Registration Dossier

Toxicological information

Genetic toxicity: in vivo

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Administrative data

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:
1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Reliable study restictions due to data obtained by read across to analog substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997
Report Date:
1996

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
GLP compliance:
yes
Type of assay:
micronucleus assay

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals 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:

Administration / exposure

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
Doses / concentrationsopen allclose all
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

Examinations

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.

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
yes
Vehicle controls validity:
valid
Positive controls validity:
valid

Any other information on results incl. tables

EC 234-277-6, zinc bis[bis(dodecylphenyl)]bis(dithiophosphatei, s generically referred to as zinc dialkylthiophosphate (ZDDP). In vitro genotoxicity study is not available for this substance. However, sufficient data are available for a group of substances, which are produced under similar manufacturing procedures and 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. They share great chemical similarity and have been considered as a category (HPV Test Plan).

CAS#

EC#

Substance Name

84605-29-8

283-392-8

Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts

4259-15-8

224-235-5

Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate)

 

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

Mouse Micronucleus Test (in vivo)

 

CAS#

Result

84605-29-8

Negative (Doses:0, 7.13, 14.3 and 28.5 mg/kg)

4259-15-8

Negative (doses:0, 6, 12 and 24 mg/kg)

 

  

Based on these results, the ZDDP material is unlikely to be cytogenic in the tested animals. For the sake of simplicity, the current technical dossier only presents the data on EC 224-235-5.

EC 234-377-6 is predicted to be non-cytogenic.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative