Minimal Irritation Research Articles

Ocular toxicity of authentic lunar dust

BackgroundDust exposure is a well-known occupational hazard for terrestrial workers and astronauts alike and will continue to be a concern as humankind pursues exploration and habitation of objects beyond Earth. Humankind’s limited exploration experience with the Apollo Program indicates that exposure to dust will be unavoidable. Therefore, NASA must assess potential toxicity and recommend appropriate mitigation measures to ensure that explorers are adequately protected. Visual acuity is critical during exploration activities and operations aboard spacecraft. Therefore, the present research was performed to ascertain the ocular toxicity of authentic lunar dust.MethodsSmall (mean particle diameter = 2.9 ± 1.0 μm), reactive lunar dust particles were produced by grinding bulk dust under ultrapure nitrogen conditions. Chemical reactivity and cytotoxicity testing were performed using the commercially available EpiOcularTM assay. Subsequent in vivo Draize testing utilized a larger size fraction of unground lunar dust that is more relevant to ocular exposures (particles <120 μm; median particle diameter = 50.9 ± 19.8 μm).ResultsIn vitro testing indicated minimal irritancy potential based on the time required to reduce cell viability by 50% (ET50). Follow-up testing using the Draize standard protocol confirmed that the lunar dust was minimally irritating. Minor irritation of the upper eyelids was noted at the 1-hour observation point, but these effects resolved within 24 hours. In addition, no corneal scratching was observed using fluorescein stain.ConclusionsLow-titanium mare lunar dust is minimally irritating to the eyes and is considered a nuisance dust for ocular exposure. No special precautions are recommended to protect against ocular exposures, but fully shielded goggles may be used if dust becomes a nuisance.

Azithromycin 1.5% ophthalmic solution: efficacy and treatment modalities in chronic blepharitis.

To assess the efficacy of topical 1.5% azithromycin in the treatment of moderate to severe chronic blepharitis and to compare the efficacy of two different treatment modalities. A randomized clinical trial included 67 patients with chronic anterior and/or posterior blepharitis, followed-up for 3 months. Signs and symptoms were graded according to severity. Patients were randomized into two groups: 33 patients in group I and 34 patients in group II. Group I patients were treated with topical 1.5% azithromycin twice a day for three days, and Group II patients were treated with topical 1.5% azithromycin twice a day for three days then at bedtime for the rest of the month. All patients were instructed to apply warm compresses and an eye-friendly soap twice daily. Patients in both groups tolerated the treatment with minimal irritation. A significant improvement in signs and symptoms was noted at the one week follow-up visit. Group II showed a more pronounced and longer-lasting improvement that persisted after three months of follow-up. Topical 1.5% azithromycin ophthalmic solution is an effective treatment option for chronic blepharitis. In moderate to severe blepharitis, a one month treatment is safe and shows better improvement than the three-day protocol with no significant relapse until three months of follow-up.

Surgical preparation of eyes

Routine surgical preparation of the skin for surgery would not be appropriate for the eye and orbit. The purpose of this article is to recommend procedures for preparation for ocular surgery in veterinary practice by veterinary nurses and veterinary surgeons. Careful surgical preparation of the ophthalmic patient will minimise peri-operative infection and ensure that there is minimal irritation of the area that could lead to post-operative inflammation and discomfort. Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Safety and toxicological evaluation of Aflapin®: A novel Boswellia-derived anti-inflammatory product

Boswellia serrata gum resin has been used for treatment of various ailments in different cultures for thousands of years. Aflapin® is a novel synergistic composition derived from B. serrata gum resin (Indian Patent Application No. 2229/CHE/2008). Aflapin is significantly better as an anti-inflammatory agent compared to the Boswellia extracts presently available in the market. To assess the safety of Aflapin, a battery of acute and sub-acute toxicity studies were conducted in various animal models according to the OECD test guidelines. The acute oral LD50 of Aflapin was greater than 5000 mg/kg in female Sprague Dawley (SD) rats. Acute dermal LD50 of Aflapin was greater than 2000 mg/kg in SD rats. A primary dermal irritation study conducted using New Zealand White rabbits indicated that Aflapin is non-irritating to skin. Aflapin caused minimal ocular irritation in a primary eye irritation test conducted on New Zealand Albino rabbits. A repeat dose 28-day sub-acute oral toxicity study in SD rats demonstrated no significant signs of toxicity. Various evaluations including hematology, clinical chemistry, gross necropsy, and histopathology did not show any significant adverse changes. The NOAEL of Aflapin was found to be greater than 2500 mg/kg body weight. These studies demonstrate broad spectrum safety of Aflapin in animal models.

Absence of hematological side effects in acute and subacute nasal dosing of erythropoietin with a low content of sialic acid

The use of human recombinant erythropoietin (EPO) as a neuroprotective agent is limited due to its hematological side effects. An erythropoietin along with a low content of sialic acid (rhEPO b), similar to that produced in the brain during hypoxia, may be used as a neuroprotective agent without risk of thrombotic events. The objective of this investigation was to assess the toxicological potential of a nasal formulation with rhEPO b in acute, subacute and nasal irritation assays in rats. Healthy Wistar rats (Cenp:Wistar) were used for the assays. In an irritation test, animals received 15 μl of rhEPO b into the right nostril. Rats were sacrificed after 24 h and slides of the nasal mucosa tissues were examined. Control and treated groups showed signs of a minimal irritation consisting of week edema and vascular congestion in all animals. In the acute toxicity test, the dose of 47,143 UI/kg was administered by nasal route. Hematological patterns, body weight, relative organ weight, and organ integrity were not affected by single dosing with rhEPO b. In the subacute toxicity test, Wistar rats of both sexes received 6,600 UI/kg/day for 14 days. The toxicological endpoints examined included animal body weight, food consumption, hematological and biochemical patterns, selected tissue weights, and histopathological examinations. An increase of lymphocytes was observed in males that was considered to reflect an immune response to treatment. Histopathological examination of organs and tissues did not reveal treatment-induced changes. The administration of rhEPO b at daily doses of 6,600 UI/kg during 14 days did not produce hematological side effects. These results suggest that rhEPO b could offer the same neuroprotection as EPO, without hematological side effects.

Safety and toxicological evaluation of a novel anti-obesity formulation LI85008F in animals

LI85008F is a novel synergistic composition of Moringa oleifera, Murraya koenigi, and Curcuma longa. These herbs are well recognized and widely used in ayurvedic system of medicine for treating a variety of diseases and are also have been used for culinary purposes for thousands of years. LI85008F inhibits preadipocyte differentiation and potentiates lipid breakdown in mature adipocytes. In diet-induced obese rats, LI85008F significantly reduced weight gain and improved serum adiponectin levels. These findings motivated the authors to determine the broad-spectrum safety of LI85008F. Acute oral toxicity, acute dermal toxicity, primary skin irritation, primary eye irritation, and dose-dependent 28-day sub-acute toxicity studies were conducted. The acute oral LD50 of LI85008F was greater than 5000 mg/kg in female SD rats and no changes in body weight or adverse effects were observed following necropsy. Acute dermal LD50 of LI85008F was greater than 2000 mg/kg. LI85008F was classified as non-irritating to skin in a primary dermal irritation study conducted using New Zealand Albino rabbits. LI85008F caused minimal irritation to eyes in a primary eye irritation test conducted on New Zealand Albino rabbits. A dose-dependent 28-day sub-acute toxicity study demonstrated no significant changes in selected organ weights. Evaluations on hematology, clinical chemistry, and histopathology did not show any significant adverse changes. The NOAEL of LI85008F was found to be greater than 2500 mg/kg body weight. These results demonstrate the broad spectrum safety of LI85008F in animal models.

Efficacy, safety, and tolerability of microsphere adapalene vs. conventional adapalene for acne vulgaris

The present study was undertaken to compare the efficacy, safety and tolerability of a new microsphere adapalene formulation and conventional adapalene in adult patients with mild to moderate acne vulgaris. This prospective, randomized, assessor-blind, multi-centric (3 centres) comparative, post-marketing phase IV study was undertaken in 175 patients with mild to moderate acne after approval by respective Institutional review boards. Patients fulfilling selection criteria were randomly assigned to either microsphere adapalene gel or conventional adapalene gel both once daily in the evening for 12 weeks after obtaining their informed consent. Efficacy variables included success rate and percent lesion reduction from baseline. Safety and tolerability was assessed on the basis of physical examination and monitoring of treatment-emergent adverse events. Of the 175 patients (88 in microsphere and 87 in conventional) 21 were lost to follow-up and considered drop-outs. There was a significant decrease (P < 0.05) in mean inflammatory and non-inflammatory lesion and total lesion counts from 1st week onwards in both groups. A significantly lower number of microsphere treated patients (50%) reported a side effect (P < 0.05) as compared to 71.3% in conventional users. A highly significant decrease was observed in dryness and erythema (P < 0.01) in microsphere group compared to conventional. Eight patients in conventional group discontinued therapy due to severe irritation as compared to none in microsphere adapalene group. Therapy with microsphere adapalene provided a better tolerability with minimal irritation compared to conventional adapalene, without compromising efficacy and could be a better therapeutic option for acne.

Improvement of photoaged facial skin in middle-aged Japanese females by topical retinol (vitamin A alcohol): A vehicle-controlled, double-blind study

Topical tretinoin formulation is still unavailable in Japan. Because topical retinol, which is less potent but may cause less irritation, is available here, we have performed a randomized, blinded, vehicle-controlled study on the face using a once-nightly regimen for the treatment of mild photoaging in middle-aged Japanese females. First, a 26-week study was conducted in 57 subjects with a 0.075% retinol cream and its vehicle on each half side of the face. Three of the 57 subjects withdrew from the study due to irritation, although this rate was much smaller than that noted in our previous study with topical tretinoin. After 26 weeks, the rates of photoaging improvement were significantly higher on the retinol side: 27 out of 54 (50%) versus 13 (24%) for the fine wrinkling and 15 out of 54 (28%) versus 1 (2%) for deep wrinkling. A similar trial with a 0.04% retinol cream for 13 weeks revealed less prominent improvements in fine wrinkling but minimal irritation. From these data, we think that retinol creams, especially 0.04% cream, are suitable for daily use in the general population because of the low irritancy, even for those with sensitive skin.

In vivo acute toxicological studies of an antioxidant extract from Mangifera indica L. (Vimang)

Mango (Mangifera indica L.) stem bark aqueous extract (MSBE) is a natural product with antioxidant, anti-inflammatory, analgesic, and immunomodulatory effects. Its formulations (e.g., tablets, capsules, syrup, vaginal oval, and suppositories) are known by the brand name of Vimang®. In view of the ethnomedical, preclinical, and clinical uses of this extract and the necessity to assess its possible toxicological effect on man, a toxicological analysis of a standard extract is reported in this paper. Acute toxicity was evaluated in mice and rats by oral, dermal, and intraperitoneal (i.p.) administration. The extract, by oral or dermal administration, showed no lethality at the limit doses of 2,000 mg/kg body weight and no adverse effects were found. Deaths occurred with the i.p. administration at 200, but not 20 mg/kg in mice. MSBE was also studied on irritant tests in rabbits, and the results showed that it was nonirritating on skin, ocular, or rectal mucosa. The extract had minimal irritancy following vaginal application.

Evaluation of anti‐wrinkle effects of a novel cosmetic containing niacinamide

Niacinamide is known to have effectiveness on sallowness, wrinkling, red blotchiness and hyperpigmented spots in aging skin. In this study, we have evaluated the anti-wrinkle effects of a new cosmetic containing niacinamide. A randomized, placebo-controlled, split face study was performed in 30 healthy Japanese females who had wrinkles in the eye areas. The tested cosmetic containing 4% niacinamide was applied on wrinkles of one side for 8 weeks, and a control cosmetic without niacinamide on another site. Anti-wrinkle effects were evaluated with two methods: (i) doctors' observation and photographs based on the guideline of the Japan Cosmetic Industry Association; and (ii) average roughness of skin surface (Ra value) using skin replica. This cosmetic showed marked and moderate improvement in 64% of the subjects with a significant difference as compared with the control site (P < 0.001). Wrinkle grades in the tested area significantly reduced more than pre-application (P < 0.001) and the control (P < 0.001). Reduction in Ra value on the tested area was more than pre-application (P < 0.01) and the control site (P < 0.05) with significant differences. Only one subject stopped the study with minimal irritation. These results indicated that the tested lotion was well tolerated and may be an optional preparation for the treatment of wrinkles in the eye areas.

Range of Motion of the First Metatarsophalangeal Joint after Chevron Procedure Reinforced by a Modified Capsuloperiosteal Flap

This study analyzed the range of motion of the first metatarsophalangeal joint following the chevron procedure with increased stabilization using a modified capsuloperiosteal flap in the treatment of hallux valgus cases. Forty-three feet of 40 patients were treated with modified chevron osteotomies. The patient selection criteria included failure of conservative treatment, painful deformity, age between 18 and 50, hallux valgus and intermetatarsal angles less than 40 degrees and 17 degrees, respectively, and no osteoarthritic changes of the metatarsophalangeal joint. The passive range of motion of the first metatarsophalangeal joint was compared to the hallux valgus and intermetatarsal angles. The mean age of patients was 30.9 +/- 9.0 (range, 18 to 46) years. The preoperative mean hallux valgus angle was 32.2 (range, 22 to 40 degrees), whereas postoperatively it was 13.1 (range, 3 to 22 degrees). The preoperative mean passive total range of motion, dorsiflexion and plantar flexion were found to be 80.2 (range, 71 to 99 degrees), 66.8 (51 to 86) degrees and 13.4 (range, 7 to 23 degrees), respectively, whereas postoperatively these values were 69.2 (range, 48 to 85 degrees), 58.6 (range, 43 to 75) degrees and 10.8 (range, 1 to 20 degrees). According to Bonney and MacNab subjective scores, the feet were evaluated as follows: 12 as excellent, 26 as good, and 5 as moderate. According to objective scores, the evaluation was as follows: 27 as excellent, 14 as good, 1 as moderate, and 1 as poor. We believe that the chevron procedure reinforced by modified capsuloperiosteal flap causes minimal irritation and damage to adjacent soft tissues. Furthermore, we conclude that this method is a benefical means of managing moderate hallux vagus deformities by decreasing the stiffness after surgery.

In vivo assessment of safety of microneedle arrays in human skin

Microneedle arrays are promising devices for the delivery of drugs and vaccines into or the skin. However, little is known about the safety of the microneedles. In this study we obtained insight in the ability of microneedles to disrupt the skin barrier, which was evaluated by transepidermal water loss (TEWL). We also determined the safety in terms of skin irritation (skin redness and blood flow) and pain sensation. We applied microneedle arrays varying in length and shape on the ventral forearms of 18 human volunteers. An effect of needle length was observed, as TEWL and redness values after treatment with solid microneedle arrays of 400 μm were significantly increased compared to 200 μm. The blood flow showed a similar trend. Needle design also had an effect. Assembled microneedle arrays induced higher TEWL values than the solid microneedle arrays, while resulting in less skin irritation. However, for all microneedles the irritation was minimal and lasted less than 2 h. In conclusion, the microneedle arrays used in this study are able to overcome the barrier function of the skin in human volunteers, are painless and cause only minimal irritation. This opens the opportunity for dermal and transdermal delivery of drugs and vaccines.

Effects of disinfectants and detergents on skin irritation

We investigated the biological response of regular human skin to alcohol-based disinfectants and detergents in a repetitive test design. Using non-invasive diagnostic tools such as transepidermal water loss, laser-Doppler flowmetry and corneometry, we quantified the irritative effects of a propanol-based hand disinfectant (Sterillium), its propanol mixture (2-propanol 45% w/w and 1-propanol 30% w/w), sodium lauryl sulfate (SLS) 0.5% and distilled water. The substances were applied in a 2-D patch test in a repetitive occlusive test design to the back. Additionally, we performed a wash test on the forearms that was supposed to mimic the skin affection in the normal daily routine of health care workers. In this controlled half-side test design, we included the single application of the hand rub, SLS 0.5% and water as well as a tandem application of the same substances. Patch test and wash test showed similar results. The alcohol-based test preparations showed minimal irritation rather comparable to the application of water. However, the detergent SLS produced stronger barrier disruption, erythema and dryness than the alcohol-based preparations. There was no additional irritation at the combined use of SLS and disinfectants. By contrary, there was even a decrease in barrier disruption and erythema induced by the tandem application of SLS followed by alcohol-based disinfection compared with the use of SLS alone. These findings show a less irritant effect of alcohol-based disinfectants on the skin than detergents. Our study shows that there is no summation of irritating effects of a common detergent and propanol and that the combination of washing and disinfection has a rather protective aspect compared with washing alone.

Treatment of molluscum contagiosum a brief review and discussion of a case successfully treated with adapelene

Molluscum contagiosum occur in 2-8 percent of children. This infection is among the most common viral skin infections in children. Although the lesions will resolve spontaneously when puberty, there are several reasons to treat them. The lesions can be cosmetically unappealing. About 10 percent of those with this infection develop a pruritic eczematous eruption. In about 4 percent of children with molluscum, the lesions are numerous and recurrent with no other coexisting immunological problem. Patients who have atopic dermatitis may develop widespread involvement with molluscum. Treatment options include destruction, topical therapy, and oral therapy. Destructive treatment modalities include curettage, cryotherapy, expression or pricking with a sterile needle, electrodesiccation, photodynamic therapy, and laser ablation. Destructive therapy is poorly tolerated in children. Topical medical therapy includes salicylic acid, glycolic acid, tretinoin, tazortene, 5 percent sodium nitrite co-applied daily with 5 percent salicylic acid topical preparations, podofilox, liquefied phenol, tretinoin, cantharidin, and potassium hydroxide. Oral treatment of molluscum includes cimetidine. No therapy is universally effective. I report herein a case of generalized numerous and recurrent molluscum treated with minimal irritation with adapelene.

Safety Study of an Antimicrobial Peptide Lactocin 160, Produced by the VaginalLactobacillus rhamnosus

Objective. To evaluate the safety of the antimicrobial peptide, lactocin 160. Methods. Lactocin 160, a product of vaginal probiotic Lactobacillus rhamnosus 160 was evaluated for toxicity and irritation. An in vitro human organotypic vaginal-ectocervical tissue model (EpiVaginal) was employed for the safety testing by determining the exposure time to reduce tissue viability to 50% (ET-50). Hemolytic activity of lactocin160 was tested using 8% of human erythrocyte suspension. Susceptibility of lactobacilli to lactocin160 was also studied. Rabbit vaginal irritation (RVI) model was used for an in vivo safety evaluation. Results. The ET-50 value was 17.5 hours for lactocin 160 (4.9 hours for nonoxynol 9, N9). Hemolytic activity of lactocin 160 was 8.2% (N9 caused total hemolysis). Lactobacilli resisted to high concentrations of peptide preparation. The RVI model revealed slight vaginal irritation. An average irritation index grade was evaluated as “none.” Conclusions. Lactocin 160 showed minimal irritation and has a good potential for intravaginal application.

Final Report on the Safety Assessment of Polyethylene1

Polyethylene is an ethylene polymer used for a variety of purposes in cosmetics as an abrasive, adhesive, binder or bulking agent, an emulsion stabilizer, a film former, an oral care agent, and as a nonaqueous viscosity-increasing agent. Polyethylene is also used in food packaging materials and medical products, including prosthetics. The molecular weight of Polyethylene as used in cosmetics varies over a wide range. The lowest reported molecular weight is 198 Daltons and the highest is 150,000. In any given polymer preparation, there can be a broad range of molecular weights. Cellular and tissue responses to Polyethylene, determined as part of implant biocompatibility testing, include fibrous connective tissue build-up around the implant material that varies as a function of the physical form of the implant material. Specific assays for osteoblast proliferation and collagen synthesis demonstrated a reduction as a function of exposure to Polyethylene particles that is inversely related to particle size. The effect of Polyurethane particles on monocyte-derived macrophages, however, had a stimulatory effect, prolonging the survival of these cells in culture. The LD50 for Polyethylene, with an average molecular weight of 450, in rats was > 2000 mg/kg. For Polyethylene with an average molecular weight of 655, the LD50 was > 5.0 g/kg. Toxicity testing in rats shows no adverse effects at Polyethylene (molecular weight not given) doses of 7.95 g/kg or at 1.25%, 2.50%, or 5.00% in feed for 90 days. Dermal irritation studies on rabbits in which 0.5 g of Polyethylene (average molecular weight of 450) was administered in 0.5 ml of water caused no irritation or corrosive effects; Polyethylene with an average molecular weight of 655 was a mild irritant. Polyethylene (average molecular weight of 450) did not cause dermal sensitization in guinea pigs tested with 50% Polyethylene (w/w) in arachis oil BP. Polyethylene, with a molecular weight of 450 and a molecular weight of 655, was a mild irritant when tested as a solid material in the eyes of rabbits. Rabbit eyes treated with a solution containing 13% Polyethylene beads produced minimal irritation and no corneal abrasions. No genotoxicity was found in bacterial assays. No chemical carcinogenicity has been seen in implantation studies, although particles from Polyethylene implants can induce so-called solid-state carcinogenicity, which is a physical reaction to an implanted material. Occupational case reports of ocular irritation and systemic sclerosis in workers exposed to Polyethylene have been difficult to interpret because such workers are also exposed to other irritants. Clinical testing of intrauterine devices made of Polyethylene failed to conclusively identify statistically significant adverse effects, although squamous metaplasia was observed. The Cosmetic Ingredient Review (CIR) Expert Panel did not expect significant dermal absorption and systemic exposure to large Polyethylene polymers used in cosmetics. The Panel was concerned that information on impurities, including residual catalyst and reactants from the polymerization process, was not available. The Panel considered that the monomer unit in Polyethylene polymerization is ethylene. In the United States, ethylene is 99.9% pure. The other 0.1% includes ethane, propylene, carbon dioxide, carbon monoxide, sulfur, hydrogen, acetylene, water, and oxygen. The Panel believed that the concentration of these impurities in any final polymer would be so low as to not raise toxicity issues. Safety tests of cosmetic-grade Polyethylene have consistently failed to identify any toxicity associated with residual catalyst. Although it was reported that one process used to cross-link Polyethylene with an organic peroxide, this process is not currently used. In addition, cosmetic-grade Polyethylene is not expected to contain toxic hexanes. The Panel was concerned that the only genotoxicity data available was nonmammalian, but taking this information in concert with the absence of any chemical carcinogenicity in implant studies suggests no genotoxic mechanism for carcinogenicity. The solid-state carcinogenicity effect was not seen as relevant for Polyethylene as used in cosmetics. The available data support the conclusion that Polyethylene is safe for use in cosmetic formulations in the practices of use and concentrations described.

Efficacy and safety of serial glycolic acid peels and a topical regimen in the treatment of recalcitrant melasma

Melasma is a common acquired disorder of facial hyperpigmentation. In this study we investigated the efficacy and safety of a combined treatment regimen including serial glycolic acid peels, topical azelaic acid cream and adapalene gel in the treatment of recalcitrant melasma. Twenty-eight patients with recalcitrant melasma were enrolled in a prospective, randomized, controlled trial lasting 20 weeks. The patients of the group receiving chemical peels underwent serial glycolic acid peels in combination with topical azelaic acid 20% cream (b.i.d.) and adapalene 0.1% gel (q.i.d., applied at night). The control group received only topical treatment including topical azelaic acid and adapalene. The clinical improvement was assessed with the Melasma Area Severity Index (MASI) at baseline and monthly during the 20-week treatment period. The results showed a prominent decrease in MASI scores at the end of the treatment in both groups, although the results were better in the group receiving chemical peels (P=0.048). All patients tolerated the topical agents well with minimal irritation observed in the first few weeks of the therapy. Three patients in the glycolic acid peel group developed a mild-degree postinflammatory hyperpigmentation with total clearance at the end of the treatment period. Therefore, the present study suggests that combined treatment with serial glycolic acid peels, azelaic acid cream and adapalene gel should be considered as an effective and safe therapy in recalcitrant melasma.

Analysis of Tear Glucose Concentration with Electrospray Ionization Mass Spectrometry

We have developed a mass spectrometry-based method that allows one to accurately determine the glucose concentration of tear fluid. We used a 1 microL micro-capillary to collect tear fluid from the tear meniscus with minimal irritation of the eye. We analyzed the 1 muL volume of collected tear fluid with liquid-chromatography electrospray ionization mass spectrometry with the use of D-glucose-6,6-d2 as an internal standard. Repeated measurements and a recovery experiment on pooled, onion-induced tears showed that the analysis of the glucose in tears was precise (4% relative standard deviation) and provided 100% recovery. We found the tear glucose concentration of one fasting nondiabetic subject to be 13 to 51 microM while the onion-induced tear glucose concentration of a different nondiabetic subject to be 211 to 256 microM.

Amended Final Report of the Safety Assessment of Dibutyl Adipate as Used in Cosmetics1

Dibutyl Adipate, the diester of butyl alcohol and adipic acid, functions as a plasticizer, skin-conditioning agent, and solvent in cosmetic formulations. It is reportedly used at a concentration of 5% in nail polish and 8% in suntan gels, creams, and liquids. Dibutyl Adipate is soluble in organic solvents, but practically insoluble in water. Dibutyl Adipate does not absorb radiation in the ultraviolet (UV) region of the spectrum. Dibutyl Adipate is not toxic in acute oral or dermal animal toxicity tests. In a subchronic dermal toxicity study, 1.0 ml/kg day-1 caused a significant reduction in body weight gain in rabbits, but 0.5 ml/kg/day1 was without effect. In a study with dogs, no adverse effects were observed when an emulsion containing 6.25% Dibutyl Adipate was applied to the entire body twice a week for 3 months. Dibutyl Adipate was tested for dermal irritation using rabbits and mice and a none to minimal irritation was observed. Dibutyl Adipate at a concentration of 25% was not a sensitizer in a guinea pig maximization study. Undiluted Dibutyl Adipate was minimally irritating to the eyes of rabbits and 0.1% was nonirritating. A significant increase in fetal gross abnormalities was observed in rats given intraperitoneal injections of Dibutyl Adipate at 1.75 ml/kg on 3 separate days during gestation, but no effect was seen in animals given 1.05 ml/kg. Dibutyl Adipate was not genotoxic in either bacterial or mammalian test systems. Clinical patch tests confirmed the absence of skin irritation found in animal tests. Clinical phototoxicity tests were negative. Dibutyl Adipate at 0.1% was not an ocular irritant in two male volunteers. In a clinical test of comedogenicity, Dibutyl Adipate produced no effect. The Cosmetic Ingredient Review (CIR) Expert Panel recognized that use of Dibutyl Adipate in suntan cosmetic products will result in repeated, frequent exposure in a leave-on product. The available data demonstrate no skin sensitization or cumulative skin irritation, no comedogenicity, and no genotoxicity. Combined with the data demonstrating little acute toxicity, no skin or ocular irritation, and no reproductive or developmental toxicity, these data form an adequate basis for reaching a conclusion that Dibutyl Adipate is safe as a cosmetic ingredient in the practices of use and concentrations as reflected in this safety assessment.

Final Amended Report on the Safety Assessment of Octyldodecyl Stearoyl Stearate1

Octyldodecyl Stearoyl Stearate is an ester that functions as a skin-conditioning agent and viscosity-increasing agent. It is reported to be used in 105 cosmetic products at concentrations from 2% to 15%. In an isolated human skin permeation and penetration study, 0.005% of the applied dose permeated the skin, around 3% was found in the epidermis, around 1.5% was in tape stripped skin layers, and around 95% stayed in the material applied to the skin. A formulation having 20.6% Octyldodecyl Stearoyl Stearate was classified as minimally to mildly irritating in an in vitro ocular irritation assay. Several tests of products containing from 7.5% to 12.7% Octyldodecyl Stearoyl Stearate using rabbits produced minimal to mild ocular irritation. One test of 100% Octyldodecyl Stearoyl Stearate (a trade compound) and another of 10% Octyldodecyl Stearoyl Stearate in corn oil using rabbits produced no ocular irritation. Tests using rabbits demonstrated that Octyldodecyl Stearoyl Stearate at use concentrations was non- to mildly irritating to skin; only one study reported moderate irritation. Octyldodecyl Stearoyl Stearate was not mutagenic, with or without S-9 activation, in an Ames test and did not produce a significant increase in micronucleated cells in a mouse in vivo study. In clinical single-insult patch tests at use concentrations, Octyldodecyl Stearoyl Stearate was nonirritating to mildly irritating; in a cumulative irritation study, it caused mild irritation. Octyldodecyl Stearoyl Stearate was nonsensitizing in clinical tests. Because few toxicity data were available on Octyldodecyl Stearoyl Stearate, summaries of data from existing safety assessments of related ingredients (Octyl Dodecanol, Stearic Acid, and Octyl Stearate) were included. Undiluted Octyl Dodecanol was nontoxic during acute oral and dermal studies using rats and guinea pigs. Stearic Acid was nontoxic to rats during acute oral studies, but caused toxicity during subchronic studies. Rabbits treated topically with the acid were not affected adversely, and mild erythema and slight induration were observed when Stearic Acid was administered intradermally to guinea pigs and rabbits. Octyl Stearate had very low acute oral toxicity in rats and mice. Octyl Dodecanol produced only transient mild ocular irritation in rabbits when administered at concentrations up to 100%. Octyl Dodecanol (30% and 100%) was nonirritating to skin in one study using rabbits. In another study using multiple species, 100% Octyl Dodecanol (described as technical grade) caused severe skin irritation in rabbits, moderate irritation in guinea pigs and rats, and no irritation in swine. Stearic Acid was non- to moderately irritating in animal studies, and did not cause photosensitization. In studies using rabbits, undiluted Octyl Stearate caused slight, transient ocular irritation, and minimal skin irritation. Stearic Acid did not induce mitotic crossovers and aneuploidy in Saccharomyces cerevisiae, and was nonmutagenic in the Ames test. In a feeding study using mice, Stearic Acid was noncarcinogenic at doses up to 50 g/kg/day. Mice given subcutaneous injections of the acid had low incidences of carcinomas, sarcomas, and lymphomas. In clinical studies, concentrations of up to 100% Octyl Dodecanol were non- to mildly irritating, nonsensitizing, nonphototoxic, and nonphotosensitizing. Stearic Acid was nonirritating at concentrations up to 100%, and at concentrations up to 13% it was nonsensitizing and nonphotosensitizing. Octyl Stearate (7.6%) in formulation was nonirritating, nonsensitizing, and nonphotosensitizing. Based on skin permeation and penetration data, the Panel does not expect any significant amount of Octyldodecyl Stearoyl Stearate to be systemically available. There is no evidence of systemic toxicity associated with any of the related chemicals reviewed in previous safety assessments. None of the available toxicology or clinical data suggest a concern about adverse skin reactions to Octyldodecyl Stearoyl Stearate, or to any of the related chemicals. There is no evidence of ocular toxicity, except for a mild, transient ocular irritation associated with Octyldodecyl Stearoyl Stearate and the related chemicals. Overall, Octyldodecyl Stearoyl Stearate was considered safe as used in cosmetics.