Reproductive Aspects
Eisenhardt S, Runnebaum B, Bauer K, Gerhard I. Environ Res 2001 Dec;87(3):123-30
Musk xylene (MX), musk ketone (MK), musk ambrette, musk moskene, and musk tibetene are synthetic fragrances. Between 1994 and 1996 these five nitromusk compounds (NMCs) were tested in the blood of 152 women who consulted the Endocrinological Department of the University Hospital of Obstetrics and Gynecology, Heidelberg, Germany, because of gynecological problems. The testing was conducted by gas chromotography with mass-specific detector and mass spectrometry in a retrospective cross-sectional study. MX was detected in 95% and MK in 85% of the blood samples (>20 ng per liter whole blood). The median concentration of MX was 65.5 ng/L and the maximum level of MX was 1183 ng/L; the corresponding values for MK were respectively 55.5 and 518 ng/L. The other three NMCs were found in only a few patients or not at all. Significant associations between MX and MK concentrations were found in blood and different clinical parameters of the endocrine system. MX and MK may act centrally as a disrupter of the (supra-) hypothalamic-ovarian axis, which may result in a mild ovarian insufficiency. On the basis of our data, a reproductive toxicity and an endocrine effect of NMCs in women cannot be ruled out. Further experimental and clinical studies should be conducted.
Liebl B, Mayer R, Ommer S, Sonnichsen C, Koletzko B. Adv Exp Med Biol 2000;478:289-305
Transition of nitro musks and polycyclic musks into human milk. Liebl B, Mayer R,
Synthetic musks are widely used in various consumer products. The identification of nitro musks in human milk in the early 1990s in connection with evidence for cancerogenicity in animal experiments have caused public concern. However, the validity of previously reported quantitative data has been questioned. Polycylic musks have hardly been investigated so far. The present study aimed at providing accurate current data on the occurrence of nitro and polycyclic musks in human milk. Samples from 40 healthy breast feeding mothers were analysed under carefully controlled conditions avoiding secondary contamination. As in earlier studies, among the nitro compounds musk xylene and ketone were the most frequently detected substances. However, much lower concentrations (roughly by a factor of 10) were found (musk xylene: median 6.1 ng/kg fat). Among the polycylic musks HHCB was found in most samples (median 64 ng/kg fat). Scientific knowledge on possible routes of exposure and health risk aspects is summarized and discussed.
Suter-Eichenbeger R, Altorfer H, Lichtensteiger W, Schrumpf M. Bioaccumulation of musk xylene (MX) in developing and adult rats of both sexes. Chemosphere. 1998 Jun;36(13):2747-62.
Bioaccumulation of musk xylene (MX) was measured by GC-ECD in adult and developing Long Evans rats. Males and females were fed with MX-containing chow (0.001, 0.01, 0.033, 0.1 g MX/kg food pellets) for 10 weeks before mating. Treatment continued during pregnancy and lactation. Offspring exhibited dose-dependent MX accumulation with 1/2-3/4 of adult female or 3-4 times adult male body fat levels (at 0.1 mg/kg food) at days 1 and 14. Milk levels were comparable to adult female adipose tissue. Data indicate significant transplacental passage and exposure via maternal milk. In rats fed with MX in adulthood, levels were highest in adipose tissue with significant amounts in other organs (ovary, adrenal). Female tissue levels were 3.7-6.8 times higher. This unexplained sex difference was unrelated to lipid content and was absent in offspring.
Abstract: The widespread use of synthetic musk fragrances and the resultant presence of these substances and their metabolites in the aquatic environment (as well as their accumulation in human adipose tissue) raises the question of whether musk fragrances display endocrine and in particular estrogenic activity. A variety of musk fragrances were tested using the E-screen assay. A statistically significant increase in proliferation rate of human MCF-7 breast cancer cells was detected for two nitro musks (musk xylene, musk ketone), a major metabolite of musk xylene ( p-amino-musk xylene), and the polycyclic musk fragrance AHTN. This indicates that these substances do, in fact, demonstrate estrogenic activity. Coincubation with the antiestrogen tamoxifen showed that the increase in proliferation rate by the musk fragrances is estrogen receptor-mediated. It must be noted, however, that the effective estrogenic strength and estrogenic potency were low compared to 17 b-estradiol.
A rat model for benign prostatic hyperplasia in man (BPH) was investigated. Citral treatment of male Copenhagen rats for 4 months via the transdermal route resulted in a marked hyperplasia of glandular epithelium and interglandular stroma in the ventral prostate. Despite the cellular hyperplasia there was not a significant increase in prostate weight. Investigations of the mechanism of action of citral showed that application of citral directly to the vagina in female, ovariectomized rats resulted in an increased proliferation of vaginal epithelium and a significant increase in the BrdUrd incorporation in vaginal epithelial cells, in short a similar effect to that of estrogen application. In an in vitro assay citral proved to inhibit estrogen binding to estrogen receptors, while no such inhibition was observed with testosterone for androgen receptors. These observations together with the estrogen implication in the BPH and the reported incidence of gynecomastia following exposure to geraniol, a precursor of citral, strongly suggest that the prostatic hyperplasia-inducing capacity of citral may be due to its estrogenic action.
Reproductive and developmental effects
In general, the monoester metabolite of the parent phthalate compound is thought to be responsible for adverse reproductive and developmental effects of phthalates. In animal testing, impacts include decreased fertility in females, fetal defects, reduced survival of offspring, birth defects, altered hormone levels, and uterine damage. Phthalates that display one or more of these effects include BBP 39 40 41 44 64 109 121, DBP40 92 131, DEP 52 92, DHP 92, DIDP 75 155, DINP 64 114 150, MBP38 130, MDP 43, and MEHP 97 129.
In males, phthalates cause prostate damage, femalelike areolas/nipples, and reproductive malformations in infants, including altered hormone levels, testicular atrophy, reduced sperm production and motility, undescended testes, hypospadias, Sertoli cell damage, and Leydig cell tumors. Phthalates that display one or more of these effects include BBP 2 64 109 121 134, DBP42 54 56 106 108 157, DEHP 8 12 56 64 65 94 124, DEP 19 82 92, DHP 92, DINP 64 114 150, DPP 55, MEHP71, MBP 71, and MPP71.
Dibuty phthalate, Dimethyl phthalate, and diethyl phthalate all appear on the European Commission's list of chemicals used in fragrance. Diethyl phthalate is the material that is most commonly used in fragrance.