Phosphorodithioic acid, mixed O,O-bis(2-ethylhexyl and iso-Bu and pentyl) esters, zinc salts

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Background irritation present

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1997

Report date:

1997

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

GLP compliance:

yes

Type of study:

Buehler test

Justification for non-LLNA method:

A klimisch score 2 Buehler study already exists on teh test substance. Therefore, it was considered scientifically unjustified to re-run the same study according to the LLNA method.

Test material

Test material information

Constituent 1

Reference substance name:

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

EC Number:

283-392-8

EC Name:

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

Cas Number:

84605-29-8

Molecular formula:

Not applicable

IUPAC Name:

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

In vivo test system

Test animals

Species:

guinea pig

Strain:

Hartley

Sex:

male/female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague Dawley, Inc
- Age at study initiation: 6-11 weeks
- Weight at study initiation: 440-493 grams
- Housing: Housed individually in wire mesh suspension cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.8-26.1
- Humidity (%): 30-70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hours

IN-LIFE DATES: From: To:

Study design: in vivo (non-LLNA)

Induction

Induction 1

Route:

epicutaneous, occlusive

Vehicle:

other: mineral oil

Induction 2

Concentration / amount:

Induction: 5% w/v
Challenge: 1% w/v

Challenge

Challenge 1

Route:

epicutaneous, occlusive

Vehicle:

other: mineral oil

Challenge 2

Concentration / amount:

Induction: 5% w/v
Challenge: 1% w/v

No. of animals per dose:

20 treated with test material, 10 naive control

Details on study design:

RANGE FINDING TESTS:
Priary Irritation after 6 hour patch aplication of test material in mineral oil at following concentrations:

Undiluted, 50, 25, 10, 5, 2.5, 1, 0.5 % w/v

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3
- Exposure period: 6 hours
- Test groups:
- Control group:
- Site: Left shoulder
- Frequency of applications: 6 to 7 days
- Duration:
- Concentrations: 5%


B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 1 and 2 days (24 and 48 hours)
- Exposure period: 6 hours
- Test groups:
- Control group: 10 naive not previously exposed to test material
- Site:
- Concentrations: 1%
- Evaluation (hr after challenge): 24 and 48 hours


OTHER:

Challenge controls:

10 naive not previously exposed to test material

Positive control substance(s):

yes

Remarks:

1-Chloro-2,4,-Dinitrobenzene

Results and discussion

Positive control results:

Postive for skin sensitization

In vivo (non-LLNA)

Results

Results 1

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

1%

No. with + reactions:

3

Total no. in group:

20

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 1%. No with. + reactions: 3.0. Total no. in groups: 20.0.

Results 2

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

1%

No. with + reactions:

0

Total no. in group:

20

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 1%. No with. + reactions: 0.0. Total no. in groups: 20.0.

Results 3

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

1%

No. with + reactions:

1

Total no. in group:

10

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 1%. No with. + reactions: 1.0. Total no. in groups: 10.0.

Results 4

Reading:

2nd reading

Hours after challenge:

48

Group:

negative control

Dose level:

1%

No. with + reactions:

0

Total no. in group:

10

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 1%. No with. + reactions: 0.0. Total no. in groups: 10.0.

Results 5

Group:

positive control

Remarks on result:

not measured/tested

Any other information on results incl. tables

Justification for Read Across from Analogue EC 283-392-8

Common Manufacturing Process:The submission substance (EC 273-527-9) and the analogue (EC 283-392-8) are produced under a common manufacturing process in which a phosphorodithioic acid ester intermediate, (RO)₂PS₂H, is produced by the reaction of phosphorus pentasulfide with an alcohol or a mixture of two alcohols of a similar class - branched alcohol containing C8, C5 and C4 carbons (submission substance) and C3 and C6 carbons (analogue). The intermediate is neutralized with zinc oxide to produce the final multicomponent substance. The reaction is performed in the presence of a highly refined base oil which accounts for 8 – 10.3 % of the final products.

Impurities:The level of impurities in the submission substance and the analogue (data source) is minimal. Impurities have been identified as residual, unreacted alcohols from the production of the phosphorodithioic acid ester intermediates (isobutanol, pentanol and 2-ethylhexanol in the submission substance and isopropyl and 1,3-dimethylbutyl alcohols in the analogue).

Same Chemical Category:The submission substance (EC 273-527-9) and the analogue (EC 283-392-8), generically referred to as ZDDPs, have been shown to have sufficient structural similarities to be included in the Zinc Dialkydithiophosphate Category (ZDDPs) in the United States Environmental Protection Agency High Production Volume (HPV) Chemical Challenge Program.

Structural Similarity:The primary feature accounting for the similarity of the submission substance (EC 273-527-9) and the analogue (EC 283-392-8) is the common organometallic core structure consisting of a central zinc metal bonded to four alkyldithiophosphate esters (ligands) by coordinate covalent bonds -Zn[(S₂P(OR)₂]_2.Structural variations between the submission substance and the analogue are related to the alkyl (R) groups of the alkyldithiophosphate ligands.

The analogue/data source (EC 283-392-8) is a multicomponent mixture of ZDDP monomers and dimers containing isopropyl dithiophosphate ligands, 1,3-dimethylbutyl dithiophosphate ligands and mixtures of isopropyl and 1,3-dimethylbutyl dithiophosphate ligands with a molecular weight range of 492 – 660 (monomer).

The submission substance (EC 273-527-9) is a multicomponent mixture of ZDDP monomers and dimers containing isobutyl dithiophosphate ligands, pentyl dithiophosphate ligands, 2-ethylhexyl dithiophosphates ligands and mixtures of isobutyl, pentyl and 2-ethylhexyl dithiophosphate ligands with a molecular weight range of 548 – 772 (monomer).

Tanimoto Fingerprint (ToxMatch Version 1.06 software) gives a similarity index greater than 0.8 (values range from 0, no similarity to 1, identical). Peer reviewed literature indicates that values greater than 0.6 are significantly similar.DSSTox similarity was 80% between the submission substance and the analogue.

Applicant's summary and conclusion

Interpretation of results:

not sensitising

Remarks:

Migrated information

Conclusions:

The irritation in 3/20 animals in the challenge phase scored after 24 hours did not persist to 48 hours, indicating an irritation response rather than a skin sensitization response.