11 Even when several reports are available on the effects of a substance in pregnancy, conflicting results are not unusual, and a complete absence of risk is impossible to demonstrate conclusively. However, dose is a critical feature of reproductive toxicity, and adverse effects will only occur when dose exceeds a certain threshold (Cragan et al 2006). Few aspects of toxicology arouse such concern as the effects of chemical substances on the female reproductive system and the development of the fetus. A principal reason for this is a lack of information. Less is known about the effect of chemicals (from whatever source) on the reproductive system than in any other area of toxicology. As with carcinogens, there is no possibility of intentional human testing, and extrapolating from studies in pregnant animals is problematic (Neubert et al 1987). A complicating factor of animal studies is that a compound may also induce adverse effects in the mother, and it can be difficult to distinguish between direct effects and indirect effects in the developing organism (Niesink et al 1996). When thalidomide was tested on rats and mice, it did not cause the teratogenic effects later seen in humans.1 On the other hand, drugs such as diflunisal were teratogenic in animal models but not in humans. While animal toxicology studies have been somewhat successful in identifying human teratogens, alert physicians and epidemiology studies have also made significant contributions. In vitro studies play a very minor role, although they are helpful in describing effects on cells or tissues (Brent 2004). For all these reasons, animal reproductive toxicity data must be extrapolated to the human situation with a degree of circumspection. It is arguable that the human body will be able to metabolize and eliminate essential oil constituents more readily than synthetic pharmaceutical drugs, since they are found not only in many spices and herbs that have been consumed by humans for thousands of years, but also some common foods (Box 11.1). It is also a reasonable assumption that such substances are safe to consume, at least in very small amounts. The safety of herbal preparations in pregnancy is frequently misrepresented. The American Pregnancy Association states, on its website: ‘Unlike prescription drugs, natural herbs and vitamin supplements do not have to be tested to prove they work and are safe before they are sold.’ (In the US, herbs are classified as dietary supplements, and manufacturers are therefore not required to provide proof of efficacy or safety.) In a review of herbs in pregnancy, Born & Barron (2005) comment: ‘Few studies about the effects of herbs have been conducted in the general population, and fewer still have been published about pregnancy use.’ In a similar review, Marcus & Snodgrass (2005) comment: ‘There are no rigorous scientific studies of dietary supplements [including herbs] during pregnancy, and the Teratology Society has stated that it should not be assumed that they are safe for the embryo or fetus.’ There are two major problems with these statements. First, there are in fact rigorous scientific studies of some herbs and essential oils during pregnancy in animals. Second, they smack of double standards, because they imply that all pharmaceutical drugs have passed through rigorous scientific studies for safety in pregnancy. They have not. The FDA classifies drugs into five categories, according to their assumed degree of safety in pregnancy (Box 11.2). Most drugs fall into category C, which means that either animal studies have revealed adverse effects, or that no studies have been done, whether in pregnant women or animals. (Less than 1% of pharmaceutical drugs are ever tested on pregnant women, for ethical and safety reasons.) If we apply the same standards to essential oils and pharmaceutical drugs, then either most drugs (whether prescription or over the counter) and most essential oils should never be used in pregnancy, or we should continue with the status quo, meaning that most drugs and essential oils are considered safe to use, with some degree of caution, during pregnancy. Endogenous mammalian estrogens comprise mainly 17β-estradiol, estriol and estrone, of which the first is the most important in premenopausal, non-pregnant women. Estrogens are responsible for the development of the female reproductive organs and secondary sex characteristics, and also protect the cardiovascular system, maintain bone integrity, cognition and behavior, and protect against skin aging. They also play an important role in glucose homeostasis, and modulate insulin sensitivity (Howes et al 2002; Ososki & Kennelly 2003). Two estrogen receptors, known as ERα and ERβ, have been identified. ERα is found in uterus, breast, ovary, testis, endometrium and hypothalamus; ERβ is found in ovary, breast, testis, prostate, thymus, spleen, adrenals, kidney, brain, bone, heart, lungs and intestines (Mosselman et al 1996; Brandenberger et al 1997; Kuiper et al 1996). Citral impairs reproductive performance in female rats by reducing the number of normal ovarian follicles (Toaff et al 1979). The effect, however, was seen only after a series of six monthly ip injections at a dose of 300 mg/kg. This is equivalent to injecting ~ 25 mL of lemongrass oil into a woman’s abdomen. Based on other research, we have restricted citral exposure in pregnancy. Carrot seed oil has been reported to cause antigestational effects in rats and mice (Dong et al 1981). In a subsequent study, sc injection of 2.5–5 mL/kg of carrot seed oil into female rats or mice prevented implantation and blocked progesterone synthesis (Chu et al 1985). These are massive doses, although wild carrot has a traditional reputation as a contraceptive. Chinese zedoary oil terminated pregnancy in 90% of mice when administered as a 10% solution on days 4–6 of pregnancy. It was equally effective on pregnant rabbits when delivered as a vaginal tampon on days 2–4 of pregnancy (An et al 1983). Ethanol extracts and decoctions of zedoary rhizomes have antifertility effects (Kong et al 1986). We have contraindicated both of these essential oils in pregnancy. Substances with estrogen-like activity are widely distributed in the plant kingdom. Estrone has been found in potatoes, beets, yeast and palm kernel oil (Zondek & Bergmann 1938), and 17β-estradiol is a constituent of willow catkins and other plants (Agarwal 1993). The hormonal actions of 17β-estradiol are mimicked by many plant constituents, known collectively as phytoestrogens. These include flavones, isoflavones, lignans and coumestans. Although the potency of many of these compounds is low compared to that of 17β-estradiol, their effects may be significant if ingested in sufficient quantities. For example, the isoflavone genistein in sweet clover was first recognized as being responsible for low fertility and abortion in grazing sheep (Hughes 1988). However, none of these compounds are likely to be found in essential oils because of their lack of volatility. Epidemiological and animal studies suggest that the weak activity of estrogenic plant constituents may have beneficial effects, e.g., in breast and prostate cancers, cardiovascular disease and post-menopausal ailments (Dixon & Ferreira 2002). However, they may also disrupt the effects of endogenous hormones and cause developmental and reproductive disturbances (Diel et al 1999). The potential risks and benefits of these compounds may depend on whether they stimulate or block estrogen receptors, their relative potencies at the two receptors (ERα and ERβ), and local concentrations of 17β-estradiol. A number of in vitro assays have been developed for estrogenic activity, focusing on binding to estrogen receptors, proliferation of estrogen-sensitive cells, stimulation of reporter gene transcription and estrogen-sensitive gene regulation in cell lines (Diel et al 1999). Some essential oil constituents have been found to bind to estrogen receptors, but with very low affinity. Citral, geraniol, nerol and eugenol displaced [3H]17β-estradiol from isolated human ERα and ERβ receptors at concentrations some 4 to 5 orders of magnitude higher than estradiol. However, they lacked estrogenic or anti-estrogenic activity in both an estrogen-responsive human cell line (below cytotoxic concentrations) and a yeast screen for androgenic and anti-androgenic compounds. In yeast cell-expressed human estrogen receptors, citral, geraniol, nerol and (E)-anethole showed very weak agonist activity, while eugenol was anti-estrogenic (Howes et al 2002). α-Terpineol was anti-estrogenic in human breast cancer MCF-7 cells (Nielsen 2008). Blair et al (2002) measured the binding affinity of 188 compounds for rat uterus estrogen receptors, including eight essential oil constituents: benzyl alcohol, 1,8-cineole, cinnamic acid, ethyl cinnamate, eugenol, isoeugenol, nerolidol and vanillin. No affinity could be measured for any of these compounds. In other research, Nishihara et al (2000) used a yeast screen to test 517 compounds for estrogenic activity, including eight essential oil constituents. Seven of these were considered inactive: benzoic acid, carvacrol, o-cresol, eugenol, isoeugenol, β-thujaplicin and thymol; p-cresol was considered active. Geldof et al (1992) suggested that citral competes with 17β-estradiol for estrogen receptors and considered it estrogenic on the basis that it causes vaginal hyperplasia in rats. However, citral and geraniol failed to show any estrogenic effects in ovariectomized mice (Howes et al 2002). The in vivo action of citral seems to be species-specific, and under Male fertility we see evidence of strain-specificity. In early, poorly described research, very weak estrogenic activity was reported after injecting rats or mice with anise oil, fennel oil and (E)-anethole. No activity was seen with oils of bay, cinnamon bark, clove, dill, orange, pimento or thyme, nor with the constituents anisaldehyde, estragole, methyleugenol, methyl isoeugenol, piperonal or vanillin (Zondek & Bergman 1938). Albert-Puleo (1980) suggested that any estrogenic activity of (E)-anethole may be due to a polymer or a metabolite rather than to the compound itself. (A polymer is a chain of, in this case, anethole molecules.) The anethole metabolite, 4-hydroxy-1-propenylbenzene, weakly displaced 17β-estradiol from ERα receptors with an IC50 value of 10− 5 M, and promoted the proliferation of cultured human MCF-7 cells at 10− 8–10− 6 M. In the latter assay, anethole had no effect up to 10− 5 M (Nakagawa & Suzuki 2003). When given orally at 80 mg/kg/day for three days, (E)-anethole caused a significant increase in uterine weight in immature female rats (Dhar 1995), suggesting a hormonal action. Anise, fennel and caraway oils demonstrated estrogenic effects in human MCF-7 cells, but did not stimulate the secretion of prolactin in vitro (Melzig et al 2003). In a yeast assay expressing human ERα receptors, oils from Pimpinella species were studied. Potencies were 5–8 orders of magnitude weaker than 17β-estradiol, and maximal responses ranged from 12.6–50.4% (Tabanca et al 2004). It was suggested that constituents other than (E)-anethole in these plants may contribute to their estrogenic activity. Circulating 17β-estradiol levels were dose-dependently reduced in female rats by both bergapten and methoxsalen, when given in the diet at ~ 100 mg/kg and ~ 200 mg/kg. Enhanced metabolism of estrogens may partly explain the reproductive toxicity of bergapten and methoxsalen cited earlier, and this may be associated with a reduction in ovarian follicular function and ovulation (Diawara et al 1999; Diawara & Kulkosky 2003). These are extremely high doses compared to the amounts of bergapten or methoxsalen present in any essential oil. It has been suggested that hop oil has estrogen-like properties (Franchomme & Pénöel 1990). However, although estrogenic substances have been found in the plant, notably 8-prenylnaringenin in the fruit (strobile) (Bradley 1992; Chadwick et al 2006), these are not found in the essential oil. Spanish sage oil (0.01 mg/mL) has been reported as estrogenic since it induced β-galactosidase activity in yeast cells (Perry et al 2001). Although some essential oil constituents exhibit estrogen-like activity in various in vitro tests, their actions are extremely weak. Moreover, estrogenic activity data from single assays are insufficient to make confident predictions about their actions in vivo. For example, estrogen receptor binding assays measure only the affinity of a substance for its receptor, but give no information about whether it is an agonist or an antagonist (Diel et al 1999). Based on evidence available at this time, and with one exception, the case for contraindicating essential oils with potential estrogenic activity in pregnancy, in breastfeeding mothers or in patients with estrogen-sensitive cancers or endometriosis is not proven. The exception is (E)-anethole and we consider that there is sufficient evidence to contraindicate essential oils with high levels of this compound in these groups. Chaste tree has been found to compensate for progesterone deficiency, and is used in traditional medicine for treating various gynecological problems. Alcoholic extracts of the plant have been found to stimulate dopamine D2 receptors, leading to inhibition of prolactin release and normalization of the menstrual cycle (Caron 1986; Jarry et al 1991). Analysis of these extracts has led to the identification of diterpenes with dopaminergic activity (Hoberg et al 1999). Recent studies have reported similar benefits using the essential oils of chaste tree fruits and leaves (Lucks 2002, 2003), and a number of sesqui- and diterpene constituents have been reported (Senatore et al 1996; Zwaving & Bos 1996; Sørensen & Katsiotis 2000). Chaste tree oil, therefore, should be avoided in pregnancy. Three isolated cases of gynecomastia have been reported in prepubertal boys who used topical products alleged to contain either lavender or tea tree oil. This study has been criticized on a number of grounds, including that insufficient essential oil would penetrate the skin from wash-off products to cause such an effect, that no controls were introduced to exclude potential environmental chemicals such as phthalates, and that no relationship was established between the cases and the in vitro effects reported. Both essential oils did show a weak estrogenic action in human breast cancer (MCF-7) cells (Henley et al 2007). Gynecomastia was reported in an embalmer who used an embalming cream containing geraniol. Abramovici & Sandbank (1988) proposed that geraniol had converted to citral in the liver, and that citral was estrogenic. However, as with the three cases above, no causality was established. The doctors who originally reported the case considered geraniol/citral to be an unlikely cause of their patient’s gynecomastia. When applied topically, citral induces malformations in chick embryos, causes selective oocyte degeneration and impaired fertility in rats. It was suggested that citral may affect tissue responses to sex hormones by inducing hyperplasia of sebaceous and prostate glands. It does not appear to be andromimetic (Abramovici 1972; Abramovici et al 1978; Toaff et al 1979). Citral, applied in ethanol at a dose of 185 mg/kg/day to the shaved dorsal skin of male Wistar rats for three months, produced benign prostatic hyperplasia (BPH; Abramovici et al 1985). This may be testosterone dependent (Servadio et al 1986). In a later study, similar application of citral for only 30 days caused BPH in adolescent male Wistar rats. This was especially marked in rats with high serum testosterone levels, suggesting possible synergy between citral and testosterone (Engelstein et al 1996). Both androgens and estrogens are capable of contributing to BPH (Wilson 1980). In these BPH studies, the amount of citral applied daily would be equivalent to ~ 10 mL for a human on a body weight basis. However, the morphology and function of the prostate exhibit marked species differences that make extrapolation to other animals and man difficult. It is apparent that the Wistar rat ventral prostate is reactive to citral. Further work demonstrated that the Wistar and Sprague-Dawley strains were the most susceptible to developing BPH, but that the F344 and Acl/Ztm rat strains remained resistant to treatment with citral (Scolnik et al 1994a). When applied to the rat ventral prostatic vascular bed, citral produced an effect resembling a classic inflammatory triple response. The ability of citral to cause BPH in some species may therefore be mediated via a non-specific inflammatory reaction modulated either by local release of neurotransmitters or through a direct effect on the endothelial cells (Scolnik et al 1994b). Perillyl alcohol (a constituent of perilla oil) inhibits expression and function of the androgen receptor by inhibiting androgen-induced cell growth and androgen-stimulated secretion of prostate-specific antigen and human glandular kallikrein in human prostate cancer cell line LNCaP. This suggests that perillyl alcohol might be useful in treating some prostate cancers (Chung et al 2006). Eugenol is also an androgen receptor antagonist, with an IC50 of 19 μM in human breast cancer MDA-kb2 cells (Ogawa et al 2010). Male rats given dietary bergapten or methoxsalen at 0, 1,250 or 2,500 ppm (corresponding to 0, ~ 75 or ~ 150 mg/kg) for eight weeks had significantly elevated levels of testosterone, and had smaller pituitary and prostate glands. Sperm counts were reduced in the high-dose group and more breeding attempts were required to impregnate females (Diawara et al 2001). These are extremely high doses, equivalent to 1,590 g or 3,180 g of bergamot oil in an adult human for bergapten. East Indian nutmeg oil has been found to reduce fertility in male mice (Pecevski et al 1981). The dose-dependent effect occurred at 60–400 mg/kg/day given 5 days per week for 8 weeks. The number of fertile mice was reduced from 95% (control) to 71% (lowest dose) and 32% (highest dose). Chromosomal damage was seen in some of the male offspring. It is difficult to draw any firm conclusions from this research. Even 60 mg/kg/day (equivalent to 4 g in an adult human) is a very high dose, especially when taken for 8 weeks, and effects on fertility are often species/strain-specific. Eugenol caused degenerative changes in the secretory cells of rat seminal vesicles when given im at doses of 0.2–0.3 mg/kg/day for 10 days. The resemblance between eugenol and other polyphenolic compounds with estrogenic activity, such as anethole and diethylstilbestrol, was discussed (Vanithakumari et al 1998). Other effects on tissues of the reproductive system include that of thyme oil, which, unlike clove, caraway, sage and melissa oils, relaxed the isolated smooth muscle of rat seminal vesicles (Zarzuelo & Crespo 2002). It is worth noting that latex condoms can be weakened by both vegetable oils and essential oils.2 Subcutaneously administered savin oil, containing 50% sabinyl acetate, prevented implantation in mice at 45 and 135 mg/kg, but not at 15 mg/kg when given on gestational days 0–4. The same pattern was observed with sabinyl acetate given at 70 mg/kg. However, no anti-fertility effect was found when savin oil was given on gestational days 8–11, indicating that the abortifacient action of sabinyl acetate is due to inhibition of implantation (Pages et al 1996). Savin oil is contraindicated in pregnancy (Table 11.1). Table 11.1 Essential oils that should be avoided by any route throughout pregnancy and lactation Bergapten or methoxsalen were given in the diet to pregnant female rats for 39–49 days (until the day before expected parturition) at 0, 1,250 or 2,500 ppm, corresponding to 0, ~ 100 mg/kg and ~ 200 mg/kg. Bergapten, but not methoxsalen, caused a significant reduction in the number of implantation sites. The number of pups per female was significantly lower at both dose levels for bergapten, and in the high-dose group for methoxsalen. Uterine weight was significantly reduced in the high-dose group for bergapten, and in both dosed groups for methoxsalen. Enhanced metabolism of estrogens may explain the observed reproductive toxicity of bergapten and methoxsalen (Diawara et al 1999; Diawara & Kulkosky 2003). Extrapolating the bergapten study to a 50 kg woman suggests that 5 g bergapten orally could reduce implantation. Since this would be equivalent to consuming 1.5–3.0 kg lime oil, the findings have no relevance to essential oil use. Doses of 50, 70 and 80 mg/kg/day po of (E)-anethole, given on days 1–10 of pregnancy, were reported to cause 33.3%, 66.6% and 100% reductions in implantation in female rats. When 80 mg/kg/day po of (E)-anethole was given on days 1–2 of pregnancy, there was no antifertility effect. When the same dose was given on days 3–5, pregnancy was prevented in all five rats. When given on days 6–10, pregnancy was prevented in three of five rats. It is suggested that this may be related to a disruption of hormonal balance (Dhar 1995). These results were not supported in an earlier study, in which female rats were given (E)-anethole at 25, 175 or 350 mg/kg by gavage for 7 days prior to mating and until day 4 of lactation. There was no reproductive toxicity at the lower doses, while some increase in mortality, stillbirths and reduction in body weight at birth was seen in the high-dose group. Body weight gain was reduced in the two higher dose groups during the pre-mating period, and this was attributed to palatability problems (ARL 1992, cited in Newberne et al 1999). There is no obvious reason for the inconsistency between these studies. The Dhar (1995) data suggest that in rats, (E)-anethole is only effective after day three of pregnancy, which might result from physiological changes leading to altered susceptibility to anethole. This includes any toxic effect on the conceptus resulting from pre-natal exposure, including structural or functional abnormalities. (Developmental toxicity also includes postnatal manifestations of such effects.) Structural defects are mainly induced in the embryonic period, whereas functional defects are established during the fetal period and later stages of development (Niesink et al 1996). There are very few data on the distribution and fate of drugs within the human embryo because it is almost impossible to design safe experiments. Some essential oil constituents could prove damaging to the development of the conceptus. That is, they could be teratogenic, or they could in some way disturb the normal outcome of the pregnancy, for instance by promoting resorption of the early embryo. Another concern is that any large or polar metabolites produced by the fetus might be unable to diffuse across the placenta to the maternal bloodstream, and may thereby become trapped inside it (Timbrell 2000). This, however, may not be important for essential oil constituents. Some, such as (E)-anethole and eugenol, would be classed as toxic if they were not rapidly detoxified in the liver (see Table 12.2). The question of whether they are toxic to the fetus depends on the amount of the substance in the mother’s circulation, and her metabolic status. Any unmetabolized compound would be expected to cross into the fetal circulation and may be toxic. The developing child is particularly sensitive to chemical insult during the first three months of pregnancy. However, the fetus remains vulnerable throughout pregnancy, and different fetal systems are sensitive to different chemicals at specific times (Reynolds 1993). Any embryo fetotoxicity caused by an essential oil is dependent on one or more of its constituents crossing the placenta. It is often assumed that drug concentrations in the conceptus reach similar levels to those in the mother’s blood. This is likely to be wildly inaccurate for general application and we do not know to what extent many foreign substances circulating in the mother’s bloodstream reach the developing child (Neubert et al 1987). A recent review lists ethanol, nicotine, PCBs, and a number of pesticides, heavy metals, illicit drugs and pharmaceuticals (or their metabolites) as being unequivocally detected in the fetal environment (Barr et al 2007). During pregnancy, the fetus receives oxygen and nutrients in its bloodstream from the mother via the placenta and umbilical cord, and its waste products are removed in the opposite direction. The fetus is vulnerable to drugs and other chemicals in the mother’s body because the placenta does not provide a very effective barrier between maternal and fetal blood. In general, the placenta will carry any uncharged, un-ionized molecule with high lipid solubility and a molecular weight of less than 1000 (Baker 1960; Heikkila et al 1992; Gedeon & Koren 2007). This includes many drugs and essential oil constituents. The passive diffusion of substances across the placenta, like the skin and cell membranes (see Chapter 4), is largely governed by lipophilicity and molecular size. It is believed that most pharmaceutical drugs cross the placenta to some degree, even those with relatively high molecular weights (Myllynen et al 2007). Essential oil constituents in general are likely to cross the placenta efficiently because of their favorable lipophilicity and low molecular weight. This does not indicate a hazard per se which, for any substance, is determined by plasma concentration and toxicity. The fetal central nervous system (CNS), because it is still growing, is more susceptible to damage by chemicals than is the adult CNS. The blood–brain barrier is somewhat under-developed at and before birth, increasing the likelihood that compounds that do cross the placenta will reach the fetal CNS (Maickel & Snodgrass 1973). 1,8-Cineole crossed the placenta in sufficient quantity to affect the activity of fetal liver enzymes when given by sc injection to pregnant rats at a dose of 500 mg/kg for four days (Jori & Briatico 1973). Although this dose represents a vastly higher maternal blood level of 1,8-cineole than would be encountered in aromatherapy, the study demonstrates the ability of some essential oil constituents to reach the fetus. Eucalyptus oil (~ 75% 1,8-cineole) showed no embryotoxicity or fetotoxicity when tested on mice (injected sc at 135 mg/kg on gestational days 6–15) and had no effect on birth weight or placental size (Pages et al 1990). Niaouli oil (50.6% 1,8-cineole) was maternally toxic and fetotoxic when injected ip to pregnant rats for 18 days at 1,350 mg/kg (Laleye et al 2004). Camphor is able to cross the placenta, as are at least some of the sulfur compounds found in garlic oil. Following accidental ingestion of camphorated oil by a pregnant woman, camphor was found to be present in the body of her stillborn baby (Riggs et al 1965). After crossing the placenta, camphor passes into fetal lung, liver, brain and kidney tissue. When taken in overdose, it also destroys the placenta, causing hemorrhage (Phelan 1976). The odor of garlic was detected in both maternal and fetal blood and in amniotic fluid in samples taken 100 minutes after a ewe was given garlic orally (Nolte et al 1992). Similarly, garlic imparts a pronounced odor to amniotic fluid after being ingested by pregnant women (Mennella et al 1995). A 30-year-old woman, at 30 weeks of gestation, ingested several cookies made with 7 g of ground nutmeg, instead of the recommended eighth of a teaspoon (Lavy 1987). Four hours later, she experienced toxic effects. The fetal heartbeat rose to 160–170 bpm, and returned to a normal 120–140 bpm within 12 hours. The fetal response was attributed to the myristicin content of nutmeg oil, and its anticholinergic (i.e., sympathomimetic) effect. It is assumed that myristicin readily crosses the placenta. When safrole, a minor constituent of nutmeg oil, was given orally to pregnant mice at 120 mg/kg on four gestational days, kidney epithelial tumors occurred in 7% of offspring, compared to none of the control animals (Vesselinovitch et al 1979). On transit through the placenta, essential oil constituents might be metabolized by local enzymes. Human term placental peroxidase (HTPP), in the presence of hydrogen peroxide, catalyzes the oxidation of eugenol to a quinone methide widely regarded as the compound responsible for its cellular toxicity. Safrole and estragole, however, which cannot form quinone methides, are not oxidized by HTPP. There is evidence that the activity of this enzyme is highest in the first trimester of pregnancy, and that it is present in human fetal tissues and possibly also in human intrauterine conceptual tissues in the organogenesis period (Zhang & Robertson 2000). This oxidation of eugenol by HTPP might explain the toxicity of clove bud oil to embryo cells described below.
The reproductive system
Reproductive toxicology
Xenobiotics in pregnancy and lactation
Fertility
Female Fertility
Estrogenic activity
Dopaminergic activity
Male Fertility
Estrogenic and androgenic activity
Other actions
Conception
Implantation
Essential oil
Toxic constituent
Concentration in oil
Anise
(E)-Anethole
< 96.1%
Anise (star)
(E)-Anethole
91.8%
Araucaria
β–Eudesmol
25.9%
Artemisia vestita
α- + β-Thujone
2.5%
Atractylis
β–Elemene + β-Eudesmol
44%
Birch (sweet)
Methyl salicylate
90.4%
Black seed
Thymoquinone
<54.8%
Buchu (diosphenol CT)
α- + β-Pulegone
< 9.1%
Buchu (pulegone CT)
β-Pulegone
< 73.2%
Calamint (lesser)
β-Pulegone
< 76.1%
Carrot seed
Not identified
–
Cassia
Not identified
–
Chaste tree
Not identified
–
Cinnamon bark
Not identified
–
Costus
Costunolide + dehydrocostus lactone
17%
Cypress (blue)
β–Eudesmol
14.4%
Dill seed (Indian)
Apiole (dill)
< 52.5%
Fennel (bitter)
(E)-Anethole
< 84.3%
Fennel (sweet)
(E)-Anethole
< 92.5%
Feverfew
Camphor
< 44.2%
Genipi
α-Thujone
79.8%
Hibawood
β-Thujaplicin
Major constituent
Ho leaf (camphor CT)
Camphor
< 84.1%
Hyssop (pinocamphone CT)
Pinocamphones
< 80%
Lanyana
α- + β-Thujone
< 32%
Lavender (Spanish)
Camphor
< 56.2%
Mugwort (common, camphor/thujone CT)
α-Thujone
11.4%
Mugwort (common, chrysanthenyl acetate CT)
α- + β-Thujone
< 2.6%
Mugwort (great)
β-Thujone
34.0%
Myrrh
β–Elemene + furanodiene
28.4%
Myrtle (aniseed)
(E)-Anethole
95.0%
Oregano
Not identified
–
Parsley leaf
Apiole (dill), possibly p-menthatriene
< 50%
Parsleyseed
Apiole (parsley)
< 67.5%
Pennyroyal
β-Pulegone
< 86.7%
Rue
Not identified
–
Sage (Dalmatian)
α- + β-Thujone
< 60%
Sage (Spanish)
Sabinyl acetate
< 9.0%
Savin
Sabinyl acetate
< 53.1%
Tansy
α- + β-Thujone
< 46%
Thuja
α- + β-Thujone
< 60%
Western red cedar
α- + β-Thujone
< 99%
Wintergreen
Methyl salicylate
< 99.5%
Wormwood (all chemotypes)
Thujones and sabinyl acetate
Varying amounts
Wormwood (sea)
α-Thujone
63.3%
Wormwood (white)
α- + β-Thujone + camphor
< 95%
Yarrow (green)
Sabinyl acetate
3.7%
Zedoary
Not identified
–
Toxicity during gestation
Crossing the placenta
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