Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Physical-chemical properties and results of in vivo studies using very similar materials suggest that oral absorption of the analogue substance (EC 271-638-7) will be extremely limited, and even more limited or absent following dermal exposure. For risk assessment purposes the substance will be assumed to be absorbed at 2% after oral and dermal exposure. 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 within the body would also be limited, mainly to the liver, fat, and kidney and adipose tissues. On the basis of similarity to mineral oil (paraffin oils), the substance could also reach the spleen, but the high molecular weight means distribution to the brain is unlikely, (in contrast to the mineral oils). Protein binding would possibly play a major role in distribution of the registered substance, as the accumulation of alpha2-microglobulin in the kidney of male rats treated with a structurally-related substance appears to suggest. It is likely that the substance will be used as a source of energy, and subjected to β-oxidation like fatty acids, but beginning within peroxisomes because of the length of the side-chain. Conjugation of final products and/or simplest components is likely to occur, allowing excretion in urine. Given its lipophilic nature, accumulation of absorbed components in adipose tissue cannot be excluded, although there was no evidence of accumulation or of any adverse effects.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
2
Absorption rate - dermal (%):
2
Absorption rate - inhalation (%):
100

Additional information

Introduction

There are no experimental toxicokinetic studies available on the analogue substance (EC 271 -638 -7). Thus, physical-chemical properties and the results of in vitro studies and in vivo acute or repeat dose toxicity studies on the substance, or structurally-related substance(s), have been used to estimate a toxicokinetic profile.

Physicochemical properties

The analogue substance (EC 271 -638 -7) is an “Unknown or Variable Composition, Complex (UVCB) reaction product”. The carbon chain lengths are up to C60. The substance is obtained by first generating the ester by reacting the hydrocarbon waxes (petroleum), oxidized starting material (CAS # 64743-00-6) with methanol, and then salting with calcium. The reactions are conducted at ambient pressure and elevated temperatures of up to 130 °C for several hours. The resulting substance is a brown crystalline solid with a maximum acid number of 13. The final product is a brown crystalline solid, with an average molecular weight of 600 g/mol. It is poorly water soluble (1.287 mg/L at 25 °C) and the log Pow value for a structural analogue (Hydrocarbon waxes (petroleum), oxidized, CAS # 64743-00-6) is greater than 9.4 (the water solubility of CAS # 64743-00-6 is 1.248 mg/L would support the read across for the log Pow). The vapour pressure of the substance is <1 Pa at 25 °C.

Absorption

Oral absorption

The main physical chemical properties that influence absorption are molecular weight, water solubility and lipid solubility. The high molecular weight, high log Pow value, together with the low water solubility suggest very limited oral absorption. 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. Public available data (EFSA Scientific Report, 2008; IPCS WHO Food Additive Series No. 5 – Food-grade mineral oil, 1974) on the structurally-related substances mineral oils (paraffin oil, CAS # 64742-46-7, 72623-86-0 and 97862-82-3) indicate that these are biochemically inert chemical substances, especially the straight chain (n) alkanes, and on ingestion most of the mineral oil (98%) remains unabsorbed in the faeces. This is the reason why sources of mineral oil are laxative in pharmacy. Small amounts of mineral oil (2%) are absorbed by the intestinal mucosa and are distributed throughout the body. A very small fraction may undergo further biochemical transformation. This value was confirmed in in vivo studies using H3-labelled mineral oil. Europe (EFSA) accepted a value of 2% for mineral oil absorption in 2008.

A proportion of the substance comprises of oxidised hydrocarbon waxes and some are in turn methyl esterified. For comparison, methyl esters of physiological fatty acids, once ingested, are likely to be absorbed as readily as fatty acids (themselves often present in the diet as esters, e.g. triglycerides), and acyl fatty acids are readily hydrolysed both in the gut lumen and post absorption to the corresponding fatty acid and methanol (Krokan et al., 1993). There are indications that absorption of methyl esters is more rapid than the unesterified fatty acid (Renner, 1986). However, the proposed material is not similar to those derived from physiological acyl chain lengths because they are considerably larger, and often branched, and this relative inertness is borne out by Clarke, (2003), showing the material not to be readily biodegradable. Hence despite the methylation, this is considered unlikely to overcome the barriers posed to physiological processes posed by the overall physical chemical properties. Hence the absorption model of the paraffin oils is still relevant. This is also supported by the results of in vivo toxicological studies, using either the registered substance or a structurally-related substance (Distillates (petroleum), oxidized light, CAS # 64742-98-9). The acute oral LD50 for the registered substance was determined to be greater than 15 mL/kg bw and the repeat-dose NOAEL, determined for the structurally-related substance, was at the limit dose of 1000 mg/kg/day. No signs of systemic toxicity were observed in the acute oral (gavage) study, and observations in animals treated at 1000 mg/kg/day with the structurally-related substance were limited to salivation after dosing, commonly observable when an irritating substance is administered by gavage. There were no necropsy findings and no toxicologically significant changes in organ weights in the repeat-dose OECD 422 study, although histopathology detected changes in kidney (in males), thyroid and stomach, mainly adaptive in nature but offering evidence that some absorption had occurred. While the changes in the stomach (i.e., minimal acanthosis, occasionally associated with hyperkeratosis) were a portal-of-entry effect, once again indicative of adaptive changes related to administration of a highly concentrated epithelial irritant, those in kidney of males (i.e., globular accumulations of eosinophilic material in the tubular epithelium, consistent with accumulation of alpha2-microglobulin) and in the thyroid (i.e., minimal to slight follicular cell hypertrophy), accompanied by relative liver weight increase, indicated that part of the administered substance has been absorbed, distributed or transported within the body and had stimulated the liver for its metabolism.

For risk assessment purposes the worst-case oral absorption of the substance will be assumed to be 2% based on similarity to paraffin oil.

Dermal absorption

The physical state, high molecular weight, high log Pow value, together with the low water solubility indicate very low potential for dermal absorption. Similarly to mineral oils, deposition in the stratum corneum is expected to occur slowly; however, the substance is not sufficiently water soluble to partition from the stratum corneum into the epidermis.

As dermal absorption is not expected to be greater than oral absorption, and the estimate of 2% oral absorption is already a worst-case estimate, no dermal absorption of the registered substance is expected to occur.

However, as a precautionary approach the same rate of oral absorption (2%) will be used for dermal absorption in order to set dermal (systemic) DNELs.

Inhalation

The registered substance has low vapour pressure and is a crystalline 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

Distribution within the body is likely to be limited by the high molecular weight and low water solubility, however, the high log Pow value suggests a higher concentration inside the cells, especially those of fatty and adipose tissues, rather than in the extracellular compartment.

Data for food-grade mineral oil (IPCS WHO Food Additive Series No. 5 – Food-grade mineral oil, 1974) indicate that oil droplets, identified as saturated alkane hydrocarbons, have been demonstrated in mesenteric lymph nodes and nodes of the porta hepatis in man. Similar droplets have been identified in human liver, spleen and adipose tissue, consistent with the calculated intake from food use, but no known harm appears associated with these residues. Similar deposition of oil and minor absorption was demonstrated in rabbits, rats and guinea-pigs fed liquid petrolatum for 7 months or more. Histochemical evidence showed absorption to be proportionate to length of exposure. The mechanism of absorption was unknown but the absorbed particles showed evidence of foreign body reaction and phagocytic ingestion.

No similar findings were noted in the OECD 422 study performed with a structurally-related substance (Distillates (petroleum), oxidized light, CAS # 64742-98-9), however, the increased accumulation of alpha2-microglobulin in the kidney of male rats suggests that protein binding could have contributed to distribution within the body. The increased relative liver weight and consequent adaptive changes in the thyroid observed at 1000 mg/kg/day in the same OECD 422 study also support that the substance reached the liver, once there stimulating its own metabolism.

Metabolism

The material is not readily biodegradable (Clarke, 2003). Available data on the structurally-related substance mineral oil indicated that the biochemical transformation of paraffin may involve hydroxylation via cytochrome P450 mono-oxygenase to the respective alcohol and then further oxidation to carboxylic acids and CO2 or solubilisation by building a glucuronide. The registered substance consists of mono- and di-carboxylic acids, oxyacids, aldehydes and ketones that have been partially derivatised to form methyl ester calcium salts. It is likely that metabolism of largest components will be slow, involving β-oxidation of the side-chain, which will start within peroxisomes instead of mitochondria, because of the length of the side chain, and produce energy and hydrogen peroxide which would be used to oxidize other substances. It is expected that the terminal metabolites obtained either after the side chain has been metabolized or by metabolism of simplest components, can be conjugated and excreted.

Elimination

The high molecular weight and low water solubility suggest that main elimination of the almost unchanged substance will be via the faeces. Excretion of the limited absorbed amount will be again mainly in faeces via the bile, with urinary excretion limited to conjugates.

Conclusion

Physical-chemical properties and results of in vivo studies using very similar materials suggest that oral absorption of Hydrocarbon waxes (petroleum), oxidized, Me esters, calcium salts (CAS # 68603-11-2) will be extremely limited, and even more limited or absent following dermal exposure. For risk assessment purposes the substance will be assumed to be absorbed at 2% after oral and dermal exposure. 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 within the body would also be limited, mainly to the liver, fat, and kidney and adipose tissues. On the basis of similarity to mineral oil (paraffin oils), the substance could also reach the spleen, but the high molecular weight means distribution to the brain is unlikely, (in contrast to the mineral oils). Protein binding would possibly play a major role in distribution of the registered substance, as the accumulation of alpha2-microglobulin in the kidney of male rats treated with a structurally-related substance appears to suggest.

It is likely that the substance will be used as a source of energy, and subjected to β-oxidation like fatty acids, but beginning within peroxisomes because of the length of the side-chain. Conjugation of final products and/or simplest components is likely to occur, allowing excretion in urine.

Given its lipophilic nature, accumulation of absorbed components in adipose tissue cannot be excluded, although there was no evidence of accumulation or of any adverse effects.

References

EFSA (2008)

Conclusion on pesticide peer review regarding the risk assessment of the active substance paraffin oils (CAS 64742-46-7, 72623-86-0 and 97862-82-3).

EFSA Scientific Report (2008) 216, 1-59

Published

Anonymous ICPS (1974)

WHO Food Additive Series No. 5 – Food-grade mineral oil The International Programme on Chemical Safety (IPCS)

Published

Anonymous (1980)

Acute Oral Toxicity LD50 (Rats)

Unpublished

Dhinsa N.K., McKenzie J. & Brooks P.N. (2005)

Oral gavage combined repeat dose toxicity study with reproduction/developmental toxicity screening test in the rat Safepharm Laboratories Limited project No. 525/575.

GLP

Unpublished

Krokan, H. E., Bjerve, K. S., & Mørk, E. (1993)

The enteral bioavailability of eicosapentaenoic acid and docosahexaenoic acid is as good from ethyl esters as from glyceryl esters in spite of lower hydrolytic rates by pancreatic lipase in vitro.

Biochimica et Biophysica Acta (BBA)-Lipids and Lipid Metabolism,1168(1), 59-67.

Published

Renner, H. W. (1986)

The anticlastogenic potential of fatty acid methyl esters. Mutation Research/Genetic Toxicology, 172(3), 265-269.

Published

Sinha, V. R., & Kaur, M. P. (2000).

Permeation enhancers for transdermal drug delivery.

Drug development and industrial pharmacy, 26(11), 1131-1140.

Published

Clarke, N. (2003)

Assessment of Ready Biodegradability; Manometric Respirometry Test

Safepharm Laboratories Limited project No. 525/511.

GLP

Unpublished