Irritant Properties Research Articles

Patch testing with components of water‐based metalworking fluids: results of a multicentre study with a second series

Although many allergens in metalworking fluids (MWF) are identified, there are still some MWF components, which are not sufficiently investigated concerning their sensitizing properties. To investigate sensitization to 10 frequently used MWF components, which are not part of the established MWF test series, in metalworkers with suspected occupational dermatitis due to MWF. Oleyl alcohol, myristyl alcohol, dimethylolurea, 4,4'-methylenebis morpholine, imazalil, 1-amino-2-propanol (monoisopropanolamine; MIPA), 2-amino-2-ethyl-1,3-propanediol (AEPD), 2,5-bis(n-octyldithio)-1,3,4-thiadiazole, zinc alkyl dithiophosphate and dibenzyl disulfide have been patch tested in 144 patients. 7 patients reacted positively to the formaldehyde releaser 4,4'-methylenebis morpholine, and 6 of these patients also reacted to formaldehyde and/or other formaldehyde releasers. 4 patients reacted positively to myristyl alcohol tested at 10% petrolatum (pet.). Additionally, 20 doubtful or irritant reactions occurred. 1 patient each reacted positively to oleyl alcohol, MIPA, and AEPD. None of the other test substances mentioned above elicited any clear-cut positive reaction. Patch testing with well-known MWF allergens showed proportions of positive reactions, which were comparable to those from other studies, e.g. 11% to monoethanolamine, 8% to colophonium and 3%-5% to various preservatives. 4,4'-methylenebis morpholine may be an important MWF allergen, although clinical relevance could not be stated definitely in every case. Myristyl alcohol should not be patch tested at 10% pet., but at a lesser concentration, due to irritant properties.

Contact allergy to sodium cocoamphoacetate present in an eye make‐up remover

This is a case report of a contact allergic reaction on the face due to a skin cleansing product containing the amphoteric surfactant sodium cocoamphoacetate, occurring in an atopic woman with multiple contact sensitivities. Because of its weak irritant properties, this surfactant is widely used in cosmetic products intended to be used for sensitive skin, including products for intimate, and baby hygiene.

The Skin Allergenic Properties of Chemicals May Depend on Contaminants – Evidence from Studies on Coumarin

Background/Aims: Positive patch tests are considered representative of a contact allergy to the tested chemical. However, contaminants and derivatives rather than the suspected chemical itself could be responsible for the allergic skin reactions. Here, we tested the importance of contaminants in the sensitizing and allergenic properties of coumarin in mice and humans. Coumarin, an ingredient in cosmetics and fragrances, was chosen as the reference chemical since conflicting results have been obtained regarding its ability to induce contact allergy. In some chemical preparations, this could be explained by the presence of coumarin derivatives endowed with allergenic properties. Methods: In mice, three different coumarin preparations were tested in the local lymph node assay. In humans, we assessed the irritant and allergenic properties of highly pure coumarin in nonallergic and fragrance-allergic patients. Results: Pure coumarin did not exhibit irritant or sensitizing properties in the local lymph node assay. In contrast, two other commercially available coumarins and three contaminants that were detected in these coumarin preparations were identified as weak and moderate sensitizers, respectively. In humans, pure coumarin was extremely well tolerated since only 1 out of 512 patients exhibited a positive patch test to the chemical. Conclusions: These results indicate that coumarin cannot be considered as a common contact allergen and further emphasize that purity of chemicals is mandatory for the assessment of their allergenicity.

The Behind‐the‐Knee test: an efficient model for evaluating mechanical and chemical irritation

The 'Behind-the-Knee' method (BTK test), using the popliteal fossa as a test site, evaluates both the inherent chemical irritation, and the potential for mechanical irritation of substrates and products. This approach eliminates some of the difficulties of in-use clinical test systems while still providing reliable results. In this publication, examples of the results of BTK tests on several materials are presented with direct comparisons, where possible, with results of in-use clinical testing conducted on the same materials. In in-use clinical tests, volunteer panelists were provided with catamenial products to use in place of their normal product. In the BTK test, samples were applied daily to the popliteal fossa using an elastic athletic band. In both studies, irritation reactions were scored visually. Levels of irritation in the BTK test are consistently higher than those of standard patch tests, illustrating the contribution of mechanical irritation to the overall irritant potential of materials and products. Repeated tests on identical test materials demonstrated that the BTK test results are reproducible. Side-by-side comparisons of the BTK test and in-use clinical tests demonstrated that the BTK test produces results of similar quality to the in-use clinical. By using several concurrent panels with a common test material, it is possible to compare the irritant properties of several materials at once. We have tested over 25 different materials in over 35 BTK studies. The test method has proven reliable and versatile in testing a wide variety of materials, including menstrual pads, topsheets, interlabial pads, pantiliners, tampons and lotion coatings on products. Unlike in-use clinicals, the BTK test allows the direct comparison of two products at one time on the same individual, and is easily adapted to investigative programs. It is subject to fewer confounding factors, is much easier to implement, has a shorter turnaround time, and is less expensive than in-use clinical testing. Importantly, unlike standard patch tests, the BTK test evaluates both the inherent chemical irritation associated with materials and the mechanical irritation owing to friction. Although the BTK test was developed using catamenial products, the test system provides a valuable alternative for evaluating any material where mechanical irritation may play a role, including textiles, facial tissues, baby and adult diapers, and laundry products that may leave residues on fabrics.

Glutaraldehyde exposure and its occupational impact in the health care environment

Despite the search for effective and less toxic substitutes, glutaraldehyde (GA) remains one of the few substances capable of high-level instrument disinfection in modern health care. Workers commonly affected include operating room nurses, radiographers, x-ray technicians and cleaners. Widespread hospital usage combined with its well-known irritant properties, has ensured an increase in occupationally-related illnesses during recent years. Operating room nurses, laboratory workers and x-ray technicians frequently contact GA in both the liquid and vapor form. Workplace exposure is usually dependent on job tasks, ventilation levels and the use of protective equipment. GA is a relatively potent irritant and sensitizer, with a well-documented history of symptoms following occupational exposure. Although mechanisms for GA toxicity have been postulated, research on the toxicological, teratogenic, and carcinogenic potential of this chemical has shown inconsistent results. Reducing workplace exposure to its lowest possible level represents the most important hazard reduction strategy. This may be achieved by keeping GA containers tightly sealed when not in use, maintaining adequate ventilation levels and the rigid adherence to appropriate personal protective equipment. Substitution with automated cold sterilization machines may be another appropriate measure, while banning unnecessary practices such as GA fogging and its use as a surface disinfectant may also be helpful in reducing occupational exposure in the health care environment.

Variations in the mRNA expression of inflammatory mediators, markers of differentiation and lipid-metabolizing enzymes caused by sodium lauryl sulphate in cultured human keratinocytes

Detergents are well known irritants. Effects of the detergent sodium lauryl sulphate (SLS) on cell toxicity using the XTT assay and mRNA expression of inflammatory mediators, markers of keratinocyte differentiation and enzymes synthesizing barrier lipids using real-time PCR were studied in cultured differentiated keratinocytes. After exposure for 24 h to SLS concentrations at 0.002% or above, toxic effects were observed. When a lower SLS concentration (0.00075%) was used the mRNA expression of inflammatory mediators peaked around 4–8 h. The expression of enzymes involved in the synthesis of cholesterol, fatty acids and ceramides and markers of keratinocyte differentiation also increased but after 24 h. In cells exposed to 0.000125–0.0015% SLS, a concentration-dependent induction of the expression of inflammatory mediators was found after 4 h. Similar changes were found after 24 h for involucrin and enzymes involved in ceramide synthesis. The mRNA expression of HMG-CoA synthase and reductase, long-chain acyl-CoA synthase and transglutaminase also peaked after 24 h, but maximal induction was observed already at 0.00075% SLS. In conclusion, SLS induces an inflammatory response in keratinocytes and alters the mRNA expression of important barrier lipid enzymes and markers of keratinocyte differentiation, of possible importance for the irritant properties of SLS.

Skin‐sensitizing and irritant properties of propylene glycol

In the several publications reviewed in this article, propylene glycol (PG; 1,2-propylene glycol) is described as a very weak contact sensitizer, if at all. However, particular exposures to PG-containing products might be associated with an elevated risk of sensitization. To identify such exposures, we analysed patch test data of 45 138 patients who have been tested with 20% PG in water between 1992 and 2002. Out of these, 1044 patients (2.3%) tested positively, 1083 showed a doubtful, follicular or erythematous reaction (2.4%) and 271 explicit irritant reactions (0.6%). This profile of patch test reactions is indicative of a slightly irritant preparation, and thus, many of the 'weak positive' reactions must probably be interpreted as false positive. No private or occupational exposures associated with an increased risk of PG sensitization were identified, except for lower leg dermatitis. Therefore, according to our patch test data, PG seems to exhibit very low sensitization potential, and the risk for sensitization to PG on uncompromised skin seems to be very low.

Synthesis and Assignment of Absolute Configuration of (−)-Oleocanthal: A Potent, Naturally Occurring Non-steroidal Anti-inflammatory and Anti-oxidant Agent Derived from Extra Virgin Olive Oils

[structure: see text] Effective total syntheses and the assignment of absolute configurations of both the (+)- and (-)-enantiomers of oleocanthal 1 (a.k.a. deacetoxy ligstroside aglycon), the latter derived from extra virgin olive oils and known to be responsible for the back of the throat irritant properties of olive oils, have been achieved. The absolute and relative stereochemistry of the naturally occurring enantiomer (-)-1 proved to be 3S,4E. Both syntheses begin with d-(-)-ribose, proceed in 12 steps, and are achieved with an overall yield of 7%. Both enantiomers proved to be non-steroidal anti-inflammatory and anti-oxidant agents.

Dérivés organiques soufrés

The organic derivatives of the sulphur include the following substances: mercaptans or thiols, sulphides, sulphoxides, benzothiazoles, sulphates, thioureas, and sulphones. Their uses are multiple (chemical industry, cosmetics, pharmaceutical industry, pesticides…). Some are used as chemical warfare (mustard gas or yperite, for example). Signs of toxicity frequently occur in the occupational field as few of them are in direct contact with the general population. A lot of these substances have a local toxicity due to their irritant properties. Their systemic toxicity is highly variable according to their chemical structure. Some of these compounds are sensitizing (sulfides, sulfoxides, sulfates…), some are mutagens (such as some sulfides); others have shown carcinogenic properties (mustard gas or yperite, for example), or teratogenic properties in animals (dimethyl sulfoxide, for example).

An European inter-laboratory validation of alternative endpoints of the murine local lymph node assay: First round

The new OECD guideline 429 (skin sensitization: local lymph node assay) is based upon a protocol, which utilises the incorporation of radioactivity into DNA as a measure for cell proliferation in vivo. The guideline also enables the use of alternative endpoints in order to assess draining lymph node (LN) cell proliferation. Here we describe the first round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in seven laboratories. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products, Swissmedic. Statistical analyses of all data were performed by an independent centre at the University of Bern, Department of Statistics. Ear-draining, LN weight and cell count were used to assess proliferation instead of radioactive labeling of lymph node cells. In addition, the acute inflammatory skin reaction was measured by ear swelling and weight of circular biopsies of the ears to identify skin irritating properties of the test items. Hexylcinnamaldehyde (HCA) and three blinded test items were applied to female, 8–10 weeks old NMRI and BALB/c mice. Results were sent via the independent study coordinator to the statistician. The results of this first round showed that the alternative endpoints of the LLNA are sensitive and robust parameters. The use of ear weights added an important parameter assessing the skin irritation potential, which supports the differentiation of pure irritative from contact allergenic potential. There were absolute no discrepancies between the categorisation of the three test substances A–C determined by each single participating laboratories. The results highlighted also that many parameters do have an impact on the strength of the responses. Therefore, such parameters have to be taken into consideration for the categorisation of compounds due to their relative sensitizing potencies.

Assessment of the Eye Irritating Properties of Chemicals by Applying Alternatives to the Draize Rabbit Eye Test: The Use of QSARs and In Vitro Tests for the Classification of Eye Irritation

Huggins has reported on the current situation relating to the development of alternatives to the Draize eye irritation test with rabbits, and an ECVAM Working Group have reviewed the efforts needed in order to replace this animal test within the next 10 years by using the results of non-animal assessment methods. Our report reviews regulatory experience gained over the last 20 years with the EU chemicals notification procedure with respect to the assessment of eye lesions observed in Draize tests. The nature of eye lesions and their importance for classification and labelling of possible hazards to human eyes are evaluated and discussed, with a view to promoting the development of specific in vitro assays which are able to discriminate between eye damage, moderate eye irritation, and minor irritation effects which are completely reversible within a few days. Structural alerts for the prediction of eye irritation/corrosion hazards to be classified and labelled according to international classification criteria, are presented, which should be validated in accordance with internationally agreed (OECD) principles for (Q)SAR system validation. Physicochemical limit values for prediction of the absence of any eye irritation potential relevant for human health can make available a definition of the applicability domains of alternative methods developed for the replacement of the Draize eye irritation test.

Phytodermatitis from Ceratocephalus falcatus

Ceratocephalus falcatus (L.) Pers. (Ranunculaceae) is a wild plant. It grows abundantly in the Van province. The species of Ceratocephalus genus possess irritant properties from the presence of an innocuous glycoside, ranunculin. Here, we document 3 patients who were admitted to our clinic in different times from different districts with a common complaint of a large irritant contact dermatitis, resembling second-degree burn injury after application of a plant poultice. The plant specimens in all patients were identified as C. falcatus and it was assessed worthwhile to report.

Additive Impairment of the Barrier Function and Irritation by Biogenic Amines and Sodium Lauryl Sulphate: A Controlled in vivo Tandem Irritation Study

Biogenic amines are potential irritants e.g. in fish-, meat-, milk- and egg-processing professions like cooks, butchers and bakers. The aim of this study was to test the irritative and barrier-disrupting properties of the biogenic amines ammonium hydroxide (AM), dimethylamine (DMA) and trimethylamine (TMA). A repeated sequential irritation of 30 min twice per day was performed over a total of 4 days (tandem repeated irritation test) on the back of 20 healthy volunteers of both sexes with AM, DMA, TMA and sodium lauryl sulphate (SLS). The epidermal barrier function was assessed with a Tewameter TM 210, stratum corneum surface pH was measured with a Skin-pH-Meter 900, inflammation was assessed with a Chromameter CR-300 on the a* axis for redness and a visual score was recorded. All tested biogenic amines (AM, DMA and TMA) induced a barrier disruption and a pH increase paralleled with a 1-day-delayed onset of inflammatory signs. These effects were further enhanced and accelerated by a sequential application of SLS together with the biogenic amines, and inflammation occurred earlier than with the single compounds. Acetic acid (AA) in contrast did only show mild barrier disruption and no significant inflammatory signs. Our system allowed a ranking of the different compounds in their irritative potential in the tandem irritation with SLS: SLS > NaOH > TMA > AA > AM > DMA. The results are suggestive that in the food-processing industry the simultaneous contact with biogenic amines and harmful detergents like SLS should be minimized.

Airways symptoms, immunological response and exposure in powder painting

Powder painting is an alternative to solvent-based spray painting. Powder paints may contain organic acid anhydrides (OAAs), which are irritants to the airways and may cause sensitisation. The aim of this study was to determine the prevalence of respiratory symptoms and immunological response among powder painters and to describe the exposure to OAAs. In all, 205 subjects in 32 enterprises participated: 93 exposed and 26 formerly exposed workers in 25 powder paint shops and 86 unexposed workers. They completed a questionnaire about working conditions and symptoms and took part in a medical examination, which included a lung function test. Urine samples, for determination of two OAAs, and blood samples, for analysis of specific antibodies against the OAAs, were taken. In addition, 33 paint samples were analysed for nine OAAs. The powder painters reported more work-related respiratory symptoms than unexposed subjects did. The prevalence of three or more symptoms was 24% in subjects with low exposure, 44% in highly exposed individuals, 46% in formerly exposed subjects and 19% in unexposed workers. Asthma symptoms were frequent, 7%, 40%, 15% and 2%, respectively. Regression analyses of the lung volumes did not show any influence of exposure. IgG, but not IgE, against the OAAs and metabolites of OAAs was found in some subjects, but no associations with the exposure could be observed. OAAs were found in only small amounts in the paint samples. The exposure to organic acid anhydrides was estimated to be low, and yet, IgG antibodies to OAA were observed in some subjects. The prevalence of work-related symptoms from the eyes and the airways was relatively high among the powder painters, and these symptoms, but not the lung volumes, were clearly related to exposure. The symptoms were probably caused by irritative properties of the powder paint dust.

An European inter-laboratory validation of alternative endpoints of the murine local lymph node assay: 2nd round

The original local lymph node assay (LLNA) is based on the use of radioactive labelling to measure cell proliferation. Other endpoints for the assessment of proliferation are also authorized by the OECD Guideline 429 provided there is appropriate scientific support, including full citations and description of the methodology (OECD, 2002. OECD Guideline for the Testing of Chemicals; Skin Sensitization: Local Lymph Node Assay, Guideline 429. Paris, adopted 24th April 2002.). Here, we describe the outcome of the second round of an inter-laboratory validation of alternative endpoints in the LLNA conducted in nine laboratories in Europe. The validation study was managed and supervised by the Swiss Agency for Therapeutic Products (Swissmedic) in Bern. Ear-draining lymph node (LN) weight and cell counts were used to assess LN cell proliferation instead of [3H]TdR incorporation. In addition, the acute inflammatory skin reaction was measured by ear weight determination of circular biopsies of the ears to identify skin irritation properties of the test items. The statistical analysis was performed in the department of statistics at the university of Bern. Similar to the EC 3 values defined for the radioactive method, threshold values were calculated for the endpoints measured in this modification of the LLNA. It was concluded that all parameters measured have to be taken into consideration for the categorisation of compounds due to their sensitising potencies. Therefore, an assessment scheme has been developed which turned out to be of great importance to consistently assess sensitisation versus irritancy based on the data of the different parameters. In contrast to the radioactive method, irritants have been picked up by all the laboratories applying this assessment scheme.

Toxicity of Hexamethylenediamine (HMDA)

Hexamethylendiamine (HMDA; CAS No. 124-09-4; 6055-52-3 for the dihydrochloride salt) is moderately toxic following acute doses/exposures with oral lethal doses in rats ranging from 750 to 1500 mg/kg. HMDA is extremely irritating to the skin and eyes and is not a sensitizer in guinea pigs. Repeated exposure inhalation studies have defined the upper respiratory tract to be the first target of HMDA. The irritation seen is proportional to the exposure concentration. Systemic damage is limited. Genetic testing is not extensive, but there is no indication of activity. HMDA is neither a developmental nor a reproductive toxin, but in one developmental study, the fetal No-observed-adverse-effect-level (NOAEL) was lower than that of the maternal animal. No carcinogenicity studies have been conducted. Documented human experience is limited, but indications of HMDA's irritative properties are found in the literature. HMDA does not persist or bioaccumulate in the environment. The chemical is not particularly toxic to fish and aquatic invertebrates but is quite toxic to algae. HMDA is rapidly absorbed and metabolized by the rat with little tissue storage.

Toxicity of Hexamethylenediamine (HMDA)

Hexamethylendiamine (HMDA; CAS No. 124-09-4; 6055-52-3 for the dihydrochloride salt) is moderately toxic following acute doses/exposures with oral lethal doses in rats ranging from 750 to 1500 mg/kg. HMDA is extremely irritating to the skin and eyes and is not a sensitizer in guinea pigs. Repeated exposure inhalation studies have defined the upper respiratory tract to be the first target of HMDA. The irritation seen is proportional to the exposure concentration. Systemic damage is limited. Genetic testing is not extensive, but there is no indication of activity. HMDA is neither a developmental nor a reproductive toxin, but in one developmental study, the fetal No-observed-adverse-effect-level (NOAEL) was lower than that of the maternal animal. No carcinogenicity studies have been conducted. Documented human experience is limited, but indications of HMDA's irritative properties are found in the literature. HMDA does not persist or bioaccumulate in the environment. The chemical is not particularly toxic to fish and aquatic invertebrates but is quite toxic to algae. HMDA is rapidly absorbed and metabolized by the rat with little tissue storage.

Allergic contact dermatitis from povidone‐iodine: a re‐evaluation study

500 consecutive patients were patch tested with a 10% povidone-iodine (PVP-I) solution, diluted 10 times in water. Readings were made at 2 and 4 days. 14 of the 500 (2.8%) showed a positive test to PVP-I. The 14 positive patients to PVP-I were subjected to a repeated open application test (ROAT) with a PVP-I solution, as is; 2 of the 14 were recorded as positive. It was concluded that only 2 of the 500 patients had true allergic contact dermatitis from PVP-I (0.4%). This study emphasizes the need for more complete investigation, when testing with some allergens, when they share both irritant and allergenic properties, such as PVP-I. The approach is important to rule out false-positive patch test reactions and to assess true clinical relevance.

An investigation into the irritant properties of some retrograde filling materials -an in vivo study

This study was done to evaluate the tissue reaction to four different retrograde filling materials. In this study 60 sterile polyethylene tubes (Meditop Corporation (M) SDN. BHD., Malaysia) were divided into 5 groups of 12 tubes each. Subsequently, the first group specimens were loaded with zinc_. free amalgam (Solila Nova, Dentsply), the second group specimens were loaded with Intermediate restorative material (IRM) (L.D. Caulk, Milford, DE), the third group specimens were loaded with Super EBA (Harry J. Bosworth CO, Skokie, IL) and the, fourth group specimens were loaded with Vitrebond (3M. St. Paul, MN, USA). In the last group the tubes were left empty to serve as control. 1 specimen from each group was implanted into the subcutaneous tissue of a single rabbit, making a total of 12 animals each containing an implant of every group. At the end of 2 wks, 4 wks and 12 wks the specimens along with surrounding tissues were removed from 4 rabbits. Subsequently the tissue was fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned, mounted and stained using usual standard technique. The sections were examined and reaction of the soft connective tissue to the material was recorded. The data was analysed statistically.

Final Report on the Safety Assessment of Potassium Silicate, Sodium Metasilicate, and Sodium Silicate1

Potassium Silicate, Sodium Metasilicate, and Sodium Silicate combine metal cations with silica to form inorganic salts used as corrosion inhibitors in cosmetics. Sodium Metasilicate also functions as a chelating agent and Sodium Silicate as a buffering and pH adjuster. Sodium Metasilicate is currently used in 168 formulations at concentrations ranging from 13% to 18%. Sodium Silicate is currently used in 24 formulations at concentrations ranging from 0.3% to 55%. Potassium Silicate and Sodium Silicate have been reported as being used in industrial cleaners and detergents. Sodium Metasilicate is a GRAS (generally regarded as safe) food ingredient. Aqueous solutions of Sodium Silicate species are a part of a chemical continuum of silicates based on an equilibrium of alkali, water, and silica. pH determines the solubility of silica and, together with concentration, determines the degree of polymerization. Sodium Silicate administered orally is readily absorbed from the alimentary canal and excreted in the urine. The toxicity of these silicates has been related to the molar ratio of SiO2/Na2O and the concentration being used. The Sodium Metasilicate acute oral LD50 ranged from 847 mg/kg in male rats to 1349.3 mg/kg in female rats and from 770 mg/kg in female mice to 820 mg/kg in male mice. Gross lesions of variable severity were found in the oral cavity, pharynx, esophagus, stomach, larynx, lungs, and kidneys of dogs receiving 0.25 g/kg or more of a commercial detergent containing Sodium Metasilicate; similar lesions were also seen in pigs administered the same detergent and dose. Male rats orally administered 464 mg/kg of a 20% solution containing either 2.0 or 2.4 to 1.0 ratio of sodium oxide showed no signs of toxicity, whereas doses of 1000 and 2150 mg/kg produced gasping, dypsnea, and acute depression. Dogs fed 2.4 g/kg/day of Sodium Silicate for 4 weeks had gross renal lesions but no impairment of renal function. Dermal irritation of Potassium Silicate, Sodium Metasilicate, and Sodium Silicate ranged from negligible to severe, depending on the species tested and the molar ratio and concentration tested. Sodium Metasilicate was negative in the local lymph node assay (LLNA), but a delayed-type hypersensitivity response was observed in mice. Potassium Silicate was nonirritating in two acute eye irritation studies in rabbits. Sodium Metasilicate (42.4% H2O) was corrosive to the rabbit eye. Sodium Silicate was a severe eye irritant in some eye irritation studies, but was irritating or nonirritating in others. A skin freshener containing Sodium Silicate was nonirritating. Sodium Metasilicate was nonmutagenic in bacterial cells. Rats given Sodium Silicate (600 and 1200 ppm of added silica) in the drinking water in reproductive studies produced a reduced number of offspring: to 67% of controls at 600 ppm and to 80% of controls at 1200 ppm. Three adult rats injected intratesticularly and subcutaneously with 0.8 mM/kg of Sodium Silicate showed no morphological changes in the testes and no effect on the residual spermatozoa in the ductus deferens. Sodium Metasilicate (37% in a detergent) mixed with water was a severe skin irritant when tested on intact and abraded human skin, but 6%, 7%, and 13% Sodium Silicate were negligible skin irritants to intact and abraded human skin. Sodium Silicate (10% of a 40% aqueous solution) was negative in a repeat-insult predictive patch test in humans. The same aqueous solution of Sodium Silicate was considered a mild irritant under normal use conditions in a study of cumulative irritant properties. The Cosmetic Ingredient Review (CIR) Expert Panel recognized the irritation potential of these ingredients, especially in leave-on products. However, because these ingredients have limited dermal absorption and Sodium Metasilicate is a GRAS direct food substance, the Panel deemed the ingredients safe for use in cosmetic products in the practices of use and concentration described in this safety assessment, when formulated to avoid irritation.