Condensation products of oil shale alkylresorcinols and formaldehyde

Endpoint summary

Description of key information

An assessment of toxicokinetic behaviour has been made based on the study data available. 

Additional information

Absorption

Oral absorption

The main physical chemical properties that influence absorption are molecular weight, water solubility and lipid solubility. The diffuse log octanol/water partition coefficient may limit the rate of test material absorption from the gut. The lack of ionisable groups suggests that absorption will not be affected by pH. It is worthy to note that due to the intended use of substance, oral exposure in humans would only occur as an accident or in cases of deliberate misuse.Single dose studies by the oral route showed low acute toxicity with no mortalities and minimal signs of systemic toxicity (hunched posture, increased salivation, pilo-erection, noisy respiration and red/brown staining around the mouth)at the limit dose of 2000 mg/kg bw, thus suggesting limited absorption. However, results obtained in a repeat-dose (28-day) oral gavage study indicate a degree of absorption via the oral route of exposure. In the 28-day oral study, systemic exposure and distribution within the body was demonstrated by changes in haematological and clinical chemistry parameters, as well as in variations of liver weights and microscopic findings, mainly at the highest dose (750 mg/kg/day). The increased liver weight, together with microscopic findings of centrilobular hepatocyte hypertrophy, is consistent with an active metabolisation of SF Resin by the liver, likely resulting in induction of enzymes located in the relevant zones for which hypertrophy was microscopically observed. Hepatocyte hypertrophy, generally considered an adaptive response to the constant load from a xenobiotic, was accompanied by increases in transaminases and plasma bilirubin levels. However, no inflammation or degenerative changes to this organ were noted. That a large dose was required to solicit these effects most likely indicates limited absorption, of the material as a whole with certain fractions of the substance being more readily absorbed over others. An estimate of absorption of 50% is made for risk assessment purposes.

 

Dermal absorption

Single dose studies by the dermal route showed low acute toxicity with no mortalities and no signs of systemic toxicity at the limit dose of 2000 mg/kg bw, thus suggesting limited, if any, absorption. However, results obtained in a Mouse Local Lymph Node Assay (LLNA) indicate a degree of absorption for the dermal route of exposure. The positive result of the LLNA indicates that SF Resin or at least some of its components (likely the alkylresorcinols), can penetrate through the skin and bind to proteins thereafter.

In the absence of any reliable quantitative data and in line with latest EC guidance on dermal absorption (EFSA Scientific Opinion.  Guidance on dermal absorption.  EFSA Journal 2012 (10(4):2665), 25% dermal absorption will be used for risk assessment purposes. This is considered a very conservative estimate as the material is a compact solid.

Inhalation absorption

SF Resin has low volatility (vapour pressure <0.0012 Pa @ 25 °C)and is a compact solid, therefore is unlikely to be available for inhalation as a vapour.

In absence of any data, and as a worst-case assumption, for risk assessment purposes absorption by inhalation will be assumed to be 100%.

 

Distribution

The results of the repeat dose oral toxicity study show that some systemic distribution of test material occurs given the wide estimate of the log octanol/water partition coefficient, different components of the resin will potentially show different distributions. The positive sensitisation response suggests that the test material has the capacity to bind to carrier proteins within the circulatory system.

 

Metabolism

The results of the repeat dose oral toxicity study in the rat suggest that some hepatic metabolism of the absorbed fraction is likely. The material may be metabolised to facilitate the renal/biliary excretion of the metabolites through conjugation of the hydroxy groups to glucuronic acid and/or sulphate. Nothing could be inferred from the results of the Ames test or in vitro cytogenetics assay in which SF Resin was not genotoxic or clastogenic in either the presence or absence of S9 metabolising system.

 

Elimination

There is no evidence to indicate the route of excretion of test material but it can be predicted that some renal or biliary excretion of material is possible following hepatic metabolism, although materials with a MW <300 g/mol tend to be excreted in the urine, and those with a MW >300 g/mol in the bile. Any test material that is not absorbed from the gut is likely to be excreted in the faeces.

 

Conclusion

SF Resin is defined as ‘condensation product of oil shale alkylresorcinols and formaldehyde, carried out in the presence of an ammonia catalyst’. It is a UVCB substance. Considering the complex nature of SF Resin, standard toxicokinetic studies are not appropriate because toxicokinetic behaviours will vary depending upon the properties and interactions of the individual constituents.

Single dose studies by the oral and dermal route suggest limited absorption. However, results obtained in a Mouse LLNA and in a repeat-dose (28-day) oral gavage study indicate a degree of absorption both for the dermal and oral route of exposure. The 28-day oral study suggests systemic exposure and distribution within the body with an active metabolisation of SF Resin by the liver followed by possible renal or biliary excretion of material. The positive sensitisation response bind to carrier proteins in the circulatory system

Physical-chemical properties and results of in vivo toxicity studies indicate that oral absorption of SF Resin will be limited as will dermal absorption and values of 50% and 25% are estimated respectively for both.

As SF Resin is of low volatility, inhalation exposure is not likely to occur at ambient temperature and pressure, however, all uses of SF Resin that require heating of the substance are hazards arising from inhalation of the fume. Therefore,in absence of any data and as a worst-case assumption, for risk assessment purposes, absorption by inhalation will be assumed to be 100%.

SF Resin is expected to be widely distributed with the different components being distributed differently as inferred from the large range of the log Kow. Metabolism of absorbed material is expected to be through conjugation of the hydroxy groups to glucuronic acid and/or sulphate in the liver so as to facilitate renal/biliary excretion.

 

References

Bednáriková M (2012). In Vitro Mammalian Cell Gene Mutation Test (OECD 476). Report no.: 600163110. Owner company: VKG Oil AS. Report date: 2012-12-13.

Dhinsa NK, McKenzie J & Brooks PN (2004). Twenty-Eight Day Repeated Dose Oral (Gavage) Toxicity Study in the Rat. Report no.: 1974/082. Owner company: Federation of Estonian Chemical Industries. Report date: 2004-11-26.

EFSA Scientific Opinion.  Guidance on dermal absorption.  EFSA Journal 2012 (10(4):2665

O’Connor BJ & Mullee DM (2004). Determination of General Physico-chemical Properties. Report no.: 1974/075. Owner company: Federation of Estonian Chemical Industries. Report date: 2004-09-07.

Sanders A (2004a). Acute Oral Toxicity in the Rat – Acute Toxic Class Method. Report no.: 1974/077. Owner company: Federation of Estonian Chemical Industries. Report date: 2004-06-01.

Sanders A (2004b). Acute Dermal Toxicity (Limit Test) in the Rat. Report no.: 1974/078. Owner company: Federation of Estonian Chemical Industries. Report date: 2004-06-01.

Sanders A (2004c). Local Lymph Node Assay in the Mouse. Report no.: 1974/081. Owner company: Federation of Estonian Chemical Industries. Report date: 2004-06-01.

Thompson PW (2004). Reverse Mutation Assay “Ames Test” using Salmonella Typhimun. Report no.: 1974/083. Owner company: Federation of Estonian Chemical Industries. Report date: 2004-05-25.

Wright PN & Jenkinson P (2004). Chromosome aberration Test in Human Lymphocytes in vitro. Report no.: 1974/084. Owner company: Federation of Estonian Chemical Industries. Report date: 2004-11-25.

Bibliography

Illing Dr. HPA (2004). Toxicity of Nine shale Oil Derived Chemicals. Owner company: VKG Oil AS. Report date: 2004-04.