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

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study was conducted on structural analog and suitable for read across. 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:

During preparation of the original submission, reporting of an existing Buehler-type skin sensitisation test was considered more appropriate than sacrifice of further vertebrate animals in the Local Lymph Node Assay.

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

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.

Any other information on results incl. tables

Read-Across Justification for EC 270-478-5

EC 270-478-5 has not been tested for skin sensitization, however experimental data from a study with the structurally related substance EC 283-382-8 was available and suitable for read-across.

Consistent with ECHA and OECD Guidance, read-across can be performed to fill data gaps for a substance when one or more analogues have similarity from multiple lines of evidence including structural, physical-chemical, mechanistic, toxicological and/or ecotoxicological bases (REFERENCES: 1. ECHA Chapter R.7a: Endpoint specific guidance. Guidance on Information Requirements and Chemical Safety Assessment, http://wko.at/up/enet/chemie/TL_ChapterR7a.pdf; 2. ECHA Practical Guide 6: How to Report Read-Across and Categories, http://echa.europa.eu/doc/publications/practical_guides/pg_report_readacross_categ.pdf; 3. OECD 2007. Guidance on grouping of chemicals. ENV/JM/MONO(2007)28).

The registered substance ZDDP EC 270-478-5, phosphorodithioic acid, mixed O,O-bis(2-ethylhexyl and iso-Bu) esters, zinc salts, is a member of the group of inter-related ZDDP substances of similar structure and chemical properties that have previously been assessed as a category under the HPV program. For the purposes of read-across to fill data gaps for this substance the analogue ZDDP EC 283-382-8, phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts, is justified for use based on its similar structure, physical chemical properties, and fate and effects profile. For some endpoints where multiple reliable analogs exist, “worst case” data is selected based on the most precautionary test result, or based on reading across from lower molecular weight to higher or from higher water solubility to lower.

The following discussion provides multiple lines of evidence justifying this read across approach:

I. Category: EC 270-478-5 substance and EC 283-382-8 analog have been demonstrated to show sufficient structural and physicochemical similarity to be included in the High Production Volume (HPV) Chemical Challenge Program under the Zinc Dialkyldithiophosphate (ZDDP) category.

II. Manufacture/Usage:  EC 270-478-5 substance and EC 283-382-8 analog are substances that are generically referred to as zinc dialkylthiophosphate (ZDDP) that are produced under similar manufacturing procedures and are intended for multifunctional use as oil additives for antioxidancy and antiwear.

III. Chemical Similarity:EC 270-478-5 substance and EC 283-382-8 analog have the general empirical formula of C#H#O4P2S4Zn and are coordination complexes of zinc metal bonded to alkyldithiophosphate ligands. ZDDP complexes exist in reversible monomeric or dimeric forms (equilibrium dependent on temperature) and a basic form. The stereochemistry of the basic form can be described as four Zn atoms arranged around a tetrahedral oxide with six alkyldithiophosphate ligands. As a group, these ZDDPs share similar alcohol ester of dithiophosphate core structures, and variations that relate to alkyl chain length and the degree of branching of the alcohol. Using Tanimoto Fingerprint (ToxMatch Version 1.06 software) to model the chemical structures of the substances and its analog showed comparable values for relevant molecular descriptors (e.g., number of H bond acceptor atoms), and gave 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 and read-across is supported.

IV. Physicochemical Properties:EC 270-478-5 substance and EC 283-382-8 analog have similar values for average molecular weight (based on the monomer structure), log Kow, water solubility, and vapor pressure; or in some instances for read-across purposes “worst case” values are selected by going from a lower to a higher molecular weight, or from a higher to a lower water solubility.

V. Biologically Active Functional Groups: The ester group is a common functional group present in each of the analogue members, and is expected to exhibit similar biological activities with little influence from the length of carbon chain. Any potential breakdown products, via physical or biological processes, are also expected to result in structurally similar chemicals. In addition, non-random patterns have been observed for the toxicological effects (e.g., available data showed low levels of acute toxicity, lack of mutagenic potential, and a trend of change in ecotoxicity potential based on molecular weight). These common behaviors and consistent trends suggest a common mechanism and mode of action thereby providing further supporting evidence for the read-across among the ZDDP members.

 

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.