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Toxicological information

Acute Toxicity: dermal

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Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1975
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-guideline, non-GLP study; study was conducted on structural analogue and suitable for read across.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1975
Report Date:
1975

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation:
- Weight at study initiation: 2.25-2.75 kg
- Fasting period before study:
- Housing: Housed individually in wire bottom cages
- Diet (e.g. ad libitum): approximately 4 ounces daily
- Water (e.g. ad libitum): ad libitum
- Acclimation period:


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.1
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):


IN-LIFE DATES: From: To:

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure:
- % coverage: 100%
- Type of wrap if used: plastic sheet


REMOVAL OF TEST SUBSTANCE
- Washing (if done):
- Time after start of exposure: test material removed 24 hours after exposure


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5 g/kg bw
- Concentration (if solution):
- Constant volume or concentration used:
- For solids, paste formed:


VEHICLE
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Lot/batch no. (if required):
- Purity:
Duration of exposure:
24 hours
Doses:
5000 mg/kg
No. of animals per sex per dose:
6
Control animals:
yes, concurrent no treatment
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: 7 and 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology including: thymus, heart, lungs, liver, kidneys, adrenal glands, spleen, gonads, gastro-intestinal tract, lymph nodes, pancreas, salivary glands, bladder, body fat, skeletal muscle, teeth, eyes and skin.

Results and discussion

Effect levels
Sex:
male
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
One animal with abraded skin died 13 days after dosing
Clinical signs:
Severe erythema and edema noted at 24 hours. By seven days treated sites were thick and escharotic.
Body weight:
Treated animals weighed significantly less than controls.
Average body weight during study
Control: 2.47 kg (start), 2.49 kg (day 7), 2.85 kg (day 14
Treated: 2.44 kg (start), 2.15 kg (day 7), 2.15 kg (day 14)
Note: Values are an average of 6 rabbits except for day 14 treated, which is the mean of 5 animals
Gross pathology:
Liver-like or necrotic-appearing areas of lung tissue observed in five rabbits. Further histology of the lungs revealed confluent bronchipnuemonia or chronic interstitial pneumonia. Two rabbits had small white liver abcesses that were determined to be of parasitic origin after histological examination.

Any other information on results incl. tables

Read-Across Justification for EC 249-109-7

EC 249-109-7 has not been tested for acute dermal toxicity, however experimental data from a study with the structurally related substance EC 224-235-5 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 249-109-7, zinc bis(O,O-diisooctyl) bis(dithiophosphate), 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 224-235-5, zinc bis[O,Obis(2-ethylhexyl)] 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 249-109-7 substance and EC 224-235-5 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 249-109-7 substance and EC 224-235-5 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 249-109-7 substance and EC 224-235-5 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 249-109-7 substance and EC 224-235-5 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:
study cannot be used for classification
Remarks:
Migrated information