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EC number: 298-577-9 | CAS number: 93819-94-4
Results for EC 270 -608 -0:
VIABILITY (OFFSPRING): Mean numbers of corpora lutea and unaccounted-for sites, mean number of pups born, live litter size, the percentage of males at birth, and postnatal survival in the 10, 40, and 160 mg/kg/day groups were similar to the control group values.
CLINICAL SIGNS (OFFSPRING): The general physical condition of all F1 pups in this study were unaffected by test item administration. No test item-related clinical findings were noted for the F1 pups.
BODY WEIGHT (OFFSPRING): Mean male and female pup body weights and body weight gains in the 10, 40, and 160 mg/kg/day groups were unaffected by test item administration during PND 1-4. No statistically significant differences from the control group were noted.
GROSS PATHOLOGY (OFFSPRING): There were no remarkable macroscopic findings in the F1 pups at the scheduled necropsy at any dosage level.
JUSTIFICATIONS FOR READ-ACROSS
EC 283-392-8 has not been tested for developmental toxicity, however experimental data on structurally related substances EC 270-608-0 (OECD 422) are available and suitable for read-across. Justifications for read-across:
EC 283-392-8 and EC 270-608-0 are generically referred to as zinc dialkylthiophosphate (ZDDP) which are produced under similar manufacturing procedures and used in commerce as multi-functional anti-wear and anti-oxidation inhibitor performance components in passenger motor oils, diesel engine oils and industrial oils such as hydraulic lubricants.
EC 283-392-8 and EC 270-608-0 consist of alkyl substituted phosphorodithioic acid structures complexed with zinc.
EC 283-392-8:phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-propyl) esters, zinc salts, referred to as “mixed isopropyl and 1,3-dimethylbutyl derivative”
EC 270-608-0:phosphorodithioic acid, mixed O,O-bis(iso-butyl and pentyl) esters, zinc salts – (CAS 68457-79-4), referred to as “mixed isobutyl and pentyl derivative”
These ZDDPs share similar core structures - alcohol ester of dithiophosphate, specific structural variations that relate to their alcohol group substituent are the alkyl chain length and the degree of branching of the alcohol charge.
Using Tanimoto Fingerprint (ToxMatch Version 1.06 software) to model chemical structures of the analogues 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); therefore chemical structures of the analogues have determined to be sufficiently close for there to be a reasonable expectation of similar toxicological effects.
Standard physicochemical properties for each substance were listed in Table 1.
Table 1. Establishment of similarity between the data donating substance and the data accepting substance
Water Sol (ppm)
Vapor Pressure (Pa at 25 oC)
C5, mixture of linear and branched
As shown in Table 1, these two substances have the same molecular weight, similar Log Kow, low vapor pressure, and both are water soluble. The similarity of the physicochemical properties of these substances parallels their structural similarity.
Biologically Active Functional Groups:
The ester group presents in each of the analogue members, and is expected to exhibit similar biological activities. Non-random patterns were observed for the toxicological effects (e.g. available data showed low levels of acute toxicity effect, lacking of mutagenic effect in bacteria, consistent trend of change in ecotoxicity effect, etc.), these common behaviors and consistent trends suggest a common mechanism/mode of action, with little influence from the length of carbon chain. These facts further supported read-across between the analogue members.
Available Data and Adequacy for Read-across:
The reproductive/developmental toxicity of EC 270-608-0 was evaluated with rats at doses as high as 160 mg/kg/day for up to 52 consecutive days in accordance with OECD 422. No substance-related effects on reproductive performance, gestation length, parturition, reproductive organs, or neurobehavioral parameters were found. Substance-related toxicity was limited to morbundity, adverse clinical signs, and epithelial hyperplasia, hyperkeratosis, and inflammation of the stomach. The NOAEL and NOEL for reproductive fertility and neonatal toxicity was determined to be 160 mg/kg/day. The parental NOAEL for systemic toxicity was 160 mg/kg/day. The parental NOAEL for portal of entry irritation and related secondary effects parental toxicity was 40 mg/kg/day.
Based on the abovementioned justifications, results from EC 270-608-0 OECD 422 study was determined to be adequateto fulfill the purposes of this endpoint.Therefore, NOAEL of 160 mg/kg/day for developmental toxicity was proposed for EC 283-392-8, and use of read-across will eliminate the need for new animal testing while allow meeting the data requirements.
In a guideline repeated dose and reproduction / developmental screening study (OECD 422) conducted according to Good Laboratory Practices, WIL Research Labs (2010) evaluated the potential toxic effects of phosphorodithioic acid, mixed O,O-bis(iso-Bu and pentyl) esters, zinc saltswhen administered to rats. This study was designed to evaluate the toxic effects, including neurobehavioral effects, of the test material to parental animals and to evaluate the potential to effect male and female reproductive performance such as gonadal function, mating behavior, conception, parturition, and early postnatal development. The test material was administered orally by gavage once daily to 3 groups of Crl:CD(SD) rats at levels of 10, 40 or 160 mg/kg/day. The low- and mid-dose groups each consisted of 10 rats/sex and the high-dose group consisted of 15 rats/sex. A concurrent control group of 15 rats/sex received the vehicle, mineral oil USP, on a comparable regimen. Ten males/group selected for pairing were dosed for 14 days prior to mating through 1 day prior to euthanasia for a total of 28 doses. Ten females/group selected for pairing were dosed for 14 days prior to mating through lactation day 3 for a total of 40-52 doses; females that failed to deliver were dosed through the day prior to euthanasia (post-mating day 25) for a total of 40 doses. The extra 5 males and 5 females in the control and high-dose groups were not used for mating and were treated beginning on study day 0; following 28 doses for the males and 40 doses for the females, these animals were assigned to the post-treatment period and remained on study for a 14-day non-dosing period.
Test item-related moribundity, clinical findings, and microscopic findings in the non glandular portion of the stomach, characterized by epithelial hyperplasia, hyperkeratosis, and inflammation, were observed in the 160 mg/kg/day group. The injury to the nonglandular portion of the stomach was localized and considered to be irritation from test item portal-of-entry effects. Based on these results, the NOEL for portal-of-entry effects was considered to be 40 mg/kg/day, and excluding the histologic injury to the nonglandular stomach, the no-observed-adverse-effect level (NOAEL) for systemic toxicity was considered to be 160 mg/kg/day. In the absence of effects on the general physical condition of the F1pups, the NOEL for neonatal toxicity was 160 mg/kg/day.
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