Reaction products of ((5E)-5-ethylidenebicyclo[2.2.1]hept-2-ene and (5Z)-5-ethylidenebicyclo[2.2.1]hept-2-ene) and 2-methyl-1,3-butadiene, epoxidized

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

GLP compliance:

no

Details on species / strain selection:

No animals were used in this desk-based assessment.

Details on test animals or test system and environmental conditions:

Not applicable

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:

Not applicable

Details on dosing and sampling:

Not applicable

Statistics:

Not applicable

Preliminary studies:

Desk-based assessment.

Details on absorption:

The molecular weight of all constituents of the substance is low i.e. in the range of 204.31 – 220.31 g/mol, it’s n-octanol/water partition coefficient in the range of 2.45 – 3.85 and water solubilities of 21.56 to 276.1mg/L. The constituents of the substance possess a neutral hydrolytic half-life (DT50) of ≤ 4.8 hours and vapour pressure 0.716 Pa at 25 °C, which are suggestive of favourable absorption via oral and inhalation routes with limited uptake via dermal route. Absorption of the substance from the gastro-intestinal tract is mainly via passive diffusion to into portal or enterohepatic circulation with delivery into the liver i.e. first pass metabolism. Although the substance is moderately soluble, the acidic/basic nature of the GI tract enhances hydrolysis of the parent constituents (by acid/base-catalysed epoxide hydrolysis) into more polar hydrolysis products which is easily absorbed into the circulatory system (see 6. Appendices – Tables for more information). Pulmonary uptake of the substance would most likely result into circulatory system or into the GI tract via mucocillary reflex. Absorption via the dermal route is potentially limited especially as the substance is a ‘UVCB’ substance with potentially variable molecular weight and with no surface activity. Transfer between the stratum corneum and the epidermis may be restricted therefore, resulting in an overall systemic uptake via this route being limited.

Details on distribution in tissues:

The substance possesses physicochemical properties (mainly: n-octanol/water partition coefficient, hydrolytic half-life and water solubility) giving a potential rapid uptake through aqueous pores or be carried through the epithelial barrier by the bulk passage of water into the liver. This is additionally based on the neutral hydrolytic half-life (DT50 ≤ 4.8 hours) potentially meaning that the distribution of the parent compound is significantly reduced. The hydrolysed product is expected to be more polar and a wide distribution is expected as it can easily be taken up into the circulatory system. This is supported by the clinical observations in the kidney i.e. nephropathy syndrome which is associated with α2u globulin accumulation in hyaline droplets, a condition not relevant to humans. Further observation included reversible changes such as centrilobular hepatocyte hypertrophy in the liver and follicular cell hypertrophy in thyroid.

Details on excretion:

The n-octanol/water partition coefficient (log Pow in the range of 2.45 – 3.85) is not suggestive of any significant potential accumulation of the parent constituents of the substance in fatty tissues after absorption from gastro-intestinal and the corresponding hydrolysis products possess expected lower n-octanol/water partition coefficient (log Pow = -0.26, 1.29 and 2.69) and higher water solubilities than the parent constituents. Systemically available substance is likely to be eliminated via urine – mainly the glucuronic metabolite. The sulfate conjugates are excreted in the urine (i.e. actively excreted by organic anion transporters and to a smaller extend via biliary excretion as demonstrated by the low level of bile acid observed in the subs acute exposure. This supported by the observed clinical changes kidney would confirm metabolism is rapid and urine as the most probably route of excretion. Elimination is assumed to be rapid, no potential for bioaccumulation is to be expected. Unabsorbed parent compound is expected to be eliminated via faeces and bile.

Metabolites identified:

not measured

Details on metabolites:

Epoxide metabolism of the substance is mainly through phase I (hydrolysis) and II enzymes as demonstrated by changes in liver centrilobular hepatocyte hypertrophy and liver enzymes activities such as the low aspartate aminotransferase and low alkaline phosphatase observed following subacute exposure to the substance. Phase I metabolism would involve the hydrolysis reaction of the epoxide groups aided by epoxide hydrolases into its corresponding vicinal diol with the addition of a water molecule. The increase alcohol metabolite is supported by the effects observed in the low level of liver enzymes activities such as low aspartate aminotransferase and low alkaline phosphatase which are involved in and facilitating naturally occurring biochemical reactions, and maintaining various metabolic processes within the liver. Since both enzymes are low, it is an indication that the hepatocyte hypertrophy observed is not associated with toxicity but rather a biochemical process of detoxification. The vicinal diol is further conjugated by phase II enzymes such as UDP-glucuronyltransferase and Sulfotransferases.

Conclusions:

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.

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 therefore the substance is expected to be widely distributed especially via 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 lack of systemic and local toxicity observed following in vivo skin irritation and sensitisation studies shows that systemic bioavailability of this substance is limited via dermal exposure. The clinical signs observed following oral sub-acute exposure support oral absorption of teste item and clinical signs 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

Additional information

Basic-toxicokinetics - expert assessment, 2018: 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)