Application of the threshold of toxicological concern approach for the safety evaluation of calendula flower (Calendula officinalis) petals and extracts used in cosmetic and personal care products.

Calendula flower (Calendula officinalis) (CF) has been used in herbal medicine because of its anti-inflammatory activity. CF and C. officinalis extracts (CFE) are used as skin conditioning agents in cosmetics. Although data on dermal irritation and sensitization of CF and CFE's are available, the risk of subchronic systemic toxicity following dermal application has not been evaluated. The threshold of toxicological concern (TTC) is a pragmatic, risk assessment based approach that has gained regulatory acceptance for food and has been recently adapted to address cosmetic ingredient safety. The purpose of this paper is to determine if the safe use of CF and CFE can be established based upon the TTC class for each of its known constituents. For each constituent, the concentration in the plant, the molecular weight, and the estimated skin penetration potential were used to calculate a maximal daily systemic exposure which was then compared to its corresponding TTC class value. Since the composition of plant extracts are variable, back calculation was used to determine the maximum acceptable concentration of a given constituent in an extract of CF. This paper demonstrates the utility and practical application of the TTC concept when used as a tool in the safety evaluation of botanical extracts.

Abnormalities of endocrine function in patients with clinically "silent" adrenal masses.

Because, in recent years, patients with incidentally discovered adrenal masses have been encountered increasingly, their endocrine function was investigated in basal conditions and after dynamic tests. Thirty-two patients (23 women and 9 men, aged 28-74 years) were studied. Lesion diameter, as documented by computed tomography and/or nuclear magnetic resonance imaging, ranged between 5 and 65 mm; the tumors were localized on the right in 22 patients, on the left in 5 and bilaterally in 5 cases. In basal conditions, urinary free cortisol (UFC) excretion, plasma adrenocorticotropin (ACTH) and cortisol levels were normal, except for 4 patients who showed high UFC and ACTH levels in the low-normal range. Ovine corticotropin-releasing hormone (CRH, 1 microgram/kg iv) was given to 18 patients, inducing normal ACTH and cortisol responses in 12, blunted responses in 4 and no response in 2 cases. No reduction in ACTH and cortisol levels after suppression tests was observed in 4 of 29 patients after dexamethasone (1 mg overnight) or in 6 of 29 after loperamide. The 4 patients who were unresponsive to both tests did not show any further inhibition after high-dose dexamethasone administration, had low plasma ACTH levels and showed impaired or absent responses to the CRH test: they were diagnosed as affected with preclinical Cushing's syndrome. An exogenous ACTH test performed in 30 patients caused a normal cortisol rise. Basal mean 17-hydroxy-progesterone (17-OHP) levels were not different from those in normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

The toxicity of p-aminophenol in the Sprague-Dawley rat: effects on growth, reproduction and foetal development.

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.