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Description of key information

In accordance with REACH Annex VIII, Section 8.8, an assessment of the toxicokinetic behaviour of the substance has been conducted to the extent that can be derived from the available information.

Toxicological Information

Acute toxicity: In an acute oral toxicity study conducted in accordance with OECD TG 420, with exception of hunched posture in all animals, there were no significant sings of systemic toxicity, clinical signs or abnormal necropsy observed when tested up to 2,000 mg/kg bw.

Local Toxicity:  Although not corrosive the substance is considered a Skin Irrit. 2 (H315 – Causes skin irritation) and non-irritant to the eye following in vitro studies conducted in accordance with OECD 431, OECD 439, and OECD 437. The test item was a skin sensitiser, (skin sensitiser. Category 1B) in accordance with Regulation (EC) No 1272/2008 (CLP) following an OECD 429 study. No mortality was reported and no local effects observed, signs of systemic toxicity or abnormal observation at necropsy was reported following the LLNA study.

Repeated dose toxicity: A sub-acute repeated dose toxicity study with combined reproductive and developmental screening (OECD 422) conducted on the source substance is available.  n-Undecanal was administered to 30 male and 30 female Crl:WI(Han) strain rats by oral gavage at dose levels of 100, 300 and 1000 ppm for up to 7 weeks. In addition, 10 male and 20 female control rats were treated with the formulation vehicle, without test item.

The key findings in this study were. Statistically significant variations in clinical biochemistry parameters were higher or lower alkaline phosphatase activity (ALP) in males and females at 300 mg/kg/day, lower total bilirubin level in males at 300 mg/kg/day, higher urea level in males at 300 mg/kg/day, higher cholesterol level in males at 300 and 1000 mg/kg/day, and lower urea level in females at 1000 mg/kg/day. Higher liver weight and liver to body weight ratio, and lower prostate and prostate to body weight ratio for males at 1000 mg/kg/day was not supported by any histopathological changes.

Histopathological changes; Histopathological changes were confined to the stomach, and consisted of Iymphogranulocytic inflammation and hyperplasia of the squamous epithelium of the forestomach in both sexes at 100, 300 and 1000 mg/kg/day, and ulcer formation in the forestomach in three males at 300 mg/kg/day (correlating to red/black foci in the forestomach of two males) and in one male at 1000 mg/kg/day. Hyperplasia of the squamous epithelium was the microscopic correlate to the irregular surface and yellowish discolouration of the forestomach recorded at necropsy at 300 and 1000 mg/kg/day. Congestion of the glandular stomach (correlating to red discolouration of of the glandular mucosa) was observed in two males at 1000 mg/kg/day. There was no microscopic correlate to thickening of the glandular mucosa recorded in three females at 1000 mg/kg/day.

Based on these considerations, a No Observed Adverse Effect Level (NOAEL) for systemic toxicity was therefore concluded to be 1000 mg/kg bw/day (no hazard identified). A No Observed Adverse Effect Level (NOAEL) for local toxicity could not be determined due to histopathological changes in the stomach of animals in all treatment groups.

Absorption

The molecular weight of the test is low i.e. < 200 g/mol, it’s n-octanol/water partition coefficient is 4.5, its water solubility is 16 mg/L, CMC of 50 -150 mg/L and vapour pressure of 25 Pa with surface tension of 41.05 mN/m. These physiochemical properties are suggestive of absorption via all routes.

Based on the molecular weight of the test item, oral uptake from the gastro-intestinal tract is mainly via passive diffusion to into portal circulation with delivery into the liver resulting into first pass metabolism which would reduce the amount of the parent compound in the systemic circulation.  Furthermore, being surface active and an irritant, gastrointestinal membrane penetration will be enhanced and therefore uptake will be favourable following oral exposure. This is supported by the microscopic changes in the forestomach, which included Iymphogranulocytic inflammation, hyperplasia of the squamous epithelium of the forestomach and ulcer formation in the forestomach following sub-acute exposure in all dose groups.

The substance is of low molecular weight and surface active, and is therefore likely to cause adverse reactions to the skin, as supported by the classification as Skin Irrit. 2. Dermal irritation would cause damage that would enhance penetration through the skin, however, transfer between the stratum corneum and the epidermis is low and therefore overall systemic bioavailability of the substance compared to oral exposure.  This further supported by the lack of adverse systemic effect following in vivo skin sensitisation study.

Having high vapour pressure coupled with low molecular weight and surface activity, passive diffusion of the test item into systemic circulation into the heart is expected and subsequently systemic bioavailability via inhalation route is higher compare to other routes of exposure.

Distribution

The substance has physicochemical properties that mean systemic bioavailability is possible, based on the molecular weight, n-octanol/water partition coefficient and the solubility and as such, a widely systemic distribution is expected.  However, since passive diffusion of the substance into portal circulation to the liver is expected, plasma concentration and plasma half-life of the parent compound in blood plasma is expected to be low.  Distribution following dermal absorption is not expected as the absorbed portion of the test item cannot be transferred between the stratum corneum and the epidermis. A wide distribution of the substance via inhalation is expected as it can easily be taken up into circulatory system. Furthermore, it also means that plasma half-life of the parent compound is higher via this route of exposure as compare to oral route.

Metabolism

The substance is expected to undergo rapid transformation through the liver via phase I and II enzymes, i.e. oxidation parent compound by the aldehyde dehydrogenase into carboxylic acid and alcohol derivatives which are further conjugated by Phase II enzymes in to more polar derivatives which would be eliminated via urine and bile. This is supported by the changes observed during the sub-acute exposure such as increase liver weight and increase biochemical parameters such as high level of alkaline phosphatase activity (ALP) and low level of bilirubin in subacute exposure in rats.

Excretion

Based on the molecular structure and surface activity, excretion into urine and bile as conjugated metabolites is assumed to be a preferred route of elimination.  These physiochemical properties of the substance mean uptake following exposure is enhanced resulting into rapid metabolism especially via oral route.  As a result, elimination is assumed to be rapid, therefore no potential for bioaccumulation is to be expected to be low. This is supported by the lack of systemic and clinical signed observed in the in vivo sensitisation as well as the repeat dose toxicity study. Elimination following inhalation exposure is expected to be slightly slower than elimination via oral route since the plasma concentration and plasma half-life of the parent compound is high. Nonetheless, systemic bioaccumulation following exposure via inhalation is not expected based on the physiochemical properties of the test item.

Conclusion

The substance has physico-chemical properties which lead to favourable absorption, distribution, metabolism and elimination (ADME). Exposure from all routes is expected and a wide distribution especially via inhalation exposure. Oral uptake is the most favourable route of uptake, this is based on the molecular weight of the test item which encourages weight passive diffusion into portal circulation to the liver where rapid metabolism will occur ensuring low plasma concentration and plasma half-life of the parent compound in the blood.  Whilst microscopic changes observed in the forestomach during sub-acute repeated dose toxicity study may be considered to be adverse clinical signs, in this instance they are considered to be a result of local irritation of the test item rather than a true effect of systemic toxicity. Although dermal exposure is expected, systemic bioavailability is expected to be low

The lack of systemic and local toxicity observed following in vivo sensitisation study shows that systemic bioavailability of this substance is limited via dermal exposure.  Although elimination via inhalation exposure is expected to be slower than oral absorption due to high plasma concentration and plasma half-life, the systemic bioaccumulation following exposure via inhalation is not expected based on the physicochemical and fate properties of the test item. Overall, the clinical signs observed following oral sub-acute exposure support oral absorption of the teste item and clinical signs reported in liver are demonstrative of distribution, biotransformation and elimination of the test item. It can be concluded that the toxicokinetic of the test item does not pose significant toxicological concern.

Key value for chemical safety assessment

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

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