Bis(O,O-diisopropyl dithiophosphate)bis(cyclohexylamine) zinc

Endpoint summary

Description of key information

Zinc, bis[O,O-bis(1-methylethyl) phosphorodithioato-.kappa.S]bis(cyclohexanamine)-, (T-4)- (CAS 52585-16-7) is considered to be absorbed from the GI tract, followed by distribution and metabolisation.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Basic toxicokinetics

In accordance with Annex VIII, Column 1, Section 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), an assessment of the toxicokinetic behaviour of the test substance Zinc, bis[O,O-bis(1-methylethyl) phosphorodithioato-.kappa.S]bis(cyclohexanamine)-, (T-4)- (CAS 52585-16-7) is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physicochemical and toxicological properties according to the Chapter R.7c Guidance document (ECHA, 2017) and taking into account further available information from source substances. There are no studies available in which the toxicokinetic behaviour of the target substance has been investigated.

Zinc, bis[O,O-bis(1-methylethyl) phosphorodithioato-.kappa.S]bis(cyclohexanamine)-, (T-4)- has a molecular weight of 690.31 g/mol. The substance is a solid at 20 °C with a water solubility of 10.2 g/L (based on phosphorus analysis), a log Pow of 1.1 and a vapour pressure of 3.8 x 10 E-05 hPa at 20 °C.

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), in particular for those that are poorly soluble in water (≤ 1 mg/L) as these would otherwise be poorly absorbed (Aungst and Chen, 1986; ECHA, 2017).

The physicochemical characteristics, especially the moderate log Pow and high water solubility are in a range that indicates high absorption from the gastrointestinal tract following oral ingestion. The indications that the substance has high oral absorption are supported by the available data on acute oral toxicity. When female Wistar rats were orally exposed to the test substance with a dose of 2000 mg/kg bw, 1/3 animals were killed for humane reasons and 2/3 animals died on Day 1, respectively. Moreover, clinical signs such as hunched posture, pilo-erection, lethargy, diarrhea, hypothermia, tonic convulsions, chromodacryorrhea and splayed gait were noted at 2000 mg/kg bw. At necropsy, dark kidneys, gaseous stomach, pale brown colored liquid present in the stomach, hemorrhage and epithelial sloughing of the gastric mucosa and non-glandular epithelium of the stomach were observed in all females. In addition, dark liver in 2/3 animals and patchy pallor of the liver in 1/3 animals were noted in females.

In conclusion, based on the available information, the physicochemical properties and acute oral toxicity data, high oral absorption of Zinc, bis[O,O-bis(1-methylethyl) phosphorodithioato-.kappa.S]bis(cyclohexanamine)-, (T-4)- (CAS 52585-16-7) can be assumed.

Dermal

Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Moreover, in general, dermal uptake is anticipated to be low, if the water solubility is < 1 mg/L; low to moderate if it is between 1-100 mg/L; and moderate to high if it is between 100-1000 mg/L. Dermal uptake of substances with a water solubility > 10000 mg/L (and log Pow < 0) will be low, as the substance may be too hydrophilic to cross the stratum corneum. Log Pow values in the range of 1 to 4 (values between 2 and 3 are optimal) are favourable for dermal absorption, in particular if water solubility is high (ECHA, 2017).

Zinc, bis[O,O-bis(1-methylethyl) phosphorodithioato-.kappa.S]bis(cyclohexanamine)-, (T-4)- (CAS 52585-16-7) is a solid with low vapour pressure. The values for log Pow and water solubility are in a range that absorption rate through the skin cannot be excluded. However, regarding the molecular weight, the molecule may be too large for dermal absorption.

The dermal permeability coefficient (Kp) can be calculated from log Pow and molecular weight (MW) by applying the following equation described in US EPA (2004):

log(Kp) = -2.80 + 0.66 log Pow – 0.0056 MW

The calculated Kp for the test substance (CAS 52585-16-7) is 1.15 x 10E-6. QSAR calculations confirmed this assumption, as a dermal flux rate of 0.00001 mg/cm2 per h was calculated indicating very low dermal absorption potential for Zinc, bis[O,O-bis(1-methylethyl) phosphorodithioato-.kappa.S]bis(cyclohexanamine)-, (T-4)- (CAS 52585-16-7).

Table 1: Dermal absorption values for Zinc, bis[O,O-bis(1-methylethyl) phosphorodithioato-.kappa.S]bis(cyclohexanamine)-, (T-4)- (CAS 52585-16-7) (calculated with Dermwin v 2.02, Episuite4.1)

Component	Structural formula	Flux (mg/cm2/h)
Zinc, bis[O,O-bis(1-methylethyl) phosphorodithioato-.kappa.S]bis(cyclohexanamine)-, (T-4)-	C24 H54 N2 O4 P2 S4 Zn1	0.00001

Based on these results, only very low dermal absorption potential is predicted for the test substance (CAS 52585-16-7).

If a substance shows skin irritating or corrosive properties, damage to the skin surface may enhance penetration. If the substance has been identified as a skin sensitizer then some uptake must have occurred although it may only have been a small fraction of the applied dose (ECHA, 2017). The available data on skin irritation and sensitisation revealed irritating and sensitising properties of Zinc, bis[O,O-bis(1-methylethyl) phosphorodithioato-.kappa.S]bis(cyclohexanamine)-, (T-4)- (CAS 52585-16-7). Therefore, enhanced penetration of the substance due to skin damage cannot be excluded. However, the available acute dermal toxicity study revealed a LD50 value > 2000 mg/kg bw. In this study, no mortality was observed and there were no clinical signs for systemic toxicity noted in any animal throughout the study.

Taking all the available information into account, the dermal absorption potential is considered to be low.

Inhalation

Zinc, bis[O,O-bis(1-methylethyl) phosphorodithioato-.kappa.S]bis(cyclohexanamine)-, (T-4)- (CAS 52585-16-7) is a solid with a low vapour pressure of 3.8 x 10 E-05 hPa at 20 °C, and therefore of low volatility. Therefore, under normal use and handling conditions, inhalation exposure and availability for respiratory absorption of the substance in the form of vapours, gases, or mists is considered to be limited (ECHA, 2017). In addition, the substance is marketed or used in a non-solid or granular form. Overall, inhalation absorption potential can be considered as negligible.

Distribution and Accumulation

Distribution of a compound within the body depends on the rates of the absorption and the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. Small water-soluble molecules and ions will diffuse through aqueous channels and pores. The rate at which very hydrophilic molecules diffuse across membranes could limit their distribution.If the molecule is lipophilic (log Pow >0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2017).

Zinc, bis[O,O-bis(1-methylethyl) phosphorodithioato-.kappa.S]bis(cyclohexanamine)-, (T-4)- (CAS 52585-16-7) has a moderate molecular weight and high water solubility. Based on the physico-chemical properties and the oral absorption potential, distribution within the body can be considered as likely. After absorption from the GI tract, the test substance (CAS 52585-16-7) will enter the blood circulating system through which it will be distributed within the body. This assumption is based on the systemic toxicity findings observed in the acute oral toxicity study. Regarding the accumulation of the test substance, the log Pow of 1.1 indicates that distribution into cells and the intracellular concentration may be higher than extracellular concentration.

Metabolism

No data are available regarding metabolism. Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v4.1, OECD, 2017). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. The prediction was performed using the SMILES code of Zinc, bis[O,O-bis(1-methylethyl) phosphorodithioato-.kappa.S]bis(cyclohexanamine)-, (T-4)- (CAS 52585-16-7): CC(C)OP(=S)(OC(C)C)S[Zn-2](SP(=S)(OC(C)C)OC(C)C)([NH2+]C1CCCCC1)[NH2+]C2CCCCC2. 20 hepatic and 2 dermal metabolites were predicted for the test substance, respectively. Primarily, hydroxylation of one or both cyclohexane rings may occur in the liver and in the skin, respectively. These predicted metabolites can be regarded as phase I metabolites which are a common prerequisite for the phase II reactions or conjugation reactions, which transfer functional groups to the phase I metabolites to increase the water solubility and the excretion of the xenobiotic. Phase II metabolism by e.g. uridine 5′-diphospho (UDP)-glucuronosyltransferases and sulfotransferases typically generates excretable hydrophilic metabolites by transferring activated glucuronic acid and sulfate-moiety to hydroxyl groups of the substrate, respectively (Aktories, 2005). Up to 58 metabolites were predicted to result from all kinds of microbiological metabolism for the test substance. Based on the experimental conditions of the available micronucleus test, the test substance induced micronuclei in human lymphocytes. Therefore, Zinc, bis(O,O-bis(1-methylethyl) phosphorodithioato-.kappa.S)bis (cyclohexanamine)-,(T-4)- is considered to be clastogenic in the in vitro micronucleus test, when tested up to precipitating or the highest evaluable concentrations. Therefore, an in vivo alkaline single-cell gel electrophoresis assay (Comet Assay according to OECD TG 489) is proposed. Based on the data of this study a decision on the classification on the classification under Regulation (EC) No.1272/2008 will be made.

Excretion

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces (via bile and directly from the GI mucosa). Only limited conclusions on excretion of a compound can be drawn based on physicochemical data. Low molecular weight (below 300 g/mol in rat), good water solubility, and ionization of the molecule at the pH of urine are characteristics favourable for urinary excretion. Due to metabolic changes, the finally excreted compound may have few or none of the physicochemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product. Thus, based on the available data no final conclusion on the excretion route is possible.

 

References

Aktories K., Förstermann U., Hofmann F. and Starke K. (2005): Allgemeine und spezielle Pharmakologie und Toxikologie. 9. Auflage, Urban & Fischer Verlag

Aungst B. and Shen D.D. (1986): Gastrointestinal absorption of toxic agents. In Rozman K.K. and Hanninen O. Gastrointestinal Toxicology.Elsevier, New York, US.

ECHA (2017): Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0, June 2017