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

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1986/10/09-1986/10/20

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study was conducted on structural analogue and suitable for read across. Guideline GLP study.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Report date:

1986

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

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

EC Number:

247-810-2

EC Name:

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

Cas Number:

26566-95-0

Molecular formula:

C12H27O2PS2.1/2Zn

IUPAC Name:

zinc bis[O-(2-ethylhexyl) O-isobutyl dithiophosphate]

Details on test material:

Test material from lot no. EC-47906 is described as amber viscous liquid with pH 5.38

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

3 male and 3 female rabbits supplied by Sgarlat's Rabbitry were acclimated to the laboratory for 5 days prior to study initiation. Apparently healthy rabbits were selected for the study and housed 1/cage in cages sized according to National Research Council standards. The rabbit rooms were maintained at 20 °C with humidity between 30-70% and 12 h light cycles. Wayne Rabbit Ration and tap water were freely available.

Test system

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

Test material was dosed as received, 0.5 ml/site, directly on the intact skin sites.

Duration of treatment / exposure:

Test substance was administered once per site and remained in contact with the skin for 4 h followed by removal of the substance by washing with deionized water

Observation period:

11 days

Number of animals:

6 (3 male, 3 female)

Details on study design:

The test substance was applied to a small area of skin covered with a gauze patch and held in contact by a rubber dam and Ace bandage for 4 h. Following the exposure period, residual test substance was removed with deionized water and animals were scored for erythema, edema, and necrosis 1, 24, 48, 72 h and daily for 11 days following removal of the test substance.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24, 48, 72 h

Score:

2.66

Max. score:

4

Reversibility:

fully reversible within: 11 days in all but 1 animal

Remarks on result:

other: Study was terminated prematurely, however reversibility is expected by Day 14

Results 2

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24, 48, 72 h

Score:

1.78

Max. score:

4

Reversibility:

fully reversible within: 11 days

Irritant / corrosive response data:

Very slight to moderate erythema was observed at 1 h and through Day 11 post removal of the test substance. Very slight to slight edema was observed at 1h and through Day 9 post removal of the test substance. Fissuring of the skin at the application site was observed on Days 4 through 11. Sloughing of the skin at the application site was observed on Day 11.

Other effects:

No other effects observed.

Any other information on results incl. tables

Read-Across Justification for EC 270-478-5

EC 270-478-5 has been tested for skin irritation, however, experimental data from a key study with the structurally related substance EC 247-810-2 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 247-810-2, Zinc bis[O-(2-ethylhexyl)] bis[O-(isobutyl)] bis(dithiophosphate), 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 247-810-2 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 247-810-2 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 247-810-2 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 247-810-2 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:

Category 2 (irritant) based on GHS criteria

Remarks:

Migrated information

Conclusions:

Under the conditions of this study, the test material produced a positive irritant effect in male and female New Zealand White rabbits.

Executive summary:

In a skin irritation study, New Zealand White rabbits were treated with 0.5 ml of test substance for 4 h. Irritation responses were graded at 1, 24, 48 and 72 h post removal of test material and daily for 11 days. The mean erythema and edema scores were 2.66 and 1.78, respectively. Very slight to moderate erythema and very slight to slight edema were observed until Day 11 and 9 post removal of the test substance with deionized water. Based on the results of this study, the test substance would be classified Category 2 in accordance with the classification system of GHS. This toxicity study is classified as acceptable and satisfies the guideline requirement for skin irritation study in rabbits.