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

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

key study

Study period:

1979/07/20-1979/10/12

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: This non-GLP study was not conducted under OECD 401, however the reported data is similar enough for the study itself not to warrant restriction. The reliability score of 2 is based on the fact that this is a read-across study.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1979

Report date:

1979

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: 16CFR1500.3

Deviations:

no

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

only male rats used.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

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

EC Number:

272-723-1

EC Name:

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

Cas Number:

68909-93-3

Molecular formula:

Too complex

IUPAC Name:

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

Details on test material:

Sample was received at the laboratory on 1979/06/28 and described as amber liquid.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

50 male Wistar rats, at least 8 weeks old when received and between 220 and 300 g, were supplied by Ace Animals and equilibrated for at least one week in the laboratory. Apparently healthy rats were selected for the test. The animals were identified by cage tags noting test material, start date, animal number and sex. Each animal was identified by an indelible body mark. Animals were housed 5/cage in suspended wire mesh cages and were provided fresh Purina rat chow and water ad libitum except for 16-20 h prior to dosing when food was removed. The animal room was maintained at 20-21°C and was kept clean in accordance with AAALAC standards.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

The test material was given orally by gavage. One group of 10 male rats was dosed at 5.0 g/kg initially. Based on the results of the initial dose, four additional groups of 10 male rats were dosed at various levels in order to determine the LD 50 of the test material. The dose was based on the sample weight as calculated from specific gravity. The vehicle, if any, was chosen because of its lack of known toxicity, lack of physiological effect and because it is relatively unreactive with other chemical substances.

Doses:

1220, 1950, 3120, 3730, 5000 mg/kg

No. of animals per sex per dose:

10 animals per dose - male

Control animals:

no

Details on study design:

Rats were observed 3-4 h after dosing and once daily for 14 days. Mortality, toxicity and pharmacological effects were recorded. Body weights were recorded pretest and in survivors at 14 days. At 14 days, all survivors were sacrificed. All animals were examined for gross pathology.

Statistics:

LD 50 was calculated according to the method of Litchfield, J.T. Jr. and F. Wilcoxon, 1949.

Results and discussion

Effect levels

Sex:

male

Dose descriptor:

LD50

Effect level:

3 600 mg/kg bw

95% CL:

> 3 100 - < 4 200

Mortality:

Deaths occurred at the three highest dose levels;. 3120, 3730 and 5000 mg/kg. 10/10 animals died at the 5.0 g/kg dose.

Clinical signs:

other: Significant predeath signs included lethargy, piloerection, diarrhea, ptosis, ataxia, flaccid muscle tone, chromorhinorrhea, chromodacryorrhea, emaciation, dyspnea and urinary incontinence. Most surviving animals were normal by the end of the observation

Gross pathology:

Necropsy observations revealed gastrointestinal abnormalities.

Other findings:

No other findings to report

Any other information on results incl. tables

Justification for Read Across from Analogue EC 272-723-1

Common Manufacturing Process:The submission substance (EC 273-527-9) and the analogue (EC 272-723-1) 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 C8 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 isopropanol and 2-ethylhexanol in the analogue).

Same Chemical Category: The submission substance (EC 273-527-9) and the analogue (EC 272-723-1), 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 272-723-1) 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 272-723-1) is a multicomponent mixture of ZDDP monomers and dimers containing isopropyl dithiophosphate ligands, 2-ethylhexyl dithiophosphate ligands, and mixtures of isopropyl and 2-ehtylhexyl dithiophosphate ligands with a molecular weight range of 492 – 772 (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:

Category 5 based on GHS criteria

Remarks:

Migrated information

Conclusions:

Under the conditions of this study, the test substance had an LD50=3600 mg/kg when administered orally to male Wistar rats.

Executive summary:

In an acute oral toxicity study, male Wistar rats were exposed to the test substance at doses of 1220, 1950, 3120, 3730, and 5000 mg/kg. The oral LD50 is 3600 mg/kg. Sublethal effects of lethargy, piloerection, diarrhea, ptosis, chromodacryorrhea, and dyspnea were observed in all groups. Necropsy observations included gastrointestinal abnormalities. Based on the results of this study, this test substance would be classified as Category 5 in accordance with the classification system of GHS. This toxicity study is classified as acceptable and satisfies the guideline requirement for acute oral toxicity in rats.