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Description of key information

Physical-chemical properties and results of in vivo studies using very similar materials suggest that oral absorption of Hydrocarbon waxes (petroleum), oxidized (CAS # 64743-00-6) 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 be also 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 Hydrocarbon waxes (petroleum), oxidized (CAS # 64743-00-6). 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 substance ‘Hydrocarbon waxes (petroleum), oxidized’ (CAS # 64743-00-6) is an “Unknown or Variable Composition, Complex (UVCB) reaction product”. The substance is obtained by the oxidation with atmospheric air of petroleum-derived hydrocarbon waxes consisting of carbon chain lengths predominantly greater than C20. The reaction product includes mono- and dicarboxylic acids, oxyacids, aldehydes, and ketone derivatives of the hydrocarbon waxes. The final product is a yellow to brown solid or waxy solid, with an average molecular weight of 744 g/mol. It is poorly water soluble (1.248 mg/L at 25 °C) with a log Pow value greater than 9.4. The vapour pressure of the substance is < 1 Pa at 25 ºC.

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.

Minimal oral absorption appears to be even more applicable to the registered substance, which is a waxy solid instead of a liquid, and this is 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 5000 mg/kg 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 (dietary) 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 cannot 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, just for risk assessment purposes the same rate of oral absorption (2%) with be used for dermal absorption in order to set dermal (systemic) DNELs.

Inhalation absorption

The registered substance has low vapour pressure and therefore is unlikely to be available for inhalation as a vapour. The low water solubility and high molecular weight and log Pow value suggest a limited absorption after inhalation. If any amount of the substance reaches the alveoli, this will be likely phagocytised by macrophages, located into the immune surveillance tissues and broken down in lysososmes and peroxisomes.

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 appears 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 the structurally-related substance 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, there stimulating its own metabolism.

Metabolism

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. 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 (CAS # 64743-00-6) 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 be also 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

Gabriel D. (1993)

Acute Oral Toxicity, Single Level – Rats [ENV930201 (Batch #57725)]

Biosearch Incorporated project No. 93-7752A

GLP

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