3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl nicotinate

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1 April 1996 - 30 April 1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study was conducted under GLP and according to the Personal Care Products Council (formerly CTFA) Guideline for Evaluating Photodermatitis.

Qualifier:

according to guideline

Guideline:

other: CTFA Guideline for Evaluating Photodermatitis (Photoallergenicity)

Deviations:

no

Principles of method if other than guideline:

Not relevant

GLP compliance:

yes (incl. QA statement)

Type of study:

other: Photoallergenicity test

Justification for non-LLNA method:

This in vivo skin sensitisation study was carried out before 11 October 2016, and meets the requirements set out in Article 13(3), first subparagraph, and Article 13(4) and is shall thus be considered appropriate to address this standard information requirement.

Specific details on test material used for the study:

- Name of test material (as cited in study report): dl-Alpha-Tocopheryl Acetate
- Physical state: Liquid
- Stability under test conditions: Unknown in ethanol, but stable under storage conditions
- Storage condition of test material: In the original container, at room temperature under nitrogen or argon atmosphere, protected from light

Species:

guinea pig

Strain:

other: Himalayan spotted (GOHI SPF-quality)

Sex:

female

Route:

intradermal and epicutaneous

Vehicle:

other: ethanol

Concentration / amount:

Induction: 100% (undiluted)
Challenge: 100% (undiluted), 75%, 50%, and 25%

Route:

epicutaneous, open

Vehicle:

other: ethanol

Concentration / amount:

Induction: 100% (undiluted)
Challenge: 100% (undiluted), 75%, 50%, and 25%

No. of animals per dose:

Control group: 10, test group: 20

Reading:

other: SI

Remarks on result:

other: not relevant

Reading:

other: disintegrations per minute (DPM)

Remarks on result:

other: not relevant

Induction:

After intradermal induction erythema, oedema, necrotizing dermatitis and exfoliation of encrustation were observed.

After epidermal induction no positive skin reactions were observed.

Challenge:

After challenge two out of 20 animals were observed with a slight erythematous skin reaction after challenge. No consistent or significant differences were detected between the radiated and irradiated test sites of animals. See table below for the results.

No spontaneous deaths occurred, no symptoms of systemic toxicity were observed and the body weight was within the normal range of variability.

Erythema reactions after challenge
	Concentration (%)	Left flank (UV-A irradiated)			Right flank (non-irradiated)
		% with positive reaction			% with positive reaction
		24 hrs	48 hrs	72 hrs	24 hrs	48 hrs	72 hrs
Test group (dl-alpha-tocopheryl acetate, n=20)	100	0	0	0	5	5	5
	75	5	5	10	10	10	10
	50	5	5	10	5	5	5
	25	0	0	0	0	0	0
Control group (n=10)	100	0	0	0	0	0	0
	75	0	0	0	0	0	0
	50	0	0	0	0	0	0
	25	0	0	0	0	0	0

In only 10% (2 out of 20) test animal slight erythematous skin reactions were observed after challenge. Those reactions were not clearly dependent on the test article concentration and most likely resulted from cutaneous hyperirritability (angry back) of the animals.

Interpretation of results:

other: Not photoallergenic

Conclusions:

Since no consistent or significant differences were seen between the irradiated and non-irradiated test sites of the animals, it can be concluded that dl-Alpha-Tocopheryl Acetate does not exhibit photoallergenic potential in the guinea pig under the study conditions.

Executive summary:

In order to assess the photoallergenic potential ofdl-Alpha-Tocopheryl Acetate, a photoallergenicity test according to the CTFA Safety Testing Guidelines was carried out in 30 female (20 test and 10 control) Himalayan spotted guinea pigs.

For the induction of sensitization the undiluteddl-Alpha-Tocopheryl Acetatewas applied epicutaneously to a skin area of 8 cm2 (marked previously with 4 intradermal injections of Freund’s Complete Adjuvant). The test sites were then exposed to 1.8 J/cm2 UVB and 10 J/cm2 UVA irradiation. This procedure was repeated 4 times within 2 weeks of the induction phase. Control animals were treated with FCA only. Three weeks after beginning of the induction a challenge was carried out by treating the experimental animals (test and control) epicutaneously on both flanks with the test article at the concentrations of 100% (undiluted), 75%, 50% and 25% (dilutions in ethanol). Treated sites were then either exposed to 10 J/cm UVA irradiation (left flank) or remained unirradiated (right flank). Cutaneous reactions, i.e. erythema and oedema formation were evaluated at 24, 48 and 72 hrs after the challenge exposure.

Two out of 20 test animals were observed with a slight erythematous skin reaction after challenge. No consistent or significant differences were detected between the irradiated and non-irradiated test sites of the animals The reactions were not clearly denendent on the test article concentration and most likely resulted from cutaneous hyperirritability (angry back) of the animals. No reactions were observed in the control group.

Considering the above experimental data it can be concluded thatdl-Alpha-Tocopheryl Acetatedoes not exhibit photoallergenic potential in the guinea pig under the study conditions. It can be assumed accordingly that the risk thatdl-Alpha-Tocopheryl Acetatecould elicit a cutaneous photoallergenic reaction in humans is low if any.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

The primary function of Tocopherol is to retard cellular lipid oxidation (Tsallas, Molgat, and Jeejeebhoy 1986). Tocopherol interdigitates with phospholipids, cholesterol, and triglycerides in the membranous parts of cells (Vanderveen and Vanderveen 1990). Tocopherol is the major lipid-soluble chain-breaking antioxidant of membranes (Kagan et al. 1992), and it is an important cellular protectant against oxidative damage (Liebler et al., 1996). It exerts antioxidant effects by trapping peroxyl radicals.(International Journal of Toxicology, 21(Suppl. 3): 51-116, 2002)

Dermal uptake of these Vitamin E forms in humans is considered to be low due to the experimental low dermal toxicity, the low water solubility, the high molecular weight (>100), the log Pow value and the fact that the substance is not irritating to skin.

In an in vitro skin absorption test (similar to OECD 428, non-GLP), it is concluded that D,L-alpha-tocopheryl acetate-3H penetrates into and through intact and stripped pig skin (Csato and Klecak, 1995). Tocopheryl acetate was substantially absorbed in the skin, but systemic availability was not observed. Also, conversion to tocopherol was not seen. In a study using rats, approximately 6% of the applied dose penetrated into the epidermis after 5 days. Most studies found that some tocopheryl acetate was converted to tocopherol. It is ecpected thatTocopheryl nicotinate esters will penetrate into epidermis not more than the corresponding acetate ester. F

rom this experiment, the dermal absorption rate of D,L-alpha-tocopherol in humans is therefore estimated to be 5%.

Tocopherol and tocopheryl acetate were not irritants or sensitizers in clinical studies. A very small percentage of patients patch-tested by the North American Contact Dermatitis Group reacted to tocopherol. Tocopheryl nicotinate was not an irritant or a sensitizer. Case reports exist for tocopherol- and tocopheryl acetate-containing products.(Cosmetic Ingredient Review, Re-Review Panel for Panel Review, 2013)

 

Tocopheryl acetate is used as an alternative to tocopherol itself because the phenolic hydroxyl group is blocked, providing a less acidic product with a longer shelf life. It is believed that the acetate is slowly hydrolyzed after it is absorbed into the skin, regenerating tocopherol and providing protection against the sun's ultraviolet rays.

 

However, Tocopheryl Acetate was not sensitizing in the guinea pig maximization test. (International Journal of Toxicology, 21(Suppl. 3): 51-116, 2002)

Therefore it is concluded that the corresponding ester, Tocopheryl nicotinate ester is also not sensitizing.