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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
September 1994
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Remarks:
The study was not conducted in accordance with any regulatory guideline nor was it conducted in accordance with GLP. In addition the number of patients forming the investigation totalled just 6 and there were no formal controls for comparison. Similarly, confounding factors such as the exposure to measured amounts of the defined sunscreen products was not controlled. However, the information is well documented and scientifically acceptable.
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Reference:
Composition 1
Objective of study:
distribution
Qualifier:
no guideline followed
Principles of method if other than guideline:
It was the objective of the study to examine the potential of various sunscreen agents, including isopentyl p-methoxycinnamate and the read-across substance (2-ethylhexyl 4-methoxycinnamate, to be dermally absorbed and to appear in the breast milk of humans.
GLP compliance:
no
Test material information:
Composition 1
Species:
human
Strain:
not specified
Sex:
female
Details on test animals and environmental conditions:
Of the six female participants, two were from city locations, two from small town locations and two from village locations. The age range was from 27 to 34 years.
Route of administration:
dermal
Vehicle:
not specified
Duration and frequency of treatment / exposure:
One female did not use the UV filter products at all and acted as control. One female used the UV filter products daily and the remaining four individuals used the UV filter products once or twice per week throughout the summer 1994.
Remarks:
Doses / Concentrations:
The exact quantities of UV filter product applied were not established.
No. of animals per sex per dose:
A total of 6 individuals were investigated
Control animals:
yes, concurrent no treatment
Positive control:
Not included
Details on study design:
Only six individuals were included in this assessment and, whilst one individual appeared to act as a negative control, the conditions were not necessarily similar for all six individuals.
Details on dosing and sampling:
It is unclear from the reference as to the level of exposure of each individual to the UV filter substances under investigation. One or more of the substances under test could be present in the UV screen formulation being used and there was no direct measure of the amounts of screening product being used by any of the inviduals. Details of the concentratins of the individual substances within the formulations were also not given.
Statistics:
No statistical analysis was applied
Details on absorption:
No details of abosrption of the identified substances were evaluated.
Details on distribution in tissues:
The distribution of substances incorporated in the UV filter formulations was investigated by the examination of breast milk samples from each individual.
Details on excretion:
No investigations on excretion were undertaken.
Metabolites identified:
not measured
Conclusions:
Isopentyl p-methoxycinnamate was not detected in any of the breast milk samples despite being identified as an ingredient in the sunscreen formulations under test. The rlated substance, 2-ethylyhexyl 4-methoxycinnamate was detected in 2 of the four breast mik samples. It is difficult to make conclusions based upon this small data set and lack of exposure data, however, it is possible that the data is indicative of either lack of dermal absorption of isopentyl p-methoxycinnamate or absorption is sufficiently low that potential levels in tissues (such as breast milk) are undetectable.
Executive summary:

Human breast milk samples were taken from six women and examined for the presence of sunscreen agents Homosalate (HMS), Isopentyl p-methoxycinnamate (IMZ), Benzophenone-3 (BP-3), Methylbenzylidenecamphor (MBC), Octyl Dimethyl PABA (DABI) and 2 -ethylhexyl 4- methoxycinnamate (OMZ). It has been reported that up to 2% of the applied substances can be absorbed via the skin according to manufacturers information. Glass-columns filled with differently acitvated silica gel were used for the extraction of each of the 10 ml milk sampIes. The extracts were cleaned by gel permeation chromatography, afterwards reduced to a volume of 150 [ll and quantitatively analysed by Capillary Gaschromatography/ Mass Spectrometry in the SIM-mode. BP-3 and 2 -ethylhexyl 4 -methoxycinnamate were unambiguously detectable in five of the six investigated samples at a concentration range between 16 and 417 ng/g (fat basis). However, isopentyl p-methoxycinnamate was not detected in any of the samples. This information would add some support to the dermal absorption study in humans in which it was concluded that dermal absorption of isopentyl p-methoxycinnamate did not occur.

Description of key information

Three dermal absorption/penetration studies with isopentyl p-methoxycinnamate were performed on pigs (ex vivo), rats (in vivo) and humans and information from a reference by Hany and Nagel (1995) on the potential for the appearance of isopentyl p-methoxycinnamate and other sunscreen agents, including the read-across substance 2-ethylhexyl 4-methoxycinnamate, in human breast milk was evaluated.

Key value for chemical safety assessment

Additional information

The toxicokinetics of isopentyl p-methoxycinnamate was primarily studied in 3 dermal absorption/penetration studies in pigs (ex vivo), rats (in vivo), and humans (all classified as Klimisch 2 studies). These studies provided information on the potential absorption of Isopentyl p-methoxycinnamate. In addition, Hany and Nagel (1995) published an analytical study (Klimisch 3) on the determination of various sunscreen agents, including isopentyl p-methoxycinnamate and the read-across substance (2 -ethylhexyl 4 -methoxycinnamate) in breast milk (see the attached pdf file). No data was available on the metabolism of isopentyl p-methoxycinnamate, however, some excretion data was presented as part of the rat dermal absorption study:

Human:

[14C]-radiolabelled test substance was applied at 0.157 and 0.164 mg/cm2on the skin of male and female volunteers. Using strip methodology, more than 50% of the administered radioactivity was recovered in the first two strips. A mean of 88.5-94.3% of the administered amount of radioactivity was recovered in the 20 strips, the predominant amount of the radioactivity was therefore detected on or in the epidermis. In the upper layers of the epidermis more radioactivity was found than in the lower layers and 0.5% of the applied radioactivity was still detected in the last strip. These results suggested that isopentyl p-methoxycinnamate did not significantly penetrate into the skin of human volunteers from two different formulations (there were no significant differences between the two formulations used - oil in water and water in oil).

Rats (in vivo):

18-23 mg of the [14C]-radiolabelled test substance was applied to the skin of male and female Sprague-Dawley rats. Absorption increased with time, with the radioactivity in and on the treated area of the skin decreasing with the duration of the percutaneous application. The absorbed amount of [14C]-labelled test substance was excreted mainly via urine with the amount of 14C remaining in the carcass and various organs being rather low (0.01 - 1.5%) at the different times after application, indicating that the absorbed amount was excreted rapidly.

Pigs (ex vivo):

The dermal absorption / penetration of isopentyl p-methoxycinnamate in oil/water and water/oil lotions were determined in an ex vivo / in vitro-model (using excised porcine back skin) at 3, 6, 16, and 24 h after topical application to the skin samples. Based on the results obtained from this skin penetration study using especially prepared back skin samples from female pigs, it can be concluded that the test substance showed dermal penetration and permeation up to 37% or 58% after 24 h in oil/water-lotion and water/oil-lotion respectively, whereas no absorption of the test substance occurred which could result in the test substance being available in systemic circulation.

In summary, isopentyl p-methoxy showed penetration/permeation up to 58% 24 h post application, but no absorption was recorded in the ex vivo pig skin model. In rats, the radiolabeled substance was absorbed through the skin up to 11.2% 24h post application and distributed in many organs before excretion via urine. However, the human study showed no significant penetration into the skin of human volunteers. The distribution study in humans (Hany and Nagel, 1995) is worthy of mention as, although it is an unreliable (Klimisch 3) study due to the small group size (6), it confirms the lack of distribution into breast milk of isopentyl p-methoxycinnamate following dermal application,in comparison with two other sunscreen agents,benzophennone-3 and the read-across substance, 2 -ethylhexyl 4 -methoxycinnamate, which were detected in 4 and 2 of the samples respectively.

When comparing the information from these studies with the opinion on "Basic Criteria for the in vitro Assessment of Dermal Absorption of Cosmetic Ingredients" (SCCP March 2006) it is concluded that the study in pigs complies most directly with the recommendations. Results from this study demonstrate skin penetration following application of isopentyl p-methoxycinnamate to the skin preparations without any "penetrated substances" being detected in the receptor fluid. Therefore, the test substance retained by the stratum corneum is not considered to be absorbed and thus is not considered to contribute to a systemic dose.