Teratology Screening - A higher prenatal safety standard

For decades, medical science has known that small amounts of skin care ingredients are absorbed into the bloodstream. This natural process explains why so many medications are now prescribed as topical creams or patches. The total absorption of a topical ingredient depends on various factors such as surface area covered, duration of exposure, frequency of reapplication, skin thickness, temperature/humidity levels, etc. During pregnancy, most absorbed chemicals will pass directly into the fetal circulation where they can potentially affect the baby's development.

The average woman puts over 200 ingredients on her skin each day as part of her cleansing and beauty routine, and it is difficult to know which may be harmful to the fetus or at what dose. Due to ethical concerns, few prospective studies of non-medicinal chemicals are done on pregnant women. Instead, researchers look at animal studies and retrospective human studies for indirect clues about their prenatal safety. As a result, there is now a large body of "teratology" (birth defect) research with uncertain implications for pregnant women and their growing babies.

The FDA states that a cosmetic manufacturer must ensure the safety of their own products but they do not offer any specific guidelines. Many skin care companies simply assume that their products are not absorbed and therefore neglect to examine the teratology studies. At Belli, we believe that pregnancy deserves a higher safety standard-one that carefully monitors the published medical literature and errs on the side of caution. We call that standard teratology screening.
Simply stated, teratology screening guards against questionable ingredients during pregnancy.

The teratology screening process begins with a comprehensive search of the published medical literature to see if an ingredient has ever been linked to a birth defect, miscarriage, or other harmful effect during pregnancy. Searches are repeated on an ongoing basis to capture all the latest information. A list of the databases and reference books used includes:

MEDLINE is the premiere biomedical database produced by the National Library of Medicine and contains over 16 million articles from 5000 international biomedical journals, from 1950 to the present.

TOXLINE is a comprehensive database produced by the U.S. National Library of Medicine and contains more than two million records that cover adverse drug reactions, carcinogenesis, drug evaluation, mutagenesis, pollution, pesticides, herbicides, radiation, teratogenesis, and all other aspects of toxicology from pre-1950 to the present.

DART (Developmental and Reproductive Toxicology) is a bibliographic database on the National Library of Medicine's Toxicology Data Network, which covers teratology and other aspects of developmental and reproductive toxicology and contains over 100,000 published references.

TERIS (Teratogen Information System) is a database of chemical agent summaries based on a thorough review of published clinical and experimental literature. Each summary includes a risk assessment derived by consensus of an Advisory Board comprising nationally-recognized authorities in clinical teratology.

LACTMED, part of the National Library of Medicine's Toxicology Data Network (TOXNET), is a database of drugs and other chemicals to which breastfeeding mothers may be exposed. It includes information on the levels of such substances in breast milk and infant blood, and the possible adverse effects in the nursing infant.

REPROTOX is an information system developed by the Reproductive Toxicology Center which contains summaries on the effects of medications, chemicals, infections, and physical agents on pregnancy, reproduction, and development. Catalog of Teratogenic Agents- Eleventh Edition (Shepard, 2004) is a comprehensive reference work that presents information on teratogenic agents, emphasizing human data and covering pharmaceuticals, chemicals, environmental pollutants, food additives, household products, and viruses. Also included are overviews of recent literature on clinical and experimental teratology, including important Japanese literature not easily available to English-language researchers.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risks- Eighth Edition (Briggs et al., 2008) provides practical, reliable information on more than 1,000 drugs that may be used by pregnant and lactating women. The recommendations help readers interpret animal and human pregnancy data to assess potential human risk when there are human data or the human data are limited or not available.

Chemically Induced Birth Defects- Third Edition (Schardein, 2000) addresses over 4100 drugs and chemicals in current use that cause malformations and congenital anomalies in the human fetus-- comprehensively reviewing experimental studies in animals and clinical data on human development, primarily in the organogenesis period.

Once the search process is complete, we then have to decide which screening criteria to use. For example, what if 3 studies show a harmful effect during pregnancy but 5 show no evidence of harm? What if some of the studies were done on humans and others on animals? High versus low doses? Topical versus oral absorption?

Rather than subjectively try to weigh the results of different or conflicting studies, we use a zero-tolerance standard that excludes ingredients if there is even a single published study showing evidence of harm during pregnancy-in either animals or humans, at any dose, and through any method of absorption. These strict criteria are objectively defined and can thus be easily replicated by other manufacturers and researchers.

If a cosmetic ingredient is red-flagged and excluded by teratology screening that does not mean that it has been proven harmful to humans through normal topical use. However, given the importance of maintaining a healthy environment for fetal development, we feel that a responsible manufacturer should avoid ingredients with even remote links to harmful effects during pregnancy and replace them with better choices instead.

To minimize exposure risks during pregnancy, physicians around the world are now recommending teratology screened skin care products to patients who are expecting or actively trying to conceive. We hope that other manufacturers will soon adopt this higher prenatal safety standard that helps promote healthy pregnancies while offering greater peace of mind.
Examples of Teratogenicity in Common Skin Care Ingredients

As a result of our teratology screening process, here are just a few of the red-flagged ingredients that we exclude from our pregnancy products:

Vitamin A and it's derivatives (retinol, retinoic acid, Retin-A, tretinoin, accutane, isotretinoin) are linked in human studies to neural crest defects1,2 and in animal studies to increased fetal death, craniofacial malformations, and cardiac malformations.3-10

Salicylic acid is linked to higher rates of fetal malformation and fetal death in animal studies.11,12

Oxybenzone, a chemical sunscreen ingredient, is linked to reduced numbers of live births in animal studies.13 It also may have harmful estrogenic effects.14

Glycolic acid, a chemical exfoliant commonly found in facial peels, is linked in animal studies to increased rates of vertebral and rib malformations, decreased fetal weight, and other skeletal malformations.15-17

Benzoyl peroxide, a common ingredient in many over-the-counter acne remedies, is linked to decreased birth weight and decreased testicular weight in animal studies.18

Aloe vera, an organic botanical ingredient known for its wound healing and anti-irritant effects, is linked to increased frequencies of embryonic death and skeletal anomalies in animal studies.19

Rosemary, an organic herbal ingredient known for its anti-oxidant effect, is linked to increased fetal death in animal studies.20

Werler MM, Lammer EJ, Rosenberg L, Mitchell AA: Maternal vitamin A supplementation in relation to selected birth defects. Teratology 42: 497-503, 1990.
Rothman KJ, Moore LL, Singer MR, et al.: Teratogenicity of high vitamin A intake. N Engl J Med 333(21):1369-1373,1995.
Hendrickx AG, Peterson P, Hartmann D, Hummier H: Vitamin A teratogenicity and risk assessment in the macaque retinoid model. Reprod Toxicol 14:311-323,2000.
Kochhar DM, Satre MA: Retinoids and fetal malformations. In: Sharma RP (ed). Dietary Factors and Birth Defects. San Francisco, Calif.: Pacific Division, AAAS, 1993, pp 134-229.
Freytag TL, Morris JG: Chronic administration of excess vitamin A in the domestic cat results in low teratogenicity. FASEB J 11(3):A412, 1997.
Mulder GB, Manley N, Grant J, et al.: Effects of excess vitamin A on development of cranial neural crest-derived structures: a neonatal and embryologic study. Teratology 62:214-226, 2000.
Palludan B: Swine in teratological studies. In: Bustad LK, McClellan RO (eds). Swine in Biomedical Research. Columbus, Oh.: Battelle Memorial Institute, 1966, pp 51-78.
Wiersig DO, Swenson MJ: Teratogenicity of vitamin A in the canine. Fed Proc 26:486, 1967.
Kamm JJ: Toxicology, carcinogenicity, and teratogenicity of some orally administered retinoids. J Am Acad Dermatol 6(4):652-659, 1982.
Tzimas G, Collins MD, Burgin H, et al.: Embryotoxic doses of vitamin A to rabbits result in low plasma but high embryonic concentrations of all-trans-retinoic acid: risk of vitamin A exposure in humans. J Nutr 126:2159-2171, 1996.
Cekanova E, Larsson KS, Orck E, Aberg G: Interactions between salicylic acid and pyridyl-3-methanol: Anti-inflammatory and teratogenic effects. Acta Pharmacol Toxicol 35(2):107-118, 1974.
Nelson BK, Synder DL, Shaw PB: Developmental toxicity interactions of salicylic acid and radiofrequency radiation or 2-methoxyethanol in rats. Reprod Toxicol 13(2): 137-145, 1999.
Gulati DK, Mounce R, Chapin RE, Heindel J: Final report on the reproductive toxicity of 2-hydroxy-4-methoxybenzophenone (CAS no. 131-57-7) in CD-1-Swiss mice. NTIS (National Technical Information Service) Report/PB91-158477, 1990.
Schlumpf M, Cotton B, Conscience M, Haller V, Steinmann B, Lichtensteiger W.: In vitro and in vivo estrogenicity of UV screens. Environ Health Perspect. 2001 Mar;109(3):239-44.
Carney EW, Freshour NL, Dittenber DA< Dryzga MD: Ethylene glycol developmental toxicity: unraveling the roles of glycolic acid and metabolic acidosis. Toxicol Sci 50: 117-126, 1999. [A]
Fiume MZ: Final report on the safety assessment of glycolic acid, ammonium, calcium, potassium, and sodium glycolates, methyl, ethyl, propyl, and butyl glycolates, and lactic acid, ammonium, calcium, potassium, sodium, and tea-lactates, methyl, ethyl, isopropyl, and butyl lactates, and lauryl, myristyl, and cetyl lactates. Int J Toxicol 17 (Suppl): 1-241, 1998. [R]
Munley SM, Kennedy GL, Hurtt ME: Developmental toxicity study of glycolic acid in rats. Drug Chem Toxicol 22(4): 569-582, 1999. [A]
Song S, Kim SH, Bae H: Combined Repeated Dose and Reproductive/Developmental Toxicities of Benzoyl Peroxide. Journal of Toxicology and Public Health: 123-31, 2003.
Nath D, Sethi N, Skingh RK, Jain AK: Commonly used abortifacient plants with special reference to their teratologic effect in rats. J Ethnopharmacol 36: 147-154, 1992
Nusier MK, Bataineh HN, Daradkah HM: Adverse effects of rosemary (Rosmarinus officinalis L.) on reproductive function in adult male rats. Exp Biol Med (Maywood) 232(6):809-813, 2007.

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