Formaldehyde, reaction products with phenol heptyl derivs. and 1,3,4-thiadiazolidine-2,5-dithione

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The following assessment of the toxicokinetic profile of Substituted thiazole, EC# 300-298-5, is based on the physical chemical properties and toxicity data on the substance, and the absorption, distribution, metabolism and/or excretion data for structurally similar substances. Metabolite and bioavailability predictions have also been determined using the OECD Toolbox software. No experimentally derived ADME data are available for this substance.

Substance Characterization

Analytical characterizations show that this substance meets the definition of a UVCB. This substance is chemically described as “reaction product of 1,3,4-thiadiazolidine-2,5-dithione, formaldehyde and phenol, heptyl derivatives”.

 

Physical Chemical Properties

Molecular weight, water solubility, log Kow, and vapour pressure are key physical chemical properties for assessing the toxicokinetics of a substance. This substance is a clear amber viscous liquid. The components generally have molecular weights of less than 500 although there are some higher MW components in the range of 500 to 700 MW. It may be said that approximately 56% is in the range of 354 to 721. The substance is poorly soluble in water (less than 1 mg/L) having a maximum solubility of 0.114 mg/l. Physical chemical testing also shows that the majority of the components are strongly hydrophobic (53% with a log Kow >9.4, however, a significant proportion (38%) has a PoW of 1.03. Consequently, more than 90% of the substance is outside the range that is likely to be easily absorbed through biological membranes, particularly as the low water solubility and non-ionisable nature will inhibit absorption of those components with a PoW in the range that may be absorbed. The substance has a negligible vapour pressure (7.6 x 10^-2Pa @ 25° C). The representative molecule structures do not include groups that are readily ionisable;the main functional groups in the test item are thiadiazoles and hydroxyls. Furthermore, neither of these groups will readily hydrolyse at environmentally relevant temperatures and pHs, so it is expected that the test item is hydrolytically stable.

 

Exposure Routes

The potential for exposure to this substance is limited by its use and physical chemical properties. The dermal contact route is considered to be the primary route of occupational exposure. Inhalation exposure is expected to be limited because this substance has a negligible vapour pressure (OECD 2003: negligible <1 Pa; ECHA R15.5: low < 0.1 Pa). Because of the use pattern oral exposure is not an anticipated route of exposure, either to workers or the general public.

 

Absorption

Dermal

The dermal absorption of the main components of this substance is expected to be limited but it is difficult to make a quantitative estimate. ECHA endpoint specific guidance chapter R.7C indicates that for substances with a MW >500 and a Log PoW >4, then a default absorption estimate should be taken to be 10%. The results of an acute dermal toxicity study in rats indicate that dermal absorption of this substance is limited. Animals were given a single dermal dose of 2000 mg/kg and observed for systemic and local effects for 14 days. The predominant finding was very slight erythema noted at the test sites of all animals. Other signs of skin irritation noted at the test sites of females were haemorrhage of the dermal capillaries, light brown discolouration of the epidermis, slight desquamation, glossy skin, scabbing and scab lifting to reveal glossy skin or dried blood. Haemorrhage of the dermal capillaries was also noted at the test site of one male. No clinical signs were observed that were indicative of systemic effects, and no gross pathological abnormalities were observed. Animals showed expected gains in bodyweight over the study period, except for one female which showed slight bodyweight loss during the first week but the expected gain in bodyweight during the second week. In a Buehler sensitisation test the substance was shown to be a weak sensitizer when tested at 50% in acetone. The use of acetone may facilitate the solubilisation and transfer of the substance into the skin and therefore may exaggerate the dermal absorbance that may be expected under normal exposure conditions.

 

The substance is poorly soluble in water and up to 91% of the test substance may have MW >500 and/or has a Log PoW within the range considered valid for prediction of dermal absorption at a default rate of 10% (EFSA Scientific Opinion: Guidance on Dermal Absorption. EFSA Journal 2012; 10(4):2665 ). The Guidance further states that Log Pow outside the range should not be used to predict absorption. However, studies with alkyl phenols indicate that skin penetration over 8 hours is only 1% of the applied dose (Monteiro-Riviere, et al, 2000). Therefore, based on the evidence and the available guidance it seems reasonable to reduce the default estimate of 10% by 90% to 1%.

 

Oral

Absorption in the gastrointestinal tract is predominantly influenced by the water solubility, ionization state, lipophilicity, and molecular weight of a chemical. The substance is only slightly soluble in water (0.114 mg/l), has a non-ionisable nature, hydrophobic with the majority being strongly hydrophobic (log Kow >9.4), and with a range of molecular weights either side of 500. The results of acute and repeat dose oral toxicity studies in rats confirm that this substance (or at least some of its components) is absorbed, although the irritant properties of the substance may be a confounder. In single dose studies using 2000 mg/kg or 5000 mg/kg of this substance, 9/10 deaths occurred at the higher dose but no deaths at the lower dose. In an OECD 422 repeat dose toxicity and reproduction/developmental screen the results show that this substance may be absorbed because it caused test material-related adverse effects, primarily small changes in organ weights. However, the substance is irritating to skin and some of the effects in the repeat dose study may have been related to the irritating properties of the substance. In vitro studies with mammalian cells show that the substance is toxic to human lymphocytes and L5178Y cells. However, in this case the substance was formulated in dimethyl sulphoxide, which can greatly facilitate the transport of water insoluble materials across cell membranes and may solubilize components of the substance in a way that could not occur in vivo. Overall it is not possible to estimate what proportion of the substance is absorbed via the oral route although it may be expected to be approximately 10 times greater (IGHRC, 2006) than that via the dermal route, i.e. approximately 10%.

 

Inhalation  

Because this substance has a relatively low vapour pressure (7.6 x 10^-2Pa @ 25° C; OECD 2003: negligible <1 Pa; ECHA R15.5: low < 0.1 Pa), the potential for inhalation exposure and uptake via the lungs is not expected. However, if this substance was to reach the respiratory tract, the physical chemical properties and its bioavailability, as inferred from the oral toxicity data, indicates that uptake is likely to occur only by means of micellar solubilization.

 

Distribution

Once this substance (or at least the absorbable components) is absorbed, it is expected to be distributed via the blood to the liver and other tissues. Due to its strong lipophilic nature it is predicted to be absorbed by cells of the organs and tissues that it contacts, although the physicochemical properties indicate that absorption may be limited. The repeat dose and reproduction/developmental screen study also provides some evidence that this substance is distributed to and absorbed by the liver and thymus, from the effects seen at the high dose levels of 500 and 1000 mg/kg/day. However, the representative structures are predicted to be not bioavailable according to the Oasis Lipinski Rules under OECD Toolbox v2.3.0.

 

Metabolism

The absorbable components of this UVCB substance are expected to be metabolized via a number of metabolic pathways. Cytochrome P450 (CYP450) enzymes are a superfamily of oxidative catalysts important in the biosynthesis and metabolism of a wide range of endogenous molecules as well as the metabolism of xenobiotics. Related compounds such as alkylphenols are known to undergo both Phase I and Phase II reactions (Thompson et al, 1995). Alkyl phenols also are known to undergo glucuronidation with the glutathione moiety attached to the benzylic carbon on the alkyl side chain. The representative structures of this UVCB substance were subjected to metabolite profiling using the OECD Toolbox v2.3.0 QSAR system and the predicted metabolites were partitioned into chemical categories based on USEPA rules (ECOSAR). The Toolbox predicted a total of 151 potential metabolites from the six representative structures, which are summarized in the table below:

 

US EPA chemical Categorization	Number	Percentage
Acid moiety|Neutral Organics	3	2%
Acid moiety|Phenols, Poly	14	9%
Aldehydes (Mono)|Phenols, Poly	10	7%
Hydrazines|Phenols, Poly	20	13%
Phenols	3	2%
Phenols, Poly	78	52%
Phenols, Poly|Thiols and Mercaptans	19	13%
Phenols|Thiols and Mercaptans	3	2%
Thiols and Mercaptans	1	1%
Total	151	100%

 

The representative structures are predicted by OECD Toolbox v2.3.0 to have metabolism half-lives that are moderate, fast or very fast and consequently the likelihood of bioaccumulation should be low.

 

 

Elimination

Because of the structural characteristics of this substance, Phase I and Phase II metabolic by-products are expected to be eliminated via renal and/or biliary excretion.

 

References

Monteiro-Riviere NA, Van Miller, JP, Simon G, Joiner RL, Brooks JD and Rivere JE (2000). Comparativein vitropercutaneous absorption of nonylphenol and nonylphenol ethoxylates (NPE-4 and NPE-9) through human, porcine and rat skin, Toxicol. and Indust. Health 16:49-57.

 

Thompson DC, Perera K and London R (1995). Quinone methide formation from para isomers of methylphenol (creosol), ethylphenol, and isopropylphenol: relationship to toxicity, Chem. Res. Toxicol. 8:55-60.

 

The Interdepartmental Group on Health Risks from Chemicals (IGHRC), Guidelines on route-to-route extrapolation of toxicity data when assessing health risks of chemicals. 2006, Institute of Environment and Health. ISBN 1-899110-41-0/978-1-899110-41-4