analysis of variance and Dunnett’s procedure.

Sex:

male/female

Genotoxicity:

negative

Toxicity:

yes

Vehicle controls validity:

valid

Positive controls validity:

valid

Conclusions:

Interpretation of results (migrated information): negative

Reference 2

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH

A read-across analogue approach can be performed for this endpoint because the source substance (CAS 4259-15-8) is structurally similar to the target substance. Both substances consist of substituted phosphorodithioic acid structures complexed with zinc, with differing alkyl chain lengths. Based on the similarity of structure, both substances are expected to have similar toxicity, or lack of toxicity, in mammalian systems.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Source substance: Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS: 4259-15-8)
Target substance: Zinc, bis(O,O-diisodecyl phosphorodithioato.kappa.s,.kappa.s’) (CAS: 25103-54-2)
For full information on purity and impurities please see the attached read-across justification report.

3. ANALOGUE APPROACH JUSTIFICATION

Source and target substances are structurally similar, differing only due to the length of the alkyl chains and degree of branching. Physico-chemical properties of the source and target substances follow a predictable pattern based on molecular size. Based on the similarity of structure, both substances are expected to have similar toxicity, or lack of toxicity, in mammalian systems. For a full justification of the read across approach please see attached read across justification report.

4. DATA MATRIX

See attached read across justification.
 

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)

GLP compliance:

yes

Type of assay:

micronucleus assay

Species:

mouse

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
- Age at study initiation: 8 weeks and 2 days
- Weight at study initiation: 29.8-37.8 g (male) and 23.3-28.8 g (female)
- Assigned to test groups randomly: yes
- Fasting period before study:
- Housing: five per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 55 +/- 15
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hours


IN-LIFE DATES: From: To:

Route of administration:

intraperitoneal

Vehicle:

- Vehicle(s)/solvent(s) used: Peanut oil
- Justification for choice of solvent/vehicle:
- Concentration of test material in vehicle:
- Amount of vehicle (if gavage or dermal): 10 mL
- Type and concentration of dispersant aid (if powder):
- Lot/batch no. (if required):
- Purity:

Duration of treatment / exposure:

24, 48, and 72 hours

Frequency of treatment:

Once

Remarks:

Doses / Concentrations:
6 mg/kg
Basis:

Remarks:

Doses / Concentrations:
12 mg/kg
Basis:

Remarks:

Doses / Concentrations:
24 mg/kg
Basis:

No. of animals per sex per dose:

5 males and 5 females per dose

Control animals:

yes, concurrent vehicle

Positive control(s):

cyclophosphamide
- Route of administration: sterile water
- Doses / concentrations: 60 mg/kg

Details of tissue and slide preparation:

CRITERIA FOR DOSE SELECTION:
Range finding study performed to find the maximum tolerated dose

TREATMENT AND SAMPLING TIMES ( in addition to information in specific fields):


DETAILS OF SLIDE PREPARATION:
Slides fixed with methanol and stained in May-Grunwald solution followed by Giemsa.

METHOD OF ANALYSIS:
Scored for micronuclei and the polychromatic erythrocyte (PCE) to normochromatic erythrocyte (NCE) cell ration.

OTHER:

Evaluation criteria:

Statistically sifnificant dose-related increase in micronucleated PCE's and the detection of a statictically sifnificant postive response for at least one dose level.

Statistics:

The frequency of micronucleated polychromatic erythrocytes between treated groups and vehicle controls were compared. Tests included Cochran-Armitage test for trend, a one-way analysis of variance and Dunnett’s procedure.

Sex:

male/female

Genotoxicity:

negative

Toxicity:

yes

Vehicle controls validity:

valid

Positive controls validity:

valid

Conclusions:

Interpretation of results (migrated information): negative

Additional information

For genetic toxicity endpoints, results are read across from the analogous ZDDP substance, CAS 4259 -15 -8, along with supporting information for zinc compounds and calcium dialkyldithiophosphate. For full details of the read across approach, please see the attached read across justification. The results of the relevant studies are summarised below.

Test material CAS# 4259-15-8, Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate), which used for read across to Zinc, bis(O,O-diisodecyl phosphorodithioato.kappa.s,.kappa.s’) (CAS 25103-54-2) is generically referred to as zinc dialkylthiophosphate (ZDDP). It is used in commerce as multi-functional anti-wear and anti-oxidation inhibitor performance components in passenger motor oils, diesel engine oils and industrial oils such as hydraulic lubricants.

The present dossier includes several testing approaches in attempt to measure the genotoxic potential of the test material: a) the ability to induce mutations in bacterial () or in mammalian cells (tk^+/-mouse lymphoma assay); b) chromosome aberration (in vivomouse micronucleus assay), c) cell transformation test using BALB/3T3 cell line. These studies are reliable without restriction (Klimisch code 1).

Negative results were obtained in the assay and the in vivo mouse micronucleus assays. However, equivocal results in the tk^+/-mouse lymphoma assay and positive results in BALB/3T3 transformation test were observed after rat liver S9 microsomal enzyme treatment. All the assays were thoroughly reviewed and assessed in accordance to REACH and OECD guidance. The following sections cover a spectrum of evidence/justifications, and the weight of evidence suggests that the test material is NOT genotoxic.

Study Results on Genotoxicity Tests

Mutagenicity Assay – (key study, present in section 7.6.1)

In vitro bacteria gene mutation assay () has been conducted on this material, and the frequencies of reverse mutations in bacteria were not significantly changed after exposure to various concentrations of the test material, with/without S9 mixture (Table 1).

Table 1:Assay Result

CAS#	Result
4259-15-8	Negative

 

 Mutagenicity Assay- in Mammalian Cells (key study, present in section 7.6.1)

In vitro mammalian gene mutation potential at thymidine kinase (TK) locus was measured using L5178Y mouse lymphoma cell line after treated with various concentrations of the test material. A test substance was judged positive if there is a positive dose response and one or more of the three highest doses exhibit a mutant frequency which is two fold greater than the background level.

As shown in Table 2, in the absence of metabolic activation, the test material did not display mutagenic activity; in the presence of S9 microsomal enzyme, 3 independent tests were conducted on two samples of the test material: (study i) study disqualified due to contamination; (study ii) cultures treated with a series of concentrations produced total growth range from 3 to 44%, and 7/7 of the cultures exhibited positive response; (study iii) cultures treated with a series of concentrations produced total growth range from 27 to 96%, and 0/7 of the cultures exhibited mutant frequencies which were significantly greater than the mean frequency of the solvent controls. However, a dose-dependent response was noted. The test material was eventually determined to be equivocal for mutagenicity , however, this finding was confounded by lack of reproducibility between repeat experiments, and the observed mutagenic activity concurrent with the presence of extensive cytotoxic damage at high doses. 

Study has shown that stressed/injured/necrotic cells release various molecules that can trigger biological responses in the remaining viable cells via indirect effect(s) after treatment with test substances (Mezayen,et al,2007). It is therefore postulated that the positive responses occurred at high ZDDP doses were partially due to cytotoxic concentrations, not direct effect(s) of metabolic transformation of test substance on mammalian DNA, or apparent genotoxicity was at least partially due to extragenomic damage(s). To support this hypothesis, the following substances were tested under the same experimental conditions: a)zinc chloride, b)zinc oleate (technical difficulties with test solution preparation encountered and data not shown) ,c)calcium analog of a ZDDP (had previously shown positive activity in these in vitro mammalian cell assays). And the following results were obtained: a)zinc chloride showed high degree of cytotoxicity (the total growth ranged from 2% to 61%) and positive for mutagenicity. The results were consistent with previous studies which demonstrated zinc ion caused cytotoxicity and mutagenicity in similarly cultured mammalian cell systems (Amakeret al., 1979); b)calcium dialkyl dithiophosphate did not exhibit mutagenicity, and relative higher cell viability was obtained (the total growth ranged from 17% to 74%). Taken together, the data suggest the dialkyldithiophosphate portion of the ZDDP molecule is non-mutagenic, the zinc subcomponent may have been the causative agent under the test conditions. Since zinc is not classified as carcinogen, the weight of evidence suggests that the test material is unlikely to be a mutagen.  

 

Table 2: tk^+/-Mouse Lymphoma Assay Results

 

CAS#	Tk^+/-Mouse Lymphoma Assay
	W/O S9	W/S9
4259-15-8	Test sample 1 Negative	Test sample 1 Equivocal
	─	Test sample 1 Positive Found contamination and erratic dose-response relationship in toxicity
	─	Test sample 1 Positive The treated group showed significantly greater mean mutant frequency than the level of the solvent controls.
	─	Test sample 2 Equivocal The treated group did NOT show significant increase in mean mutant frequency comparing to the level of the solvent controls, but a dose response was observed.
Calcium Dialkyl dithiophosphate	Not tested	Negative
ZnCl2	Not tested	Positive

 

BALB/3T3 Transformation Test (Supporting study, present in section 7.6.1)

In vitro BALB/3T3 transformation test protocol (1982) was designed to assess the ability of chemicals to induce changes in the morphological and growth properties of cultured mammalian cells. The observed changes were presumed to be similar to phenotypic changes that accompany the development of neoplastic or pre-neoplastic lesions in vivo. The test procedures were different from the two-stage protocols described in the OECD Series on Testing and Assessment No. 31 (2007). Considering this is not a required endpoint for REACH registration, the BALB/3T3 transformation test was regarded as supporting study in this dossier for the sake of completion.

As shown in Table 3, the test substance demonstrated transformation activity with S-9 activation, and statistically significant increases in transformation frequencies occurred only at the highest tested dose which associated with noticeable cytotoxicity. Similar to the strategy used in the tk^+/-Mouse Lymphoma Assay, calcium dialkyldithiophosphate and ZnCl₂were tested for transformation activity, negative and positive results were observed, respectively.

BALB/3T3 transformation test is sensitive to epigenetic changes, and widely used for mechanistic studies on such as cell proliferation, altered intercellular gap junction communication, ability to inhibit or induce apoptosis,etc., which are induced by spontaneous changes or exogenous factors (false positive for genetic outcome). As complementary to the tk^+/-Mouse Lymphoma Assay (genetic events), the transformation studies on this ZDDP substance demonstrated the zinc subcomponent, not the dialkyldithiophosphate portion, may have been the causative agent for epigenetic events which ultimately led to cell transformation.

Table 3:BALB/3T3 Transformation Test Results

CAS#	W/O S9	W/S9
4259-15-8	Negative	Positive
Calcium Dialkyl dithiophosphate	Not tested	Negative
ZnCl2	Not tested	Positive

   *: expressed as ratio between treated group vs. solvent control.

Mouse Micronucleus Test (in vivo) -(key study, present in section 7.6.2)

In the “Mammalian Erythrocyte Micronucleus Test”, no statistically significant increases in micronucleated polychromatic erythrocytes over the levels observed in the vehicle controls were observed in either sex, or at any harvest time point, or dose levels in mice (Table 4).

Table 4: Mouse Micronucleus Test (in vivo)

CAS#	Result
4259-15-8	Negative (doses:0, 6, 12 and 24 mg/kg)

  

Intrinsic Properties of the Test Substance by Using QSAR Tool

The test material was profiled with DNA binding and Benigni/Bossa rulebase grouping methods by using OECD toolbox 1.1.01. QSAR analyses showed negative predictions on DNA binding potentials for parental and 45 possible metabolites, and supported the conclusion that the test material is non-genotoxic.

Other Relevant Evidence:

A 28-day repeated dose study via oral gavage, and a reproduction/development toxicity screening test are available for this substance. In these studies, the test substance was unable to induce hyperplasia and/or pre-neoplastic lesions.

Published carcinogenicity studies using fresh motor oil, commonly containing 1%~3% ZDDP, in rodent species yield limited number or no tumors in treated animals (Kaneet al,. 1984; McKee and Pryzygoda, 1987; Saffiotti and Shubik, 1963; McKee and Plutnick, 1989; Schreiner and Mackerer, 1982). Evidence supports premise that ZDDP materials lack carcinogenic potential.

CONCLUSION

It is concluded that the test substance is not expected to present a significant risk for mutagenicity or carcinogenicity in humans.

Reference:

Amacher et al. Mammalian Cell Mutagenesis: Maturation of Test Systems. Banbury Report 2, 277-293, 1977

Kane, M., LaDov, E., Holdworth, C., and Weaver, N. (1984). Toxicological characteristics of refinery streams used to manufacture lubricating oils.Amer. J. Ind. Med.5:183-200.  

Mezayen, R.EI., Gazzar, M.EI., Seeds, M.C., McCall, C.E.,,, and Nicolls, M.R. Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin. (2007)Immunology Letters.111:36-64.

McKee, R.H., and Przygoda, R. (1987). The genotoxic and carcinogenic potential of engine oils and highly refined lubricating oil.Environ. mutagen.9(suppl. 8), 72 Abstract.

McKee, R.H., and Plutnick, R.T. (1989). Carcinogenic potential of gasoline and diesel engine oils.Fundamental and Applied Toxicology.13:545-553.

Renznikoff, Bertram, J.S., Brankow, D.S. and Heidelberger, C. (1973). Quantitative and qualitative studies of chemical transformation of cloned C3H mouse embryo cells sensitive to post-confluence inhibition of cell division.Cancer Res.33:3239-3249.

Saffiotti, U., and Shubik, P. (1963). Studies on promoting action in skin carcinogenesis.Natl. Cancer Inst. Monogr.10, 489-507.

Schreiner,, and MacKerer, C.R., (1981). Mutagenic Testing Of Gasoline Engine Oils. Inpolynuclear Aromatic Hydrocarbons:Chemical and Biological Effects(M. Cooke, A.J. Dennis, and G.L. Fisher, Eds.), pp705-712. Battelle Press.

 

Short description of key information:
A summary of CAS# 4259 -15 -8/EC# 224 -235 -5 genotoxicity test results is used as read across for Zinc, bis(O,O-diisodecyl phosphorodithioato.kappa.s,.kappa.s’) (CAS 25103-54-2).

It is concluded that the test substance is not expected to present a significant risk for mutagenicity.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

The weight of evidence suggests that the test substance is not expected to present a significant risk for mutagenicity or carcinogenicity in humans, therefore classification is not required in accordance with Directive 67/548/EEC and EU CLP (Regulation (EC) No. 1272/2008). Theories of justification present in the above “Discussion” section.