Ceraphyl 55

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert statement based on available experimental work , QSAR and physical/chemical properties.

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Evaluation based on reliable experiments and internationally accepted QSAR tools.

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Not applicable.

GLP compliance:

no

Remarks:

Not applicable.

Test material

Test material information

Constituent 1

Details on test material:

Not applicable

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

ORAL ROUTE
In the 28-day repeat dose oral toxicity study in rats at 1000 mg/kg, no treatment-related changes in male and females rats were observed except for some effects noted in a several parameters concerning hematology, clinical chemistry and organ/body weight. Hence, this indicated that, if any, only minor absorption had occurred.
In order for a substance to be absorbed it must cross biological membranes. Most substances cross by passive
diffusion. This process requires that a substance be soluble in both lipid and water. In general, moderate Log P
values (between 0-4) are favorable for absorption. Ceraphyl 55 possesses a high Log P value (range of 4.0-8.6) and
a very low water solubility, which will evidently limit passive diffusion. Checking with the Lipinsky rule of five, Ceraphyl 55 agrees with the conditions of a molecular mass less than 500 daltons, less than 5 hydrogen bond donors (none) and less than 10 hydrogen bond acceptors (2 0xygen atoms), but its log P > 5. Further, it has more than 10 rotable bonds (12).
The absorption of highly lipophilic substances (Log P of >4) in the gastrointestinal tract can be hampered by the
inability of such substances to dissolve into the gastrointestinal fluids and make contact with the mucosal surface. Such substances may undergo micellular solubilisation in the presence of bile salts, which may enhance their absorption. Although enzymatic hydrolysis may take place in the intestine due to pancreatic fluids, it is expected that Ceraphyl 55 will largely remain unchanged and not absorbed.
To estimate the quantitative absorption of Ceraphyl 55 as function of pivalic acid, one of its metabolites, the individual NOELs for repeated oral exposure can be compared. The respective NOEL of Ceraphyl 55 is 1000 mg/kg/d, whereas the 28-day NOEL of pivalic acid is 30 mg/kg/d. Based on molecular weights, this means that at least less than 8% of Ceraphyl 55 may be absorbed and/or metabolized. Higher amounts would have resulted in similar effects as seen at 30 mg/kg/d for pivalic acid, at Ceraphyl 55 dosages of 1000 mg/kg/d or lower. The actual relative amount of Ceraphyl 55 that is metabolized and/or absorbed is probably much lower than 8%, as no single adverse histopathological finding was reported in the 28-day study.

INHALATION
Due to the nature and the use of this substance it is unlikely that there will be significant aerosol formation
and thus inhalation should not be a significant route of exposure. Further, molecules with longer carbon chains are less likely to be absorbed by inhalation.

DERMAL
For a chemical to be readily absorbed by the skin, it has to pass the lipophilic stratum corneum to reach the viable epidermis. For this it requires a low molecular mass (<500 Da), adequate solubility in oil, and a moderately high partition coefficient (Log Pow>4). Ceraphyl 55 has a molecular mass of 285 Da and a relatively high lipophilicity with a Log Pow>4. Therefore, it is expected to pass the stratum corneum relatively easy. However, the rate of transfer between the stratum corneum and the epidermis might well be limited due to the same hydrophobic property and the relatively long and branched carbon chains (C13).
A low potential for dermal absorption or metabolism of Ceraphyl 55 is suggested by the results of an acute dermal test on five male and five New Zealand White rabbits (MB Research Laboratories, 2004). No mortality occurred after exposing the rabbits to a semi-occlusive dorsal application corresponding with a dose of 2000 mg/kg. The body weight values were in the normal range and the necropsy did not reveal any abnormalities. The result of the study showed that the acute dermal toxicity LD50 of Ceraphyl 55 was >2000 mg/kg.
Examination of local skin effects showed no evidence of potential for irritation, but skin sensitization was observed in three of the four studies reported in this dossier. Positive sensitization was observed in local lymph node assays (LLNAs) after applications of ≥ 25% Ceraphyl 55 in an acetone/olive oil mixture. Although only limited absorption is required for inducing sensitization, the chemical must gain access to the viable epidermis in order to elicit a cutaneous immune response. Hence, the fact that Ceraphyl 55 is a potential sensitizer at relatively high concentrations supports that under these conditions only a relatively small fraction is able to reach the viable epidermis and probably to be absorbed there. In addition, it may well be possible that the sensitization is induced by an impurity instead of Ceraphyl 55 itself, which could be the reason that relatively high concentrations were needed.
Spontaneous hydrolysis of Ceraphyl 55, before dermal adsorption occurs, is not very likely due to the fact that esters of pivalic acid are relatively resistant to hydrolysis. This is confirmed by the fact that topical exposure to Ceraphyl 55 does not induce irritation in contrast to pivalic acid which can induce serious irritation of the skin.

Details on distribution in tissues:

Since under normal conditions, no significant uptake or absorption is expected through either of the three routes (dermal, respiratory or oral), evaluation of possible distribution of Ceraphyl 55 and/or its metabolites is of little relevance.

Details on excretion:

None of the three possible routes show significant uptake or absorption of Ceraphyl 55. In case of oral uptake, Ceraphyl 55 is expected to be almost completely excreted unchanged via the feces.

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

As stated in previous sections, metabolism of Ceraphyl 55 is thought to be only relevant after oral uptake. However, based on the 28-day repeat-dose oral toxicity, there was no toxic evidence of absorption or metabolism.
Due to its hydrophobic character, Ceraphyl 55 will probably form micelles in the gastro-intestinal environment. Digestion of similar hydrophobic substances is greatly aided by emulsification, i.e. the breaking up of fat globules into much smaller emulsion droplets. Bile salts and phospholipids are amphipathic molecules that are present in the bile. Motility in the small intestine breaks fat globules apart into small droplets that are coated with bile salts and phospholipids, which prevent the emulsion droplets from re-associating.
Fatty acid esters are generally hydrolyzed by a bile salt-dependent pancreatic carboxyl esterase, releasing the long chain alcohols that are absorbed in the gastrointestinal tract. Studies of fatty alcohol metabolism in fibroblasts suggest that primary alcohols are metabolized by alcohol dehydrogenase to corresponding aldehydes and then by aldehyde dehydrogenase to acids. Higher alcohols are not bound by proteins and administration of other alcohols may affect metabolism. Ceraphyl 55, an odd-numbered pivaloyl ester, is very stable and resistant toward enzymatic and chemical hydrolysis, and thus, release of hydrolysis products is expected to be very limited.
Ceraphyl 55 consists of a C13-rich alcohol (methyl-branched) with a total range of C11 to C14 fatty alcohols. In contrast to even-numbered fatty acids, odd-numbered fatty acids tend to accumulate mainly in epididymal fat and might not be favorable substrates for beta-oxidation-related enzymes. Branched fatty alcohols pose another problem for basic fatty acids metabolism as beta-oxidation may be significantly hindered by the presence of the methyl-branches.
Experimental work shows that Ceraphyl 55 degrades very slowly in systems holding microbial populations originating from activated sludge.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
The evaluation of the toxicokinetics of Ceraphyl 55 shows that based on its physicochemical properties, exposure to Ceraphyl 55 through inhalation is very unlikely, and absorption via the dermal route is rather limited. Also no significant absorption of Ceraphyl 55 is expected after oral uptake. Hence, the major part of Ceraphyl 55 is expected to be excreted without being absorbed or being metabolized.
Finally, these conclusions support the low potential for bioconcentration or generation of metabolites of Ceraphyl 55 regardless the route of administration.