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Concern has been raised over the safety of diethanolamine (DEA) which may be present as a minor component of alkanolamide ingredients of cosmetic formulations. Skin penetration data were therefore generated for a range of typical formulations under in-use conditions. Seven rinse-off formulations (A-E, G and H), a leave-on emulsion (F), representing prototype cosmetic formulations and containing representative levels of DEA were prepared. Target levels of DEA were attained by inclusion of DEA as either (14)C-DEA or a combination of (14)C-DEA and unlabeled DEA. Skin permeation and distribution were evaluated using human skin in vitro, static diffusion cells and phosphate buffered saline (pH 7.4) as the receptor phase. At least 12 replicate epidermal membranes were prepared from a minimum of four donors for each test group. Receptor phase samples were taken at appropriate time intervals. At the end of the test period, radioactivity remaining on the skin surface and on the diffusion cell donor cap was determined before the skin samples were tape-stripped. The remaining tissue was solubilized and radioactivity determined. Permeation was very low from all vehicles applied under in-use conditions (range 1-48 ng/cm(2) over 24 h). Comparison was also made between permeation and distribution of DEA from an infinite dose of a simple aqueous solution and the leave-on formulation (F) through paired samples of fresh and frozen full thickness skin from the same donors. When applied as an infinite dose in aqueous solution DEA permeation at 24 h was greater through frozen than through fresh skin. From the leave-on formulation, permeation was similar and very low for both fresh and frozen skin. Recovery of DEA after application of the aqueous solution to fresh human skin and subsequent aqueous and organic extraction of the epidermal and dermal tissue indicated that the majority (>98%) of DEA was in the aqueous extract, suggesting that DEA was in the free state and not associated with the lipid fraction. These data provide a basis for the estimation of the potential systemic exposure and safety margins for DEA in representative cosmetic formulations.

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Accurate exposure information for cosmetic products and ingredients is needed in order to conduct safety assessments. Essential information includes both the amount of cosmetic product applied, and the frequency of use. To obtain current data, a study to assess consumer use practices was undertaken. The study included three widely used cosmetic product types: lipstick, body lotion, and face cream. Three hundred and sixty women, ages 19-65 years, who regularly use the products of interest, were recruited at ten different geographical locations within the US. The number of recruits was chosen to ensure a minimum of 300 completes per product type. Subjects were provided with prototype test products, and kept diaries and recorded detailed daily usage information over a two week period. Products were weighed at the start and completion of the study in order to determine the total amount of product used. Statistical analysis of the data was conducted to derive summary distribution of use patterns. The mean and median usage per application, respectively, for the three products was: face cream, 1.22 g and 0.84 g; lipstick, 10 mg and 5 mg; and body lotion, 4.42 g and 3.45 g. The mean and median usage per day for the three products was: face cream, 2.05 g and 1.53 g; lipstick, 24 mg and 13 mg; and body lotion, 8.70 g and 7.63 g. The mean number of applications per day for face cream and lipstick was 1.77 and 2.35, respectively. For body lotion, the mean number of applications per day was dependent on body area, and was 2.12, 1.52, 1.11, 0.95, 0.43, 0.26, and 0.40 for hands, arms, legs, feet, neck and throat, back, and other body areas, respectively. The effect of product preference on use practices was also investigated. This study provides current cosmetic exposure information for commonly used products which will be useful for risk assessment purposes.

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The human skin penetration of N-nitroso-N-methyldodecylamine (NDOMA) from isopropyl myristate (IPM) and two vehicles representative of cosmetic/personal care formulations was determined in vitro. When applied as an infinite dose in IPM (1 microgram/microliter) the average total absorption over 48 hr was 0.10 +/- 0.01% of the applied dose (all data are expressed as means +/- SE). When applied as a finite dose in a representative oil-in-water emulsion formulation the average total absorption over 48 hr was 4.66 +/- 0.76% of the applied dose. When applied as a finite dose in a representative shampoo formulation for 10 min, followed by rinsing (to represent in-use exposure conditions), the average total absorption over 48 hr was 0.75 +/- 0.17% of the applied dose. Approximately 72% of the NDOMA in the applied shampoo formulation was removed by rinsing. The overall data indicated that NDOMA could penetrate the skin but that penetration was low. The rate and extent of absorption, however, could be affected by differences in the vehicle of application, time of exposure and whether the formulation is (and the conditions are designed to mimic) a rinse-off or leave-on product.

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N1(-)[tris(hydroxymethyl)]methyl-4-nitro-o-phenylenediamine was fed in the diet to groups of 30 male and 55 female Sprague-Dawley rats at levels of 0.2, 0.6 and 2.0% for up to 6 months. One mid-dose and two high-dose females developed palpable mammary masses that were subsequently diagnosed as mammary adenocarcinomas at a 13-wk interim kill involving 10 rats/sex/group. After 14 wk, 25 females per group with no apparent masses were mated in a reproduction/teratology study. Mammary tumours developed in a dose-related fashion both in the pregnant rats and in the remaining 20 females/group that continued on treatment for 6 months. On gestation day 20 (wk 17-18) the final incidences of mammary adenocarcinomas in the low-, mid- and high-dose mated dose groups were 20, 60 and 84%, respectively, while the corresponding incidences in the non-mated females at 6 months were 5, 40 and 85%. Most mammary tumours were encapsulated but, at 6 months, lung metastases were noted in four rats, and four females also had Zymbal's gland tumours. Non-neoplastic changes in male and female rats considered to be related to treatment included increases in thyroid follicular cell size accompanied by an accumulation of golden-brown pigment, multifocal hepatic necrosis with non-suppurative inflammation, and renal tubular pigmentation. Increases in foetal variations in the mid- and high-dose groups were considered to be related non-specifically to retarded growth. Malformations observed in the high-dose group were found primarily in single foetuses and were not considered to be treatment related. Although the mean numbers of micronucleated polychromatic erythrocytes in bone marrow obtained from high-dose treated females after 13 wk slightly exceeded historical negative control values, the data were not considered indicative of a genotoxic effect because of the absence of either a dose relationship or a substantive increase in the frequency of micronucleated cells.

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Human skin penetration of N-dimethylnitrosamine (DMN) from three vehicles has been determined in vitro. When applied as an infinite dose in isopropyl myristate (IPM, 1 microgram/microliter) the average total absorption over 48 hr was 2.6 +/- 1.2% of the applied dose (all data presented are expressed as means +/- standard errors). When applied as a finite dose in a representative oil-in-water emulsion vehicle the average total absorption over 48 hr was 4.0 +/- 0.3% of the applied dose. When applied as a finite dose in a representative shampoo vehicle for 10 min followed by rinsing (i.e. to represent in-use exposure conditions) the average total absorption over 48 hr was 1.1 +/- 0.1% of the applied dose. Approximately 72% of the DMN in the applied shampoo vehicle was removed by rinsing. There was considerable evaporative loss of DMN from the IPM and oil-in-water emulsion vehicles, such that absorption was complete within 3 hr of application. The overall data indicate that DMN can penetrate the skin rapidly but that in practice the amount actually available for penetration is significantly reduced by high permeant volatility. In contrast, application of N-nitrosodiethanolamine (NDELA) at a concentration of 1 microgram/microliter as an infinite dose generated an average total absorption over 48 hr of 23.6 +/- 6.4%, representing a total flux of 103.9 +/- 28.4 micrograms/cm2. In the case of NDELA, no evaporative loss was evident.

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Disperse Blue 1 is an anthraquinone dye used at low levels in semipermanent hair color formulations. Dietary administration of Disperse Blue 1 in a National Toxicology Program (NTP) carcinogenesis bioassay produced transitional- and squamous-cell tumors, leiomyomas, and leiomyosarcomas of the urinary bladders of male and female F344/N rats. The occurrence of tumors in the urinary bladder of rats was associated with urothelial hyperplasia and the presence of urinary calculi. Despite the occurrence of urinary bladder calculi and other nonneoplastic changes, there was no evidence of urinary bladder carcinogenesis in B6C3F1 mice fed Disperse Blue in the diet for up to 2 years. A study conducted in rats of the same strain by Burnett and Squire confirmed the occurrence of calculi and transitional-cell neoplasms in the rat bladder. However, no mesenchymal-cell tumors were detected at a comparable dietary level. Further, Burnett and Squire found evidence of reversibility of the proliferative changes in the rat urinary bladder following cessation of treatment at 6 months. Disperse Blue 1 has been tested in a variety of in vivo and in vitro genotoxicity assays and was negative in vivo but produced a weak and mixed pattern of genotoxic responses in vitro which may be attributable to a constituent of the commercial preparations. Evaluation of the available data for Disperse Blue 1 and comparison with the responses observed in the urinary bladders of rats administered other rodent bladder carcinogens considered to act through a secondary mechanism indicate that a threshold approach is appropriate for assessing risk. With this approach, an uncertainty factor of 1000 applied to the no-observed-adverse-effect level in the NTP bioassay yielded a safe exposure level of 45-56 micrograms/kg/day. In contrast, with a conventional quantitative risk assessment approach, the exposure level corresponding to an upper limit on lifetime risk of 10(-6) to 10(-5) was 0.39 to 3.9 micrograms/kg/day, respectively. The safe level of Disperse Blue 1 derived using the threshold approach is approximately 20 times greater than the maximum average daily applied dose of 2.7 micrograms/kg/day associated with its use in semipermanent hair color formulations, while the exposure associated with the 10(-5) risk level using the linearized multistage model in the conventional approach was determined to be 1.5 times greater. Because oral absorption is substantially more than dermal absorption, the actual margin of safety is most likely much greater than either of these comparisons suggests.(ABSTRACT TRUNCATED AT 400 WORDS)

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p-Aminophenol (p-AP) was fed in the diet to groups of 40 male and 45 female Sprague-Dawley rats at levels of 0.07, 0.2 or 0.7% for up to 6 months. Methaemoglobin levels were determined after 6 wk. During wk 12, urine was collected from ten rats/sex/group for evaluation of mutagenicity in the Ames test. Clinical chemistry, haematology and histopathology studies were performed in subgroups after 13 and 27 wk. In addition, after 13 wk, 25 females/group were mated to untreated males in a teratology study. After 20 wk, 20 males/group were removed from the test diets and mated to untreated virgin females in a dominant lethal mutagenicity study. These males remained untreated until they were killed at 27 wk. Rats that had been maintained on the test diets throughout the study were also killed at wk 27. The high dose level of 0.7% p-AP resulted in a significant (10-15%) reduction in body-weight gain in both sexes. There was no increase in the level of methaemoglobin and, other than slight reductions in total erythrocytes and haemoglobin in female rats at 13 wk, there were no toxicologically important differences between groups in haematology or clinical chemistry values at any time during the 27 wk of treatment. Dose-related nephrosis was seen in both sexes after 13 and 27 wk and in the high-dose males that were removed from the test diet for a 7-wk recovery period. The compound was not teratogenic, but an increase in developmental variations associated with maternal toxicity was noted at the mid- and high-dose levels. In the dominant lethal study, an increase in the total number of resorptions (but not litters with resorptions) was observed in the high-dose group in the first of two matings but this observation was not confirmed in a follow-up study. Mutagenic activity was not detected in the urine of rats fed p-AP.

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Although antihistamines are widely used for symptomatic treatment of seasonal (allergic) rhinitis, the role of histamines in the pathogenesis of infectious rhinitis is not clear. Two antihistamines, orally administered chlorpheniramine maleate (CM) and diphenhydramine hydrochloride (DH) administered by intranasal spray, were used under double-blinded, randomized, placebo-controlled conditions to assess both tolerance and efficacy in volunteers with experimental rhinovirus (RV) colds. In the initial trial, CM (4.0 mg per treatment) was ingested 4 times daily for 4 days beginning 24 h after intranasal inoculation of RV type 29 in susceptible volunteers. In the second trial, DH was sprayed intranasally 4 times daily (2 mg per treatment) for 5 days beginning 24 h after inoculation of RV type 39. Clinical colds occurred in 60% of the CM group (n = 13) and 73% of the placebo (n = 15) in the first study, and in 66% of the DH group (n = 12) compared with 81% in the placebo group (n = 11) in the second. Both CM and DH were well tolerated but had no significant effects on nasal symptoms or nasal mucus production. The findings provide additional evidence against an important role for histamine in the pathogenesis of nasal symptomatology in rhinovirus colds.

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The role of parasympathetic/cholinergic mechanisms in the syndrome of the common cold is not clear. Under double-blind, randomized, placebo-controlled conditions, we intranasally administered the anticholinergic atropine methonitrate (AM) to assess its tolerance in uninfected adults and therapeutic efficacy in volunteers with experimental rhinovirus (RV) colds. Healthy adults given sprays of AM intranasally 250 or 500 micrograms 4 times a day for 5 days developed nasal dryness and systemic side effects more often than did placebo (P) recipients. In 2 separate challenge studies, treatments were begun with AM 125 micrograms 3 times a day (AM = 8, P = 7) or AM 250 micrograms 4 times a day (AM = 9, P = 7) for 5 days, 24 h after intranasal inoculation of RV type 39. The low AM dose was well tolerated but had no effect on nasal mucus weights or nasal symptom scores in persons with RV colds. The higher dose of AM was associated with subjective drying and a reduction in nasal mucus production. These findings suggest that cholinergic mechanisms have a role in the pathogenesis of RV colds but that more work is necessary to determine if anticholinergic compounds will be of practical value in their treatment.

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The perception of resistive loads added to nasal breathing was assessed in ten healthy adults using established psychophysical methods previously described for oral breathing. Detection threshold, that is, the smallest incremental resistance that the subject could detect 50% of the time, was determined at three different time periods (0, 30, and 60 min) on two separate days to determine the reproducibility of values over time. Nasal airway resistance measurements were made before and after threshold determinations to determine the influence of baseline resistance on the ability to detect added loads as well as to assess any effects of the procedure itself on resting nasal airway resistance. Analyses of the data revealed that subject-to-subject differences were the largest source of variability in threshold values followed by time period-to-time period differences and day-to-day variability. Although it was the smallest variability source, day-to-day variability still was significantly greater than zero. In contrast to previously published reports on resistive load detection during mouth breathing, the degree of baseline resistance did not appear to influence the subject's ability to detect added resistive loads during nasal breathing. These techniques may provide a methodological basis for objectively evaluating the effects of pharmacologic agents on perceived nasal patency.

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The utility of an anterior rhinomanometric method for the assessment of decongestant drug activity is illustrated with representative clinical data. Controlled studies employing topical nasal spray, nasal inhaler, and oral syrup formulations were conducted under single- or double-blind conditions in patients with allergic or coryzal rhinitis. The method provided an objective means to distinguish active from placebo (vehicle) treatments and to discriminate differences in decongestant activity between two active formulations. Furthermore, objectively determined increases in nasal patency paralleled the patients' subject-ve perception of improved airflow. In conclusion, this rhinomanometric methodology provided objective confirmation of drug activity with orally-administered, inhaled, and topically-applied decongestant drug formulations.

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