3,7,11,15-tetramethylhexadecane-1,2,3-triol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

assessment of toxicokinetic behavior

Type of information:

other: In accordance with REACH Annex VIII (8.8) an assessment of toxicokinetic behavior has been conducted to the extent that can be derived from the relevant available information.

Adequacy of study:

key study

Study period:

The assessment was conducted in February 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Relevant studies were reviewed by a qualified toxicologist with a view to fulfilling the requirements of Annex VIII (8.8).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

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

GLP compliance:

no

Remarks:

Not relevant for assessment

Test material

Test material information

Constituent 1

Reference substance name:

3,7,11,15-tetramethylhexadecane-1,2,3-triol

EC Number:

277-923-2

EC Name:

3,7,11,15-tetramethylhexadecane-1,2,3-triol

Cas Number:

74563-64-7

Molecular formula:

C20H42O3

IUPAC Name:

3,7,11,15-tetramethylhexadecane-1,2,3-triol

Test material form:

liquid: viscous

Details on test material:

- Physical appearance: colourless viscous liquid
- Storage conditions: at room temperature

Specific details on test material used for the study:

Phytantriol is a colorless to light yellow, viscous liquid.

Results and discussion

Any other information on results incl. tables

Oral Bioavailability:

No oral bioavailability study with Phytantriol has been conducted. In a combined sub-acute toxicity and reproductive/developmental toxicity screening study in the rat (OECD 422) and its preceding dose-range finding study, systemic toxicity was observed at high doses.This indicates that Phytantriol is absorbed in the gastrointestinal tract.

Phytantriol was analyzed in plasma samples of rats from the dose range finding study. Phytantriol was administered by oral gavage to three male and female rats at doses of 500 and 1000 mg/kg bw/d. Phytantriol was detected in samples of males and females only at 6 h after a single administration but not after 1 and 3 h; this may be due to the high detection limit of the analytical method. After 15 days of daily administration, Phytantriol could be detected in 3 h blood samples in a dose-dependent way. These data indicate that Phytantriol has a tmax of > 3h and may accumulate over repeated administration.

Phytantriol was analyzed in plasma samples of rats from the repeated dose toxicity study with developmental / reproductive screen. Phytantriol was administered by oral gavage to male and female rats at doses of 50, 150, and 500 mg/kg bw/d. Plasma was taken and analyzed on day14 at 6 h after administration. Phytantriol was detected in samples of all dose groups in dose-dependent concentrations. Average plasma levels (n = 5) are given in the table below:

F0-animals: At 6 hours post-dose on Day 14. Values are in ng/mL:

 

Group	Males	Females
1 (vehicle control)	<LLOQ1	<LLOQ
2 (50 mg/kg/day)	1958 ± 271	1699 ± 536
3 (150 mg/kg/day)	4371 ± 1926	3544 ± 1291
4 (500 mg/kg/day)	6700 ± 1675	5966 ± 2151

1: LLOQ was 200 ng/ml

Phytantriol was also detected in pups after birth. It has not been elucidated if the pups received the Phytantriol via the placenta during gestation or via milk during weaning.

Phytantriol is bioavailable after oral exposure. It has a tmax > 3h, accumulates in the body and can be found in plasma in a dose-dependent concentration.

Dermal Penetration:

Csato et al.(1997) has determined the dermal penetration of Phytantriol in three different formulations using pig skin. Ethanol, polyethylene glycol (PEG 400), and paraffin oil containing 0.5% Phytantriol were used. Phytantriol was labeled with ³H. The penetration of each formulation into the skin was evaluated at 1, 6, and 18h. Ro 04-3724/000 penetrated into the horny layer and living layers of the skin from each tested formulation. The highest penetration values in the stratum corneum and in the living skin tissue were detected when Phytantriol was dissolved in ethanol. Paraffin oil and PEG 400 provided for lower skin penetration of the test compound. Virtually no penetration of the test article through the skin layers into chamber fluid was detected from all the 3 tested formulations in this experiment. Detailed data are given in Table 1.

In conclusion, the experimental data of this study show that Phytantriol penetrates into the intact pig skin, the horny layer in particular and also into epidermis/dermis. The 0.5% ethanolic solution of the test compound provides for higher skin penetration as opposed to the same strength formulations prepared in paraffin oil or polyethylene glycol. The penetration of the test article through the pig skin from the 3 tested formulations maximum 5.5%.

Table 1: Dermal penetration of Phytantriol through pig skin (Csato 1997)

 

(in EtOH)	1h	6h	18h
Remaining on surface	55%	59%	44%
Stratum corneum	21%	20%	34%
Epidermis and Dermis	3.6%	3.3%	5.4%
Chamber fluid	0.0%	0.0%	0.1%
(in PEG)	1h	6h	18h
Remaining on surface	94%	77%	77%
Stratum corneum	4.8%	12%	14%
Epidermis and Dermis	0.5%	2.0%	2.3%
Chamber fluid	0.0%	0.0%	0.0%
(in Paraffin oil)	1h	6h	18h
Remaining on surface	84%	81%	59%
Stratum corneum	7.4%	8.9%	8.1%
Epidermis and Dermis	1.5%	1.1%	1.0%
Chamber fluid	0.0%	0.0%	0.0%

Metabolism:

Metabolism of Phytantriol in humans was assessed using Lhasa Meteor Nexus software (Meteor version 3.0.0).

Most probable metabolism would be the oxidation of the primary or secondary alcohol to the respective carboxylic acid or ketone. Also, double oxidation of both, the primary and secondary alcohol, resulting in the formation of the α-keto β-hydroxy acid is predicted. The carboxylic acid and also the α-keto acid can then be conjugated with glucuronic acid or sulfate.

Another plausible metabolism pathway starts with the hydroxylation of a terminal primary methyl group of the phytol chain followed by its oxidation to the carboxylic acid and conjugation with glucuronic acid or sulfate.

Also a combination of both metabolism steps, hydroxylation of terminal methyl and oxidation of primary and secondary alcohols could possibly occur.

At the bottom line, metabolism of Phytantriol will lead to substances that are of higher water solubility than Phytantriol itself, which facilitates its excretion.

Applicant's summary and conclusion

Conclusions:

Phytantriol is bioavailable after oral exposure. It has a tmax > 3h, accumulates in the body and can be found in plasma in a dose-dependent concentration.
Experimental data of this study show that Phytantriol penetrates into the intact pig skin. The penetration of the test article through the pig skin from the 3 tested formulations maximum 5.5%.
Metabolism of Phytantriol will lead to substances that are of higher water solubility than Phytantriol itself, which facilitates its excretion.