Evidence Of Nephrotoxicity Research Articles

(197) Natural Aphrodisiacs Consumption by Male Workers in the Katanga province, DR Congo

Abstract Introduction In a previous cross-sectional study to determine the prevalence of ED among artisanal mineworkers, we found a significant association between aphrodisiacs consumption and erectile dysfunction (Musa et al. under review). Objective This study aimed at investigating the main reasons of aphrodisiacs consumption and their possible health effects in male workers in the Katanga province. Methods We conducted a mixed method study in which a first quantitative phase (survey) was conducted from March 2021 to May 2021, and included by convenience sampling, 127 artisanal miners and 122 drivers of collective taxis. All participants responded to the IIEF in the first survey. We measured urea, creatinine, sGOT, sGPT, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglyceride in serum. The second qualitative phase (interviews) took place later, and included 16 participants from the first quantitative study, 8 in each group. Results Self-reported aphrodisiacs consumption was 1.6 as prevalent among taxi-drivers compared to miners. ED was 1.5 as prevalent among aphrodisiacs' consumers compared to controls. Total cholesterol and LDL were significantly higher in aphrodisiac consumers than in non-consumers. Cultural perceptions about masculinity, support of erectile function and/or prevention of ED were themes that emerged from interviews in both groups. Two most consumed aphrodisiacs including Securidaca longepedunculata and Mitragyna stipulosa were taken with alcohol. No evidence of nephrotoxicity or hepatotoxicity was found. Conclusions In a population with high rate of herbal treatment use, we found a high prevalence of natural aphrodisiac plants that are widely consumed instead of pharmacologically proved synthetic drugs probably due to cultural beliefs. More ethno botanical studies of plants consumed as aphrodisiacs including isolation and rigorous identification of the active constituents are needed to provide the poor population with the right information and to protect them against unwanted toxic effects. Disclosure No.

Dosing Colistimethate Every 8 h Results in Higher Plasma Concentrations of Active Colistin Than Every 12-Hourly Dosing without Increase in Nephrotoxicity: A Phase 1 Pharmacokinetics Trial in Healthy Adult Volunteers.

Despite its use for decades, pharmacokinetic (PK) and safety studies on colistin are limited. We conducted a phase l, open-label trial to evaluate the safety and PK of multiple doses of intravenous (IV) and aerosolized colistimethate sodium (CMS) administered separately and in combination. In total, 31 healthy adults were enrolled into three cohorts of 9, 10, and 12 participants, respectively. Each cohort received increasing doses of CMS over three dosing periods as follows: Period 1 (IV only), 2.5 mg/kg every 12 h (q12h) to 3.3 mg/kg every 8 h (q8h); Period 2 (aerosolized only), 75 mg 2–4 doses, and Period 3 (combined IV aerosolized), in which was Periods 1 and 2 combined. Safety assessments, serum and lung concentrations of colistin analytes (colistin A, colistin B, CMS A, and CMS B), and kidney biomarkers were measured at specified time points. Increasing the CMS dose from 2.5 mg/kg q12h to q8h resulted in a 33% increase in serum colistin A concentrations from 3.9 μg/mL to 5.3 μg/mL—well above the accepted target of 2 μg/mL for 6 h after dosing, without evidence of nephrotoxicity. However, there was an increase in neurotoxicity, primarily perioral and lingual paresthesias, and self-limited ataxia. IV administration did not increase the lung concentrations of colistin.

Evaluation of bone and kidney toxicity of BT2-peg2, a potential carrier for the targeted delivery of antibiotics to bone.

Previous studies have demonstrated that the bone targeting agent BT2-peg2 (BT2-minipeg2, 9), when conjugated to vancomycin and delivered systemically by intravenous (IV) or intraperitoneal (IP) injection accumulates in bone to a greater degree than vancomycin alone, but that this accumulation is associated with severe nephrotoxicity. To determine whether this nephrotoxicity could be attributed to BT2-peg2 itself, we used a rat model to assess the distribution and toxicity of BT2-peg2 after IP injection of 11 mg/kg twice daily for 21 days. The results demonstrated that BT2-peg2 accumulates in bone but there was no evidence of nephrotoxicity or any histopathological abnormalities in the bone. This suggests the nephrotoxicity observed in previous studies is likely due to the altered pharmacokinetics of vancomycin when conjugated to BT2-peg2 rather than to BT2-peg2 itself. Thus, BT2-peg2 may be a safe carrier for the enhanced delivery of antibiotics other than vancomycin to the bone as a means of combating bone infection. However, the data also emphasizes the need to carefully examine the pharmacokinetic characteristics of any BT2-peg2-antibiotic conjugate utilized for treatment of bone infections.

A Pharmacologic "Stress Test" for Assessing Select Antioxidant Defenses in Patients with CKD.

Oxidative stress is a hallmark and mediator of CKD. Diminished antioxidant defenses are thought to be partly responsible. However, there is currently no way to prospectively assess antioxidant defenses in humans. Tin protoporphyrin (SnPP) induces mild, transient oxidant stress in mice, triggering increased expression of select antioxidant proteins (e.g., heme oxygenase 1 [HO-1], NAD[P]H dehydrogenase [quinone] 1 [NQO1], ferritin, p21). Hence, we tested the hypothesis that SnPP can also variably increase these proteins in humans and can thus serve as a pharmacologic "stress test" for gauging gene responsiveness and antioxidant reserves. , setting, participants, & measurementsA total of 18 healthy volunteers and 24 participants with stage 3 CKD (n=12; eGFR 30-59 ml/min per 1.73 m2) or stage 4 CKD (n=12; eGFR 15-29 ml/min per 1.73 m2) were injected once with SnPP (9, 27, or 90 mg). Plasma and/or urinary antioxidant proteins were measured at baseline and for up to 4 days post-SnPP dosing. Kidney safety was gauged by serial measurements of BUN, creatinine, eGFR, albuminuria, and four urinary AKI biomarkers (kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, cystatin C, and N-acetyl glucosaminidase). Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (r=-0.85 to -0.95). All four proteins manifested statistically significant dose- and time-dependent elevations after SnPP injection. However, marked intersubject differences were observed. p21 responses to high-dose SnPP and HO-1 responses to low-dose SnPP were significantly suppressed in participants with CKD versus healthy volunteers. SnPP was well tolerated by all participants, and no evidence of nephrotoxicity was observed. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.

Abstract CT015: Safety and long-term efficacy of radioligand therapy using Lu-177 labeled PSMA ligands in metastatic prostate cancer: A single center experience over 5 years

Abstract Aim: Metastatic prostate cancer (mPC) has still a poor prognosis. First- and second-line chemotherapy with docetaxel or cabazitaxel is often toxic and prolongs life by only a few months. Also novel agents like abiraterone, enzalutamide or Ra-223-chloride confer a limited survival benefit. Prostate-specific membrane antigen (PSMA) is a glutamate carboxypeptidase II overexpressed especially in poorly differentiated prostate cancer (1) and is a very attractive target for diagnosis and therapy (theranostics) with radiolabeled small molecules. Internalization and retention within the tumor cell provides very promising and highly selective treatment effects of multiple metastases with PSMA radioligand therapy (PRLT) (2-5). Methods: 224 mPC patients (mean age 71 years, mean Gleason score 8), screened by Ga-68 PSMA or F-18 DCFPyl PET/CT imaging, were treated with 1 - 9 cycles (3.5 - 12 GBq Lu-177 PSMA per cycle) between April 2013 and October 2017 and included in the intention to treat analysis with a median follow-up time of 16 months (3 - 55). Previous treatments were surgery (154), external beam radiation (151), chemotherapy (110), androgen deprivation (206) and Ra-223 chloride (19). The serum prostate antigen (PSA) levels were monitored before and after therapy. Response to therapy was also determined by RECIST as well as according to molecular imaging criteria using standardized uptake values (SUV) on Ga-68 PSMA PET/CT studies. Hematological and organ toxicity was documented according to CTCAE v4.03. Results: Reduction in serum PSA was observed in 157/224 (70%) patients; 121/224 patients (54%) demonstrated a PSA decline by >50%, best response was complete remission with undetectable PSA. Ga-68 PSMA PET/CT after at least 2 PRLT cycles in 200 patients demonstrated complete remission in 6 (3%), partial remission in 70 (35%), stable disease in 55 (27.5%) and progressive disease in 69 (34.5%) patients. RECIST revealed 46 (23%) partial remissions, 6 (3%) complete remissions, 84 (42%) with stable disease and 64 (32%) disease progressions. The median overall survival was 27 months. Median progression-free survival was 18 months. No severe (G3-4) bone marrow toxicity was observed and patients didn't show any evidence of nephrotoxicity or any other significant organ toxicity. Mild xerostomia occurred in less than 3% of all patients. Conclusion: Lu-177 PSMA radioligand therapy appears to be effective for the treatment of metastatic prostate cancer with only minimal toxicity, offering a significant benefit in overall and progression-free survival even in patients whose disease had progressed despite all standard treatments. Randomized controlled studies are required to best determine the place of this theranostic approach in the management of mPC. Citation Format: Harshad R. Kulkarni, Thomas Langbein, C Atay, Aviral Singh, Christiane Schuchardt, Coline Lehmann, Martin Pomper, Kenneth J. Pienta, Richard P. Baum. Safety and long-term efficacy of radioligand therapy using Lu-177 labeled PSMA ligands in metastatic prostate cancer: A single center experience over 5 years [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT015.

Continuous Infusion Vancomycin for Treatment of Methicillin-Resistant Staphylococcus aureus in Cystic Fibrosis Patients

To report 3 cases of methicillin-resistant Staphylococcus aureus (MRSA) in pediatric patients with cystic fibrosis (CF), all of whom had inadequate serum concentrations of vancomycin with conventional intermittent dosing and who achieved therapeutic serum concentrations with continuous infusions of vancomycin. In the first case, a 3-year-old patient failed to achieve therapeutic vancomycin trough concentrations despite 2 dose adjustments up to 19 mg/kg every 6 hours. A continuous infusion was initiated and a therapeutic steady-state level was obtained. The remaining case reports describe 2 patients who were readmitted to the hospital after having received intermittent dosing as outpatients. Continuous infusions were started upon readmission, and therapeutic serum concentrations were achieved in both patients. MRSA is a common pathogen in patients with CF. Intravenous vancomycin, a time-dependent antibiotic that is extensively eliminated by the kidneys, is frequently used to treat MRSA infections. Serum trough concentrations of 15-20 mg/L are considered therapeutic, but these levels are difficult to achieve in patients with CF because of increased renal clearance. Continuous infusions of vancomycin were successfully used in the patients described here and resulted in decreased total daily doses of vancomycin, clinical improvement, and no evidence of nephrotoxicity. Although more extensive studies are necessary, the cases presented here suggest that continuous infusion vancomycin is a safe and convenient therapy for MRSA infections.

Pharmacokinetics and Safety of Single and Multiple Doses of ACHN-490 Injection Administered Intravenously in Healthy Subjects

ACHN-490 is an aminoglycoside with activity against multidrug-resistant pathogens, including those resistant to currently used aminoglycosides. Two randomized, double-blind, placebo-controlled clinical studies investigated the pharmacokinetics (PK), safety, and tolerability of ACHN-490 injection in healthy subjects. Study 1 used a parallel-group design with escalating single (SD) and multiple doses (MD). Study 2 explored a longer duration of the highest dose tolerated in the first study. Subjects were randomly assigned to receive either ACHN-490 injection or a placebo administered by a 10-min intravenous infusion. Study 1 enrolled 39 subjects (30 active and 9 placebo) and consisted of a single dose of 1 mg/kg body weight followed by ascending SD and MD cohorts of 4, 7, 11, and 15 mg/kg for 10, 10, 5, and 3 days, respectively. Study 2 enrolled 8 subjects (6 active and 2 placebo) who received 15 mg/kg for 5 days. Safety was assessed from adverse event (AE) reporting, standard clinical laboratory procedures, and testing for renal, cochlear, and vestibular function. ACHN-490 exhibited linear and dose-proportional PK, with agreement between the studies for PK parameters assessed. The 15-mg/kg dose did not accumulate with repeated dosing over 5 days. Mean steady-state (±standard deviation) area under the concentration-time curve from 0 to 24 h (AUC(0-24)), maximum concentration of drug in serum (C(max)), half-life (t(1/2)), clearance, and volume of distribution at steady state (V(ss)) for the 15-mg/kg, day 5 dose were 239 ± 45 h·mg/liter, 113 ± 17 mg/liter, 3 ± 0.3 h, 1.1 ± 0.1 ml/min/kg, and 0.24 ± 0.04 liters/kg, respectively. AEs were mild to moderate and rapidly resolved. No evidence of nephrotoxicity or ototoxicity was observed.

Desferrithiocin analogue iron chelators: iron clearing efficiency, tissue distribution, and renal toxicity.

The current solution to iron-mediated damage in transfusional iron overload disorders is decorporation of excess unmanaged metal, chelation therapy. The clinical development of the tridentate chelator deferitrin (1, Table1) was halted due to nephrotoxicity. It was then shown by replacing the 4'-(HO) of 1 with a 3,6,9-trioxadecyloxy group, the nephrotoxicity could be ameliorated. Further structure-activity relationship studies have established that the length and the position of the polyether backbone controlled: (1) the ligand's iron clearing efficiency (ICE), (2) chelator tissue distribution, (3) biliary ferrokinetics, and (4) tissue iron reduction. The current investigation compares the ICE and tissue distribution of a series of (S)-4,5-dihydro-2-[2-hydroxy-4-(polyether)phenyl]-4-methyl-4-thiazolecarboxylic acids (Table1, 3-5) and the (S)-4,5-dihydro-2-[2-hydroxy-3-(polyether)phenyl]-4-methyl-4-thiazolecarboxylic acids (Table1, 8-10). The three most effective polyether analogues, in terms of performance ratio (PR), defined as mean ICE(primate)/ICE(rodent), are 3 (PR 1.1), 8, (PR 1.5), and 9, now in human trials, (PR 2.2). At the onset of the clinical trial on 9, no data were available for ligand 3 or 8. This is unfortunate, as 3 has many advantages over 9, e.g., the ICE of 3 in rats is 2.5-fold greater than that of 9 and analogue 3 achieves very high levels in the liver, pancreas, and heart, the organs most affected by iron overload. Finally, the impact of 3 on the urinary excretion of kidney injury molecule-1 (Kim-1), an early diagnostic biomarker for monitoring acute kidney toxicity, has been carried out in rats; no evidence of nephrotoxicity was found. Overall, the results suggest that 3 would be a far superior clinical candidate to 9.

Aerosolized amikacin for treatment of pulmonary Mycobacterium aviuminfections: an observational case series

BackgroundCurrent systemic therapy for nontuberculous mycobacterial pulmonary infection is limited by poor clinical response rates, drug toxicities and side effects. The addition of aerosolized amikacin to standard oral therapy for nontuberculous mycobacterial pulmonary infection may improve treatment efficacy without producing systemic toxicity. This study was undertaken to assess the safety, tolerability and preliminary clinical benefits of the addition of aerosolized amikacin to a standard macrolide-based oral treatment regimen.Case PresentationsSix HIV-negative patients with Mycobacterium avium intracellulare pulmonary infections who had failed standard therapy were administered aerosolized amikacin at 15 mg/kg daily in addition to standard multi-drug macrolide-based oral therapy. Patients were monitored clinically and serial sputum cultures were obtained to assess response to therapy. Symptomatic improvement with radiographic stabilization and eradication of mycobacterium from sputum were considered markers of success.Of the six patients treated with daily aerosolized amikacin, five responded to therapy. All of the responders achieved symptomatic improvement and four were sputum culture negative after 6 months of therapy. Two patients became re-infected with Mycobacterium avium intracellulare after 7 and 21 months of treatment. One of the responders who was initially diagnosed with Mycobacterium avium intracellulare became sputum culture positive for Mycobacterium chelonae resistant to amikacin after being on intermittent therapy for 4 years. One patient had progressive respiratory failure and died despite additional therapy. There was no evidence of nephrotoxicity or ototoxicity associated with therapy.ConclusionAerosolized delivery of amikacin is a promising adjunct to standard therapy for pulmonary nontuberculous mycobacterial infections. Larger prospective trials are needed to define its optimal role in therapy of this disease.

Safety of Cidofovir in High-Risk Paediatric Patients.

Purpose: Cidofovir has efficacy in the treatment of adenovirus and cytomegalovirus (CMV) infection in immunocompromised individuals. It is licensed for the treatment of CMV retinitis in AIDS patients over the age of 12 years, and is nephrotoxic and contra-indicated with the use of other concomitant nephrotoxic agents. Its use has been further limited due to concerns regarding an individual's ability to tolerate the hydration regimens associated with cidofovir administration. Despite this it is a valuable anti-viral agent particularly in the setting of haemapoietic stem cell transplantation. This study assessed the safety of cidofovir in a high-risk paediatric population.Methods: A retrospective review of all episodes of cidofovir administration at the Oncology Unit at the Children's Hospital at Westmead from 2000–2005 was undertaken. The dose of cidofovir and renal function (measured by urea and creatinine) pre and post infusion were recorded, and the medical notes reviewed for adverse events and concomitant use of other nephrotoxic drugs.Results: A total of 233 cidofovir infusions in 23 patients were studied.Patients: Age range 5 months - 19 years (mean 6.6 years). Sex: male 17 (74%), female 6 (26%). Clinical setting: 16 (70%) were post allogeneic stem cell transplantation, 4 (17%) were post autologous stem cell transplation, 3 (13%) had other malignancies. Indications for cidofovir: In 20 (87%) for proven adenovirus identified in stool, urine, nasopharyngeal aspirate, CSF, or tissue biopsy; 2 (9%) for adenovirus prophylaxis as part of haplo-identical stem cell transplant conditioning, 1 (4%) for extended coverage in sepsis without an identified organism. Cidofovir doses: 111 (48%) were 1mg/kg, 75 (32%) were 3mg/kg, 47 (20%) were 5mg/kg. All episodes of cidofovir administration received the same standard recommended regimen of oral probenecid 40mg/kg at hour -3, 20ml/kg of intravenous 0.9% NaCl from hour −1 to 0, cidofovir infusion with 20ml/kg 0.9% NaCl from hour 0 to +1, maintenance intravenous fluids from hour +1 to +3, followed by oral probenecid 20mg/kg at hour +3 and +9. All patients received concomitant nephrotoxic agents: 4 (17%) received 1, 4 (17%) received 2, 5 (22%) received 3, and 10 (43%) received 4 or more agents. In 19 (83%) patients with normal renal function (defined by urea/creatinine within normal range for age), there was no evidence of nephrotoxicity (defined as >150% increase in urea/creatinine from baseline) following cidofovir therapy - mean change in urea/creatinine pre and post infusion −7.5%/+5.6%. There was no deterioration in renal function in 4 (17%) patients with pre-existing renal impairment (defined by urea/creatinine above the upper limit of normal) - mean change in urea/creatinine pre and post infusion −10.9%/+3.0%. Symptomatically cidofovir was tolerated by 20 (87%) patients without adverse events. Cidofovir therapy was associated with significant morbidity in 3 (17%) patients - 1 developed blindness and axonal degeneration of unknown aetiology, and in 2 patients, both with pre-existing pneumonitis post allogeneic stem cell transplantation, the fluid regimen precipitated a respiratory deterioration secondary to fluid overload.Conclusion: Cidofovir is a safe and well tolerated drug in a high-risk paediatric population, even with the use of concomitant nephrotoxic agents. An aggressive fluid regimen may not be necessary, with particular care required in patients with significant pulmonary disease in whom the fluid regimen may precipitate respiratory compromise.

γ-Glutamyl Transpeptidase-Deficient Mice Are Resistant to the Nephrotoxic Effects of Cisplatin

We have proposed that the nephrotoxicity of cisplatin, a widely used chemotherapy drug, is the result of the binding of cisplatin to glutathione and the subsequent metabolism of the cisplatin-glutathione complex via a gamma-glutamyl transpeptidase (GGT)-dependent pathway in the proximal tubules. To test the hypothesis that GGT activity is essential for the nephrotoxicity of cisplatin, the effects of cisplatin were examined in wild-type and GGT-deficient mice. Mice were treated with 15 mg cisplatin/kg. Five days after treatment, renal histopathology, blood urea nitrogen levels, serum creatinine, platinum excretion, and platinum accumulation in the kidney were examined. Half the mice were supplemented with N-acetylcysteine, which has been shown to correct low levels of tissue glutathione in GGT-deficient mice. The data show that cisplatin was nephrotoxic in wild-type mice but not in GGT-deficient mice. The wild-type mice, with and without N-acetylcysteine supplementation, had significantly elevated levels of blood urea nitrogen, serum creatinine, and renal tubular necrosis. There was no evidence of nephrotoxicity in the GGT-deficient mice regardless of N-acetyl cysteine supplementation. No differences in platinum excretion were seen comparing wild-type and GGT-deficient mice, nor was there any significant difference in renal platinum accumulation. These data suggest that renal cisplatin toxicity is dependent on GGT activity, and is not correlated with uptake. The results support our hypothesis that the nephrotoxicity of cisplatin is the result of the metabolism of the drug through a GGT-dependent pathway.

Final Report on the Safety Assessment of PEG-2, -3, -5, -10, -15, and -20 Cocamine

The PEGs Cocamine are the polyethylene glycol ethers of the primary aliphatic amine derived from coconut oil. These ingredients are used in cosmetic formulations as surfactants which function as emulsifying and solubilizing agents. Very little data were available on metabolism and toxicity, and no clinical data were found or provided. Toxicity data, including reproductive and developmental toxicity, carcinogenesis data, and clinical testing data available from previous safety assessments on Polyethylene Glycol and Coconut Oil were summarized. The principal finding related to PEGs was based on clinical data in burn patients; PEGs were mild irritant/sensitizers and there was evidence of nephrotoxicity. No such effects were seen in animal studies on intact skin. Cosmetic manufacturers should adjust product formulations containing Polyethylene Glycol to minimize any untoward effects when products are used on damaged skin. Various PEGs Cocamine were found to be mild to moderate skin irritants and were ocular irritants. PEG-15 Cocamine was negative in bacterial mutagenicity studies. Although metabolites of ethylene glycol monoalkyl ethers are reproductive and developmental toxins, it was considered unlikely that the relevant metabolites would be found in or produced from the use of PEGs Cocamine in cosmetic formulations. Of concern was the possible presence of 1,4-dioxane and ethylene oxide impurities. The importance of using the necessary purification procedures to remove these impurities was stressed. The limited data on PEGs Cocamine and the related data on other ingredients, however, were not sufficient to support the safety of PEGs Cocamine for use in cosmetic formulations. Additional data needs include: (1) physical and chemical properties, including impurities, and especially nitrosamines; (2) genotoxicity in a mammalian system; if the results are positive, then a dermal carcinogenesis study using National Toxicology Program (NTP) methods may be needed; (3) 28-day dermal toxicity using PEG-2 Cocamine; and (4) dermal sensitization data on PEG-2 Cocamine.

Addendum to the Final Report on the Safety Assessment of PEGs Lanolin to Include PEG-5, -10, -24, -25, -35, -55, -100, and-150 Lanolin; PEG-5, -10, -20, -24, -30, and -70 Hydrogenated Lanolin; PEG-75 Lanolin Oil; and PEG-75 Lanolin Wax1

The safety of selected polyethylene glycols (PEGS) Lanolin polymers was previously reviewed. This review completes the safety assessment of all the PEGs Lanolin polymers and related cosmetic ingredients. PEGs Lanolin are prepared by ethoxylating the hydroxy fatty acids, hydroxy esters, sterols, and alcohols present in whole lanolin. The number of moles of ethylene oxide reacted with each respective lanolin component corresponds to the average polyethylene glycol chain length. PEGs Lanolins, PEGs Hydrogenated Lanolins, PEG Lanolin Oil, and PEG Lanolin Wax are used as emulsifying, soluhilizing, and cleansing agents. PEGs Hydrogenated Lanolins are also hair-conditioning agents and skin-conditioning emollients. Few data on the PEGs Lanolin were available regarding systemic toxicity, mutagenicity, carcinogenicity, and clinical safety. Related compounds including PEGs, Lanolin, and Lanolin Oil have been previously reviewed. Based on clinical data in burn patients, PEGs were mild irritants/sensitizers and there was evidence of nephrotoxicity. No such effects were seen in animal studies on intact skin. Cosmetic manufacturers should continue to adjust product formulations to minimize any untoward effects when products are used on damaged skin. No evidence of phototoxic effects was found in clinical studies. Comedogenic effects have resulted from the use of cosmetic products containing lanolin compounds. No evidence of mutagenicity, carcinogenicity, or reproductive and developmental toxicity was found with these related compounds. Although metabolites of ethylene glycol monoalkyl ethers are reproductive and developmental toxins, it was considered unlikely that the relevant metabolites would be found in or produced from the use of PEGs Cocamine in cosmetic formulations. Based primarily on data from ingredients with related structures, it was concluded that PEG-S, -10, -24, -25, -35, -55, -100, and -150 Lanolin; PEG-S, -10, -20, -24, -30, and -70 Hydrogenated Lanolin; PEG-75 Lanolin Oil; and PEG-75 Lanolin Wax are safe for use in cosmetic formulations under the present practices of use.

Final Report on the Safety Assessment of Ceteareth-2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18,-20,-22,-23,-24,-25,-27, -28, -29, -30, -33, -34, -40, -50, -55, -60, -80, and -100

Ceteareths, used in a large number of cosmetics as surfactants, are the polyethylene glycol (PEG) ethers of Cetearyl Alcohol (q,v.). To supplement the limited available data on Ceteareths, previous findings from the safety assessment of Polyethylene Glycol (PEG), several fatty alcohols (Cetearyl Alcohol, Cetyl Alcohol, and Stearyl Alcohol), and Steareths were considered. These data indicate little evidence of toxicity. Although various metabolites of monoalkyl ethers of ethylene glycol are reproductive and developmental toxins, given the methods of manufacture of Ceteareth compounds, there is no likelihood of such compounds being present as impurities. Further, there would be only limited ethylene glycol monomer linked by an ether group to the Ceteareth moiety for the PEG-5 compounds, little for the PEG-10 compounds, and virtually none for the PEG-20 and higher compounds. Even if linked to ethylene glycol monomer, it was considered unlikely that the Ceteareth moieties would be metabolized (e,g., via β-oxidation) to simple methyl, ethyl, propyl, or butyl alkyl groups. As the current data indicate, such short alkyl chains are needed in order for the production of toxic alcohol or aldehyde dehydrogenase metabolites. For longer alkyl chains there is evidence of diminishing toxicity, and extrapolation to much longer chains such as expected in the Ceteareth moieties suggests that there is no reproductive or developmental hazard posed by these Ceteareth compounds. The principal clinical finding related to PEGs is based on data in bum patients— PEGs were mild irritants/sensitizers and there was evidence of nephrotoxicity. No such effects were seen in animal studies on intact skin. Cosmetic manufacturers should adjust product formulations containing Polyethylene Glycol to minimize any untoward effects when products are used on damaged skin. In the absence of specific impurities data, the possible presence of 1,4-dioxane and ethylene oxide impurities was of concern. The importance of using the necessary purification procedures to remove these impurities was stressed. Creams containing Ceteareth-20 enhanced drug absorption. Ceteareth-15 (10% in formulation) was minimally irritating to rabbits after a single dermal exposure. In ocular studies, ethoxylated Cetearyl Alcohol solution was a severe irritant to unrinsed rabbit eyes and moderately irritating to rinsed eyes. In clinical studies, Ceteareth-15 (1.5 % in formulation) produced minimal irritation when tested in both a 4- and 21-day patch test, and was not a sensitizer when tested (1.35% in formulation) in a repeat-insult patch test. Based on the limited data on Ceteareths and the extensive data on chemically related ingredients, it was concluded that these ingredients are safe as used in cosmetic formulations. These ingredients, however, should not be used on damaged skin.

Final Report on the Safety Assessment of Ceteth-1, -2, -3, -4, -5, -6, -10, -12, -14, -15, -16, -20, -24, -25, -30, and -45

The Ceteth family of ingredients are the polyethylene glycol (PEG) ethers of cetyl alcohol. They are manufactured by the ethoxylation of cetyl alcohol with the number of moles of ethylene oxide corresponding to the average polyethylene glycol chain length desired. Not all of the polymer chain lengths covered in this assessment are currently reported to be used, but all are listed as cosmetic ingredients and may have been used in the past and could be used in the future. Ceteths are surfactants used as emulsifying, cleansing, and solubilizing agents in cosmetic formulations. Limited safety test data are available on ingredients in the Ceteth family, all consistent with surfactant properties. In separate studies, 2.5% Ceteth-2 was irritating to abraded skin, but 3.0 % was not irritating to intact skin. Dose-dependent irritation was noted for Ceteth-2 and Ceteth-10 at concentrations ranging from 5% to 100%. Ceteth-20 was found to enhance transposition of a marker from phage λ to bacterial DNA. Toxicity data, including reproductive and developmental toxicity, carcinogenesis data, and clinical testing data, available from previous safety assessments on Polyethylene Glycol and Cetyl Alcohol, were summarized. Although PEGs were mild irritants/sensitizers, there was evidence of nephrotoxicity in burn patients exposed to PEGs, and no such effects were seen in animal studies on intact skin. This led to a recommendation that PEGs not be used on damaged skin. Irritant effects of Ceteths on abraded skin not seen with intact skin likewise suggested that cosmetic manufacturers should not use Ceteths in products that may be used on damaged skin. Although metabolites of ethylene glycol monalkyl ethers are reproductive and developmental toxins, it was considered unlikely that the relevant metabolites would be found in or produced from the use of Ceteths in cosmetic formulations. Of concern was the possible presence of 1,4-dioxane and ethylene oxide impurities. The importance of using the necessary purification procedures to remove these impurities was stressed. Inhalation of Cetyl Alcohol at 26 ppm for 6 hours caused mucosal irritation, but shorter exposures at a concentration of 9.6 mg/L caused no irritation. Based on this data and with particle size and cosmetic use concentrations, Ceteths were considered to be safe for aerosolized use. Based in part on the limited data available on Ceteths included in the report and on the previous reviews of the two components found in Ceteths, it was concluded that Ceteth-1, -2, -3, -4, -5, -6, -10, -12, -14, -15, -16, -20, -24, -25, -30, and -45 are safe in the present practices of use.

Final Report on the Safety Assessment of Oleth-2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -15, -16, -20, -23, -25, -30, -40, -44, and -501

The Oleth family of ingredients are the polyethylene glycol (PEG) ethers of oleyl alcohol. They are manufactured by the ethoxylation of oleyl alcohol with the number of moles of ethylene oxide corresponding to the average polyethylene glycol chain length desired. Not all of the polymer chain lengths covered in this assessment are currently reported to be used, but all are listed as cosmetic ingredients and may have been used in the past and could be used in the future. Oleths are surfactants used as emulsifying, cleansing, and solubilizing agents in cosmetic formulations. Limited safety test data are available on ingredients in the Oleth family, all consistent with surfactant properties. In feeding studies, Oleth-20 was associated with reduced body weight gain. Hepatic lesions in one exposure group were not found in any other exposure group, but were found in the controls. Oleth-20 and Oleth-10 were found to have moderate ocular irritation potential, and Oleth-10 was considered to be a cumulative skin irritant. Toxicity data, including reproductive and developmental toxicity, carcinogenesis data, and clinical testing data, available from previous safety assessments on Polyethylene Glycol and Oleyl Alcohol, were summarized. The principal finding related to PEGs, based on clinical data in burn patients, is that PEGs were mild irritant/sensitizers and there was evidence of nephrotoxicity. No such effects were seen in animal studies on intact skin. Cosmetic manufacturers should adjust product formulations containing Polyethylene Glycol to minimize any untoward effects when products are used on damaged skin. Although metabolites of ethylene glycol monoalkyl ethers are reproductive and developmental toxins, it was considered unlikely that the relevant metabolites would be found in or produced from the use of Oleths in cosmetic formulations. Of concern was the possible presence of 1,4-dioxane and ethylene oxide impurities. The importance of using the necessary purification procedures to remove these impurities was stressed. Based on particle size and cosmetic use considerations, it was not considered that these ingredients, in formulation, are respirable. Based in part on the limited data available on Oleths included in the report and on the previous reviews of Polyethylene Glycol and Oleyl Alcohol, it was concluded that Oleth-2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -15, -16, -20, -23, -25, -30, -40, -44, and -50 are safe in the present practices of use.

Final Report on the Safety Assessment of PEG-2, -3, -4, -6, -8, -9, -12, -20, -32, -50, -75, -120, -150, and -175 Distearate’

PEG Distearate compounds are the polyethylene glycol (PEG) diesters of Stearic Acid. They are manufactured by the esterification of Stearic Acid with a the number of moles of ethylene oxide corresponding to the average polyethylene glycol chain length desired. PEGs Distearate are used as emulsifying, cleansing, and solubilizing agents in a wide variety of cosmetic formulations. Not all of the polymer chain lengths covered in this assessment are currently reported to be used, but all are listed as cosmetic ingredients and may have been used in the past and could be used in the future. Very little toxicity data are available for the PEGs Distearate. Related compounds including PEGs, PEGs Stearate, Steareths, and Stearic Acid, have previously been reviewed. In general, PEGs have a low level of toxicity whether the exposure is oral or dermal. Minimal ocular irritation is seen with PEGs, PEGs Stearate, Steareths, and Stearic Acid. No evidence of mutagenicity, carcinogenicity, or reproductive and developmental toxicity of these related compounds was found. Based on clinical data in bum patients, PEGs were mild irritant/sensitizers and there was evidence of nephrotoxicity. Cosmetic manufacturers should continue to adjust product formulations to minimize any untoward effects when products are used on damaged skin. PEGs Stearate, Steareths, and Stearic Acid were not irritants, sensitizers, or phototoxins. Because of the possibility of residual ethylene oxide and/or 1,4-dioxane impurities in PEGs Distearate, cosmetic formulators are urged to continue efforts to remove these impurities before blending PEGs Distearate into cosmetic formulations. Although metabolites of ethylene glycol monoalkyl ethers are reproductive and developmental toxins, it was considered unlikely that the relevant metabolites would be found in or produced from the use of PEGs Distearate in cosmetic formulations. Based on the available data on related compounds, and current industry practices in the use and manufacture of PEGs Distearate, it was concluded that PEG-2, -3, -4, -6, -8, -9, -12, -20, -32, -50, -75, -120, -150, and -175 Distearate are safe for use in cosmetic formulations under the present practices of use.

Final Report on the Safety Assessment of PEG-2, -3, -5, -10, -15, and -20 Cocamine1

The PEGs Cocamine are the polyethylene glycol ethers of the primary aliphatic amine derived from coconut oil. These ingredients are used in cosmetic formulations as surfactants which function as emulsifying and solubilizing agents. Very little data were available on metabolism and toxicity, and no clinical data were found or provided. Toxicity data, including reproductive and developmental toxicity, carcinogenesis data, and clinical testing data available from previous safety assessments on Polyethylene Glycol and Coconut Oil were summarized. The principal finding related to PEGs was based on clinical data in burn patients; PEGs were mild irritant/sensitizers and there was evidence of nephrotoxicity. No such effects were seen in animal studies on intact skin. Cosmetic manufacturers should adjust product formulations containing Polyethylene Glycol to minimize any untoward effects when products are used on damaged skin. Various PEGs Cocamine were found to be mild to moderate skin irritants and were ocular irritants. PEG-15 Cocamine was negative in bacterial mutagenicity studies. Although metabolites of ethylene glycol monoalkyl ethers are reproductive and developmental toxins, it was considered unlikely that the relevant metabolites would be found in or produced from the use of PEGs Cocamine in cosmetic formulations. Of concern was the possible presence of 1,4-dioxane and ethylene oxide impurities. The importance of using the necessary purification procedures to remove these impurities was stressed. The limited data on PEGs Cocamine and the related data on other ingredients, however, were not sufficient to support the safety of PEGs Cocamine for use in cosmetic formulations. Additional data needs include: (1) physical and chemical properties, including impurities, and especially nitrosamines; (2) genotoxicity in a mammalian system; if the results are positive, then a dermal carcinogenesis study using National Toxicology Program (NTP) methods may be needed; (3) 28-day dermal toxicity using PEG-2 Cocamine; and (4) dermal sensitization data on PEG-2 Cocamine.

Final Report on the Safety Assessment of PEG-7, -30, -40, -78, and -80 Glyceryl Cocoate1

PEGs Glyceryl Cocoate polymers are the polyethylene glycol ethers of glyceryl cocoate. They function as skin conditioning agents, emollients, surfactants, nonionic emulsifying agents, and solubilizing agents in cosmetic formulations. Only limited data on the safety of PEG-7 Glyceryl Cocoate were found, and no data were available on the higher molecular weight polymers in this group. Data from previous safety assessments of Polyethylene Glycol (PEG), and several fatty acids (Stearic Acid, Oleic Acid, Lauric Acid, Palmitic Acid, and Myristic Acid) were considered relevant and added to the review. PEG has low oral and dermal toxicity. The fatty acids have slight oral toxicity, but little or no dermal toxicity. Dermal application of PEG-7 Glyceryl Cocoate at a concentration of SO% did not produce irritation in mice and guinea pigs, but did produce slight irritation in rabbits. Intracutaneous injection of PEG-7 Glyceryl Cocoate at a concentration of 10% did not produce sensitization. This same concentration was not an ocular irritant in animal tests. PEG-7 Glyceryl Cocoate was not phototoxic at a concentration of SO%. Although monoalkyl ethers of ethylene glycol are reproductive and developmental toxins, given the methods of manufacture of PEG-7 Glyceryl Cocoate, there is no likelihood of such compounds being present as impurities. The structure of the PEGs Glyceryl Cocoate polymers is such that it is unlikely that they would cause reproductive or developmental effects. PEG did not produce reproductive toxicity in oral toxicity studies. Oleic Acid in feed at a concentration of 15% did impair reproductive capacity in female rats, but growth and general health were not affected. No data were available on genotoxicity or carcinogenicity of PEGs Glyceryl Cocoate. PEG was not genotoxic. The fatty acids were generally not genotoxic, but positive results were seen for Oleic Acid in one assay. Neither PEG nor the fatty acids were carcinogenic in animals tests. Of concern was the possible presence of 1,4-dioxane and ethylene oxide impurities. The importance of using the necessary purification procedures to remove these impurities was stressed. In clinical studies PEG-7 Glyceryl Cocoate was neither a dermal irritant nor a photosensitizer. The principal clinical finding related to PEGs is based on data in burn patients—PEGs were mild irritant/sensitizers and there was evidence of nephrotoxicity. No such effects were seen in animal studies on intact skin. Cosmetic manufacturers should adjust product formulations containing Polyethylene Glycol to minimize any untoward effects when products are used on damaged skin. In recognition that PEG-7 Glyceryl Cocoate can enhance the skin penetration of other chemicals, care should also be exercised in using these ingredients in products where the penetration of other ingredients is aconcern. Based on the limited data on PEGs Glyceryl Cocoate and on safety assessments of other related ingredients, it was concluded that PEG-7, -30, -40, -70, and -80 Glyceryl Cocoate are safe as used in rinse-off products and safe at concentrations up to 10% in leave-on products.

Addendum to the Final Report on the Safety Assessment of PEGs Lanolin to Include PEG-5, -10, -24, -25, -35, -55, -100, and -150 Lanolin; PEG-5, -10, -20, -24, -30, and -70 Hydrogenated Lanolin; PEG-75 Lanolin Oil; and PEG-75 Lanolin Wax1

The safety of selected polyethylene glycols (PEGS) Lanolin polymers was previously reviewed. This review completes the safety assessment of all the PEGs Lanolin polymers and related cosmetic ingredients. PEGs Lanolin are prepared by ethoxylating the hydroxy fatty acids, hydroxy esters, sterols, and alcohols present in whole lanolin. The number of moles of ethylene oxide reacted with each respective lanolin component corresponds to the average polyethylene glycol chain length. PEGs Lanolins, PEGs Hydrogenated Lanolins, PEG Lanolin Oil, and PEG Lanolin Wax are used as emulsifying, soluhilizing, and cleansing agents. PEGs Hydrogenated Lanolins are also hair-conditioning agents and skin-conditioning emollients. Few data on the PEGs Lanolin were available regarding systemic toxicity, mutagenicity, carcinogenicity, and clinical safety. Related compounds including PEGs, Lanolin, and Lanolin Oil have been previously reviewed. Based on clinical data in burn patients, PEGs were mild irritants/sensitizers and there was evidence of nephrotoxicity. No such effects were seen in animal studies on intact skin. Cosmetic manufacturers should continue to adjust product formulations to minimize any untoward effects when products are used on damaged skin. No evidence of phototoxic effects was found in clinical studies. Comedogenic effects have resulted from the use of cosmetic products containing lanolin compounds. No evidence of mutagenicity, carcinogenicity, or reproductive and developmental toxicity was found with these related compounds. Although metabolites of ethylene glycol monoalkyl ethers are reproductive and developmental toxins, it was considered unlikely that the relevant metabolites would be found in or produced from the use of PEGs Cocamine in cosmetic formulations. Based primarily on data from ingredients with related structures, it was concluded that PEG-S, -10, -24, -25, -35, -55, -100, and -150 Lanolin; PEG-S, -10, -20, -24, -30, and -70 Hydrogenated Lanolin; PEG-75 Lanolin Oil; and PEG-75 Lanolin Wax are safe for use in cosmetic formulations under the present practices of use.