cis-2-methyl-4-propyl-1,3-oxathiane

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

An assessment of toxicokinetics, based on available data, in accordance with Annex VIII, Section 8.8.1 of Regulation (EC) No 1907/2006

Type of information:

other: Desk-based assessment

Adequacy of study:

key study

Study period:

Not applicable

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Objective of study:

toxicokinetics

Principles of method if other than guideline:

An assessment of toxicokinetics, based on available data, in accordance with Annex VIII, Section 8.8.1 of Regulation (EC) No 1907/2006 (REACH)

GLP compliance:

no

Specific details on test material used for the study:

Detailed information on the 'test material identity' is provided in the attached document including information on individual constituents.

Details on species / strain selection:

Desk-based assessment.

Details on test animals or test system and environmental conditions:

Desk-based assessment.

Details on exposure:

Desk-based assessment.

Duration and frequency of treatment / exposure:

Desk-based assessment.

No. of animals per sex per dose / concentration:

No animals were used in this desk-based assessment.

Positive control reference chemical:

Desk-based assessment.

Details on study design:

Desk-based assessment.

Details on dosing and sampling:

Not applicable

Statistics:

Not applicable

Preliminary studies:

Not applicable

Details on absorption:

The molecular weight is low i.e. 160.277 g/mol, the logarithmic n-octanol/water partition coefficient is 2.98, water solubility is 1400 mg/L and vapour pressure is 50 Pa, 95.0 Pa at 20°C and 25°C. These physicochemical properties are suggestive of favourable absorption via the oral and inhalation routes. Based on the low molecular weight and high water solubility, 100 % oral absorption can be assumed mainly via passive diffusion into portal circulation with delivery into the liver i.e. first pass metabolism. This is supported by the systemic effects on liver and kidney weights as well as the effects liver enzyme activities observed in the repeated dose toxicity study (OECD 422; Applicant, 2019).
The vapour pressure is 50 Pa, 95.0 Pa at 20°C and 25°C meaning there is likelihood of volatilisation and subsequent inhalation. Based on the low molecular weight coupled with high water solubility bioavailability via this route is possible. Passive diffusion into pulmonary circulation is possible and a high plasma concentration of the substance as well as high plasma half-life is expected since the rate first pass metabolism in the lung is slower than in the liver. This is supported by the systemic observations following acute inhalation toxicity study in rat. These systemic effects included; decreased respiratory rate, hunched posture, ataxia and isolated instance of lethargy post-exposure (OECD 436; Applicant, 2019).
Based on the surface tension of the substance, 60.5 ± 0.05 mN/m (refer to IUCLID Section 4.10), dermal absorption would be limited since the transfer of the substances between the stratum corneum and the epidermis would be restricted. This is demonstrated by the lack of significant systemic and local toxicity in the in vivo sensitisation study on the read-across substance (OECD 404 & 406; Applicant, 2003). For absorption calculation, a default value of 100 % skin absorption according to ECHA 2014. Chapter R.7c can be applied as conservative approach for risk assessment.

Details on distribution in tissues:

The substance has physicochemical properties (mainly molecular weight and high water solubility and vapour pressure) resulting upon oral exposure, that the substance can easily pass through aqueous pores via the portal vein into first pass metabolism with reduction in overall systemic distribution of parent compound. As a result, systemic distribution of the parent compound especially via oral route will be limited and therefore resulting into a reduced half-life of the parent compound in blood plasma. This is supported by the high liver weight associated with periportal hepatocyte vacuolation and increased kidney weight with nephropathy syndrome which is associated with α2u globulin accumulation in hyaline droplets, a condition common only to rats. A wide distribution is expected following inhalation exposure since the low molecular weight and high water solubility will lead to passive absorption, therefore resulting in the substance being present in the heart and general circulatory system. A high plasma half-life as demonstrated by these systemic effects which included; decreased respiratory rate, hunched posture, ataxia and isolated instance of lethargy post-exposure. Systemic distribution via dermal absorption is limited as demonstrated by the lack of systemic toxicity observed during the guinea pig maximisation study and in vivo skin irritation study using a read-across substance.

Details on excretion:

Based on the absorption, distribution and potential metabolic pathways highlighted coupled with available systemic data, the substance will most likely be excreted via bile and urine. The increase in kidney weight associated with hyaline droplets in nephron tubular cell and increase in urinary parameters such as creatinine, glucose and ketones demonstrate possible renal/urinary elimination. The logarithmic n-octanol/water partition coefficient 2.98, water solubility is 1400 mg/L and the molecular weight of 160.277 g/mol are suggestive of no accumulation of this substance in fatty tissues after absorption from oral and inhalation routes. Based on the molecular structure and solubility, excretion into urine as conjugated metabolites is assumed to be a preferred route of elimination. A small percentage of the parent compound may also be excreted via bile.

Metabolites identified:

not measured

Details on metabolites:

The substance as an organosulphur derivatives is expected to undergo oxidative metabolism mainly through phase I with further conjugation via Phase II enzymes as demonstrated by increased liver weight associated with periportal hepatocyte vacuolation and alkaline phosphatase activity in the liver of both sexes following sub-acute exposure to the substance. The substance is expected to undergo oxidative reaction mediated by NADPH and cytochrome P450 enzymes into kentones and semialdehydes which will be further oxidised into acidic derivatives. This is supported by increased concentration of ketones in the urine of exposed rats in the sub-acute studies. Another route of metabolism which is expected to be less significant is hydrolysis via cytosolic enzymes into hydroxylated derivatives which will again be further oxidised to give semialdehyde and acidic derivatives. These metabolic intermediates are expected to undergo phase II metabolism forming mainly conjugative derivatives of glucuronic acid and sulphate metabolites. The organosulphur derivative is expected to undergo oxidation of sulphur forming corresponding sulfoxide and sulfone derivatives. These metabolic intermediates will undergo conjugation by glutathione transferase forming glutathione conjugation.

Conclusions:

The substance possesses physicochemical properties which are favourable for ADME. The substance has physicochemical properties which will not lead to potential bioaccumulation. The oral and inhalation routes are most preferred routes of exposure for the substance and limited bioavailability is expected via dermal exposure. The physicochemical properties ensure easy absorption from the gut into the portal vein and pulmonary uptake resulting into rapid metabolism and elimination. Therefore, no significant bioaccumulation is expected, and the substance is expected to undergo rapid transformation to more polar metabolites resulting into rapid elimination via bile and urine. It can be concluded that the basic toxicokinetics of the substance do not pose significant toxicological concern through the evaluation of the available data.

Executive summary:

A desk-based assessment of the basic toxicokinetics of the substance, in accordance with Regulation (EC) 1907/2006: Annex VIII - Section 8.8.1. The substance possesses physico-chemical properties which are favourable for ADME. Exposure from oral and inhalation routes are most favourable and the substance is expected to be widely distributed especially via oral and inhalation exposure. Based on the log Pow of < 3 and BCF < 2,000, bioaccumulation is not significant and elimination is expected to be rapid. The physico chemical propertiesensure via the oral route easy absorption from the gut into the portal vein andpulmonary uptakeresulting into rapid metabolism and elimination. Therefore, no significant bioaccumulation is expected, and the substance is expected to undergo rapid transformation to more polar metabolites resulting into rapid elimination via bile and urine. The clinical signs observed following acute oral, sub-acute exposure support oral absorption of test item and clinical signs and adaptive effects reported in organs such as the liver is demonstrative of distribution, biotransformation and elimination of the test item. It can be concluded that the basic toxicokinetics of the test item does not pose significant toxicological concern through evaluation of available data.

Description of key information

Toxicokinetics Assessment: no bioaccumulation potential; desk-based assessment in accordance with Regulation (EC) 1907/2006: Annex VIII, Section 8.8.1 (2018)

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

Basictoxicokinetics (expert assessment, 2019): The substance possesses physicochemical properties which are favourable for ADME. Exposure from oral and inhalation routes are most favourable with limited distribution of the parent substance based on the hydrolysis half-life and full distribution of the hydrolysis products expected. The plasma half-life of the parent constituents of the substance would be significantly reduced with no potential for systemic bioaccumulation. The parent compound is rapidly metabolized to more polar hydrolysis product substances which are readily eliminated via urine and bile. The clinical signs observed following oral sub-acute exposure support oral absorption of the substance and clinical signs reported in liver and kidney are demonstrative of distribution, biotransformation and elimination of the substance. These observations coupled with measured and predicted physico-chemical properties, hydrolysis products and the observed recovery of all clinical effects, it can be concluded that the basic toxicokinetics of the substance do not pose significant toxicological concern through the evaluation of the available data.

References:

1. ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7c: Endpoint Specific Guidance, June 2017)