bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac autonomic regulation after lung exposure to carbon nanotubes
Authors: Legramante JM , Valentini F. , Magrini A. , Palleschi G. , Sacco S. , Iavicoli I. , Pallante M. , Moscone D. , Galante A. , Bergamaschi E. , Bergamaschi A. , Pietroiusti A.
Published: September 2009

The ultrafine (UF) component of airborne pollution may impair cardiovascular autonomic control, a high-risk condition for cardiovascular adverse events. Since engineered nanoparticles, such as single-walled carbon nanotubes (SWCNTs) share physicochemical properties with UF, they might have similar adverse effects. Aim of the study was to evaluate arterial baroreflex function (BRF) at baseline, 24 h after the first instillation, immediately before the second one, and 2 weeks later, in adult Wystar-Kyoto conscious rats undergoing two intratracheal instillations of SWCNT (eight rats) or phosphate buffer saline (PBS) (five rats) at 2-week interval. During each session, 30-min continuous recording of arterial pressure and pulse interval was performed by a telemetered catheter implanted in the abdominal aorta of the rats. BRF was studied by the sequence technique. SWCNTs dispersed in PBS (1 mg/ml) were administered immediately after sonication (1 μg/g body weight). A significant decrease in the number of baroreflex sequences (from 498 ± 27.1 at baseline to 287 ± 40.2 at the recording performed after 4 weeks; P < 0.05) was observed in SWCNT-instilled rats, whereas no significant change was detected in controls. These data suggest that SWCNTs may alter the BRF, thus affecting the autonomic cardiovascular control regulation.
Liquid flame spray for generating metal and metal oxide nanoparticle test aerosol
Authors: Mäkelä JM , Aromaa M. , Rostedt A. , Krinke TJ , Janka K. , Marjamäki M. , Keskinen J.
Published: September 2009

A flame-based method for generating nanoparticles with production rate in the order of g/min is presented to be used in a variety of applied studies concerning nanoparticle measurements and toxicological tests. In this study, ferric oxide, titanium dioxide, and silver nanoparticles were produced by this technique, as an example of the variety of producible compounds, and number and surface area were measured by state-of-art aerosol instruments. In the primary experiments of this study, the generator was used in a conventional way, in a fume cupboard, and the aerosol was measured from the exhaust duct of the cupboard. It has been shown that this steady, turbulent flame generator is also suitable for producing high-concentration aerosols in a wider concept. The generated aerosol was measured by variety of aerosol instrumentation to show the applicability of the generator. When using the generator intentionally as a source of aerosol in the flame processing room, mean nanoparticle sizes of 5—60 nm and active surface area concentration ranges of 1—10,000 μm2/cm 3 were covered for the room aerosol.
Airway barrier dysfunction induced by exposure to carbon nanotubes in vitro: which role for fiber length?
Authors: Rotoli BM , Bussolati O. , Barilli A. , Zanello PP , Bianchi MG , Magrini A. , Pietroiusti A. , Bergamaschi A. , Bergamaschi E.
Published: September 2009

Although carbon nanotubes (CNTs) are increasingly used, their biological effects are only incompletely characterized. However, experimental evidence suggests that the intratracheal instillation of CNTs causes the formation of interstitial granulomas and progressive pulmonary fibrosis in rodents. Using human epithelial Calu-3 cells as a model of airway epithelium in vitro, we have recently reported that the exposure to commercial multi-walled CNTs (MWCNTs) causes a progressive decrease of the transepithelial electrical resistance (TEER), pointing to a CNT-dependent impairment of the epithelial barrier function. To characterize better this behavior, we compared the effects of two types of MWCNTs and single-walled CNTs (SWCNTs) of different lengths on the TEER of Calu-3 monolayers. All the materials were used at a dose of 100 μg/mL corresponding to an exposure of 73 μg/cm2 of cell monolayer. Only the longer MWCNTs and SWCNTs cause a significant decrease in TEER. To elucidate the mechanism underlying the changes in barrier function, the expression of the junction proteins occludin and ZO-1 has been also assessed. No significant decrease in the mRNA for either protein is detectable after the exposure to any type of CNTs. It is concluded that the impairment of barrier function in Calu-3 monolayers is a peculiar effect of CNTs endowed with clear cut fiber properties and is not referable to marked changes in the expression of junction proteins.
Genotoxic effects of nanosized and fine TiO2
Authors: Falck GCM , Lindberg HK , Suhonen S. , Vippola M. , Vanhala E. , Catalán J. , Savolainen K. , Norppa H.
Published: September 2009

The in-vitro genotoxicity of nanosized TiO2 rutile and anatase was assessed in comparison with fine TiO2 rutile in human bronchial epithelial BEAS 2B cells using the single-cell gel electrophoresis (comet) assay and the cytokinesis-block micronucleus test. BEAS 2B cells were exposed to eight doses (1—100 μg/cm2) of titanium(IV) oxide nanosized rutile (>95%, <5% amorphous SiO2 coating; 10 × 40 nm), nanosized anatase (99.7%; <25 nm), or fine rutile (99.9%; <5 μm) for 24, 48, and 72 h. Fine rutile reduced cell viability at lower doses than nanosized anatase, which was more cytotoxic than nanosized rutile. In the comet assay, nanosized anatase and fine rutile induced DNA damage at several doses with all treatment times. Dose-dependent effects were seen after the 48- and 72-h treatments with nanosized anatase and after the 24-, 48- (in one out of two experiments), and 72-h treatments (one experiment) with fine rutile. The lowest doses inducing DNA damage were 1 μg/cm2 for fine rutile and 10 μg/cm 2 for nanosized anatase. Nanosized rutile showed a significant induction in DNA damage only at 80 μg/cm2 in the 24-h treatment and at 80 and 100 μg/ cm2 in the 72-h treatment (with a dose-dependent effect). Only nanosized anatase could elevate the frequency of micronucleated BEAS 2B cells, producing a significant increase at 10 and 60 μg/cm 2 after the 72-h treatment (no dose-dependency). At increasing doses of all the particles, MN analysis became difficult due to the presence of TiO2 on the microscopic slides. In conclusion, our studies in human bronchial epithelial BEAS 2B cells showed that uncoated nanosized anatase TiO2 and fine rutile TiO2 are more efficient than SiO 2-coated nanosized rutile TiO2 in inducing DNA damage, whereas only nanosized anatase is able to slightly induce micronuclei.
Inconsistent approach to the treatment of chronic digoxin toxicity in the United States
Authors: Kirrane BM , Olmedo RE , Nelson LS , Mercurio-Zappala M. , Howland MA , Hoffman RS
Published: September 2009

Evidence-based guidelines do not exist for the treatment of patients with chronic mild—moderate digoxin toxicity. We sought to evaluate differences among specialists in the use of digoxin-specific antibody fragments and the decision to admit these patients. A sample of cardiologists, emergency physicians, and medical toxicologists was surveyed. The survey detailed four hypothetical cases of chronic digoxin toxicity created by consensus among authors. All cases had the same digoxin concentration, but signs and symptoms varied in an attempt to explore four different thresholds. For each scenario, clinicians made decisions about admission and treatment. Survey response varied: cardiologists 17%, emergency physicians 6.7%, and toxicologists 39%. Statistically significant difference was found in the administration of Fab among cardiologists (67%), emergency physicians (82%), or toxicologists (91.5%) and admission rate (cardiologists 34%, emergency physicians 28%, and toxicologists 46%). Differences exist among clinicians of various specialties regarding treatment of chronic digoxin toxicity. These differences may reflect diverse perspectives or knowledge gaps and may translate into excess cost or less than ideal care. Exploring these differences may improve patient care, improve interactions among providers, and set the stage for development of consensus guidelines and research.
Two-year follow-up of two patients after severe thallium intoxication
Authors: Pelclová D. , Urban P. , Ridzoň P. , Šenholdová Z. , Lukáš E. , Diblík P. , Lacina L.
Published: September 2009

Information on the prognosis and electrophysiological follow-up of severe thallium poisoning is limited. We report two patients (mother and daughter) who were repeatedly exposed to thallium poisoning experienced hair loss, polyneuropathy, and visual impairment. Nerve conduction studies (NCSs), visual evoked potentials (VEP), brainstem auditory evoked potentials (BAEP) changes, and optical neuropathy developed within a few months latency after the first subjective signs. Normal findings of these electrophysiological methods in the first 2 weeks therefore led in one of our patients to exclusion of thallium as the cause of symptoms. Thallium poisoning was, however, later confirmed by toxicological analysis of blood and/or urine and feces in both the patients and in the microscopic hair analysis of the daughter. Both patients were treated with Prussian blue that increased the elimination of thallium in urine and feces. The hair loss was fully reversible. During a 2-year follow-up after the poisoning, polyneuropathy in the lower extremities improved substantially, but residual impairment in both motor and sensory function, NCSs, VEP, and BAEP remained. Additionally, severe asymmetrical vision impairment persists in both women, with central scotomata and impaired color discrimination in both eyes. Substantial improvement of their visual function is unlikely.
Of ‘Normal Sex’ and ‘Real Rape’: Exploring The Use of Socio-Sexual Scripts in (Mock) Jury Deliberation
Authors: Ellison Louise , Munro Vanessa E.
Published: September 2009

This article explores a series of 27 jury deliberations, undertaken by volunteer members of the public, following their observation of a mini-rape trial reconstruction. While research with ‘real’ jurors is prohibited in England and Wales, previous social attitude and experimental studies have suggested that jurors in sexual assault trials may well be influenced by dubious stereotypes about rape, rapists and rape victims. In this article, the authors explore the relationship between these (mis)conceptions about rape and public expectations regarding socio-sexual conduct more broadly. The authors examine the scripts that were invoked, defended and relied upon by mock jurors in order to distinguish ‘normal’ (hetero)sexual seduction from rape. More specifically, this article explores participants’ expectations (both descriptive and normative) in relation to the communication of consent, the role of male initiative, and the location, timing of and parties to sexual intercourse, as well as the relevance of the use of physical force, the fact of the parties’ drunkenness or the nature of their respective post-coital conduct.
Critical Legal Studies and the Politics of Space
Authors: Butler Chris
Published: September 2009

A growing body of work over the past two decades has been explicitly concerned with the interdisciplinary connections between law and questions of space. Traversing topics such as the regulation of the city, control of public space and the symbolic dimensions of spatial conflicts, this literature constitutes an important contribution to critical legal scholarship. However, there is still much work to be done on the development of the theoretical foundations of this field. This article will present the writings of the French philosopher and sociologist Henri Lefebvre as revealing a sophisticated theory of space with potentially profound implications for the research program of critical legal studies. Lefebvrean ideas are directly relevant to the renewal of critical approaches to the structure and form of planning law and regimes of urban governance. His work also contains fertile resources for research into the transformation of traditional forms of political citizenship into the broader concept of urban citizenship. Both these examples highlight the importance of the politics of space for critical legal thought and the role Lefebvre’s social theory may play in its future development.
‘Gay Couple’s Break Like Fawlty Towers’: Dangerous Representations of Lesbian and Gay Oppression in an Era of ‘Progressive’ Law Reform
Authors: Cobb Neil
Published: September 2009

This article reconsiders the politics of knowledge production surrounding the discursively constructed sexual subject in light of the politico-cultural debates that ensued over enactment of the controversial 2007 Equality Act (Sexual Orientation) Regulations. Exploring the rise, in the course of these debates, of what it terms the ‘bed and breakfast paradigm’ of lesbian and gay oppression, the article questions whether that paradigm provides a suitably representative account of housing-related discrimination experienced by lesbians and gay men. It then goes on to highlight the silence during the debates that surrounded the pervasive intra-familial discrimination experienced by young lesbians and gay men within the home; a consequence, it finally argues, of law’s power to define the parameters of explanatory discourse around antidiscrimination protections according to an implicit public/private binary.
Racial Ideas and Gendered Intimacies: the Regulation of Interracial Relationships in North America
Authors: Thompson Debra
Published: September 2009

This article compares the regulation of interracial intimacies in North America, contending that anti-miscegenation laws in the United States and Canada’s Indian Act regimes are both striking and comparable examples of the state’s regulation of the intimate sphere. The author argues that the social signifiers of race and gender, tied together with sexuality, are interlocking sets of power relations and these intersecting discourses are integral to understanding the comparative regulation of interracial intimacy in North America. In the circumstances of anti-miscegenation laws and the Indian Act, the transgression of gendered/raced social boundaries, the control of raced/gendered sexualities, the interlocking and mutually reinforcing nature of patriarchal, white supremacist and capitalist systems of domination, the threat of non-white access to white capital, and the predicament of racial categorization exist as a corollary of the state’s regulation of interracial intimate life. This article reveals the law and state as important sites of the creation and manipulation of racial boundaries, acting as producers and reproducers of racial ideas, and demonstrates that the interracial transgressions of sexual space were also perceived as transgressions of social, economic, and political boundaries between races, posing a threat to the dominant white and masculine hegemony in North America in the late 19th and early 20th centuries.
Imperialism and Nationalism in Early Modernity: The ‘Cosmopolitan’ and The ‘Provincial’ in Shakespeare's Cymbeline
Authors: Heinze Eric
Published: September 2009

The discourses of conquering empire and vassal nation are varied, often internally contradictory. The empire may represent openness and diversity, or militarist brutality. The underling nation may represent autonomy and self-determination, or narrow provincialism. Those discourses spawn ideologies of liberation (‘the empire liberates the nation’, ‘the nation must be liberated from the empire’) and counter-ideologies of oppression (‘the empire oppresses the nation from without’, ‘the empire prevents oppression by dominant national groups of subordinate national groups’). Such concepts are central to Shakespeare’s Cymbeline. Bound to pay tribute to Caesar Augustus, Britain’s King Cymbeline contemplates a national rebellion against pax romana, while at the same time exercising its own dominance over Wales and other conquered territory in the Isles. Parallels to the reign of James I are apparent, where England is embarking upon its ascent to empire, its pax britannica, in the face of Welsh, Scottish or Irish resistance. Several discourses emerge as hallmarks of power politics in early modernity: cosmopolitan empire, oppressive empire, cosmopolitan nation, oppressive nation.
‘It Still Makes Me Shudder’
Authors: Dwyer Philip G.
Published: September 2009

This article looks at a number of French testimonies of massacres during the Revolutionary and Napoleonic Wars committed by combatants, for the most part against civilians. Much of what we know about massacres is based on personal testimonies that are invariably from the perspective of the perpetrator, in this case, troops of the Grande Armée. Just as important as understanding why massacres occurred is to understand how they were represented, recalled and remembered by those who witnessed them. In this, memoirs become an indispensable tool for what they tell us about how the killings were justified, either from the individual or the state’s point of view, and for the insights one can glean into the minds of those that either committed or witnessed the atrocities taking place. Descriptions of massacres are commonly used to highlight the horror of war rather than the horror of the event itself. Massacre was also a means of underlining the difficulties encountered by the French in conquering, that is, in ‘civilizing’, Europe. Massacre, the article concludes, was an accepted if not an acceptable part of eighteenth-century European warfare. This, however, did not attenuate the horror; it was something that many veterans had difficulty recalling, even decades after the events described.
The Indian Army, Partition, and the Punjab Boundary Force, 1945—1947
Authors: Marston Daniel P.
Published: September 2009

How effective was the Indian Army in serving as aid to the civil power in the chaotic period leading up to the independence and partition of India in 1947? This article attempts to shed fresh light, by examining recent scholarship and newly available archival materials, on the performance of the Indian Army, as embodied in the Punjab Boundary Force, in countering and containing the communal violence that rocked India during the momentous events of 1947. The Indian Army’s challenges and achievements during this testing period provide valuable lessons for every army faced with political upheaval and communal violence.
Preservice Classroom Teachers’ Attitudes Toward Music in the Elementary Curriculum
Authors: Hash Phillip M.
Published: September 2009

The purpose of this study is to survey preservice classroom teachers at Calvin College in Grand Rapids, Michigan, to determine their attitudes toward music in the elementary curriculum. Research questions examined participants’ (a) musical abilities and experience as well as beliefs regarding (b) the roles of the classroom teacher and music specialist, (c) their comfort level with teaching music as a subject and integrating music with other disciplines, (d) the importance of music in relation to other subjects, and (e) the importance of various outcomes of the general music program. A survey was administered to 116 preservice elementary classroom teachers enrolled in either student teaching or early field experience during the 2008—2009 academic year. Data indicated that most of these respondents do not feel comfortable teaching music as a subject, believe music should be taught by a specialist, and disagree that classroom teachers should be capable of teaching music. Results also suggest that participants regard music as less important than other subjects and nonmusical outcomes of music instruction as more important than musical outcomes. The majority of respondents, however, agree that music can improve achievement in other disciplines and are supportive of music integration. These findings were helpful in designing the music portion of an art and music methods course at Calvin College and may have implications for elementary music methods classes offered at other institutions.
Final Report On the Safety Assessment of m-Phenylenediamine and m-Phenylenediamine Sulfate1
Authors: Andersen F. Alan
Published: September 2009

The ingredients m-Phenylenediamine and m-Phenylenediamine Sulfate are aromatic amines that function as hair colorants in cosmetic products. Both are currently used in hair dye products at concentrations of up to 3%. Percutaneous absorption of m-Phenylenediamine has been demonstrated in animals. Three metabolites excreted in urine have been identified. The oral LD50 of m-Phenylenediamine in rats is between 360 and 650 mg/kg. Subchronic studies in rats (oral) indicated some lesions in the liver but no kidney injury, while one study in rabbits (dermal) indicated some liver and kidney toxicity. Another dermal study in rabbits failed to show any liver or kidney toxicity. Skin irritation and sensitization were found in guinea pigs exposed to m-Phenylenediamine. Clinical data indicated some evidence of sensitization. A short-term study in rats (oral) reported an absence of any neurotoxicity. One study in female rats identified fetotoxicity but no evidence of terata. Other studies reported neither birth defects nor fetal deaths. Both positive and negative results were found in various mutagenesis assay systems. In studies with mice and rats, neither m-Phenylenediamine (both oral and dermal exposure) nor hair dye formulations (dermal exposure only) containing m-Phenylenediamine were carcinogenic. Based on the concentrations of m-Phenylenediamine shown to produce sensitization in animal studies, it was concluded that these ingredients can be used safely in hair dyes at concentrations of up to 10%.
Final Report On the Safety Assessment of 2-Amino-6-Chloro-4-Nitrophenol and 2-Amino-6-Chloro-4-Nitrophenol Hydrochloride1
Authors: Andersen F. Alan
Published: September 2009

2-Amino-6-Chloro-4-Nitrophenol and its hydrochloride salt are substituted aromatic compounds that function as colorants in hair dyes. Only the hydrochloride salt is currently reported to be used. 2-Amino-6-Chloro-4-Nitrophenol is poorly absorbed through the skin. Less than 0.25% of 2-Amino-6-Chloro-4-Nitrophenol found in a nonoxidative hair dye was absorbed. Less than 0.2% of 2-Amino-6-Chloro-4-Nitrophenol found in an oxidative hair dye was absorbed. In subchronic oral studies in rats, a no observable adverse effect level of 30 mg / kg / day for 2-Amino-6-Chloro-4-Nitrophenol was determined; at higher doses, increased organ weights were seen. A 2% solution of 2-Amino-6-Chloro-4-Nitrophenol applied under occlusive conditions was found to be nonirritating to rabbits. At 0.1%, 2-Amino-6-Chloro-4-Nitrophenol was nonsensitizing; at 2%, there was sufficient skin coloration from the dye that assessment of sensitization was difficult; but no obviously sensitized areas were reported. An oral teratogenicity study in rats showed no birth defects. In one Ames test, Salmonella strains TA97, TA98, and TA100 showed an increase in mutations, with and without metabolic activations. Strain TA1535 was negative, however. In another Ames test, Salmonella strains TA97 and TA100 showed no increase in mutations upon treatment with 2-Amino-6-Chloro-4-Nitrophenol, diluted in dimethylsulfoxide, with and without metabolic activation. Strain TA98 was negative with metabolic activation but positive without activation. In follow-up testing with strain TA98-NR, there was no increase in mutations in the absence of activation. Mutagenicity assays in mammalian systems were negative. The poor absorption through the skin, lack of any teratogenic effect, and negative mutagenesis data in certain Ames test strains and in mammalian systems suggested that any systemic effects from the use of actual products were unlikely. It was possible to conclude that the highest concentration of 2-Amino-6-Chloro-4-Nitrophenol tested (2%) is safe for use in hair dye formulations.
A Mechanistic Basis for the Beneficial Effects of Caloric Restriction On Longevity and Disease: Consequences for the Interpretation of Rodent Toxicity Studies
Authors: Leakey Julian E. A. , Seng John E. , Barnas Crissy R. , Baker Vanessa M. , Hart Ronald W.
Published: September 2009

Caloric restriction in rodents has been repeatedly shown to increase life span while reducing the severity and retarding the onset of both spontaneous and chemically induced neoplasms. These effects of caloric restriction are associated with a spectrum of biochemical and physiological changes that characterize the organism's adaptation to reduced caloric intake and provide the mechanistic basis for caloric restriction's effect on longevity. Here, we review evidence suggesting that the primary adaptation appears to be a rhythmic hypercorticism in the absence of elevated adrenocorticotropin (ACTH) levels. This characteristic hypercorticism evokes a spectrum of responses, including reduced body temperature and increased metabolic efficiency, decreased mitogenic response coupled with increased rates of apoptosis, reduced inflammatory response, reduced oxidative damage to proteins and DNA, reduced reproductive capacity, and altered drug-metabolizing enzyme expression. The net effect of these changes is to (1) decrease growth and metabolism in peripheral tissues to spare energy for central functions, and (2) increase the organism's capacity to withstand stress and chemical toxicity. Thus, caloric restriction research has uncovered an evolutionary mechanism that provides rodents with an adaptive advantage in conditions of fluctuating food supply. During periods of abundance, body growth and fecundity are favored over endurance and longevity. Conversely, during periods of famine, reproductive performance and growth are sacrificed to ensure survival of individuals to breed in better times. This phenomena can be observed in rodent populations that are used in toxicity testing. Improvements over the last 30 years in animal husbandry and nutrition, coupled with selective breeding for growth and fecundity, have resulted in several strains now exhibiting larger animals with reduced survival and increased incidence of background lesions. The mechanistic data from caloric restriction studies suggest that these large animals will also be more susceptible to chemically induced toxicity. This creates a problem in comparing tests performed on animals of different weights and comparing data generated today with the historical database. The rational use of caloric restriction to control body weight to within preset guidelines is a possible way of alleviating this problem.
Body Weight Impact On Spontaneous Diseases in Chronic Bioassays
Authors: Turturro Angelo , Hass Bruce , Hart Ronald , Allaben William T.
Published: September 2009

Tests to evaluate toxicity should be consistent and reproducible. These crucial elements have been brought into question because the controls of near-replicate experiments have significant variability in parameters such as survival and common tumor incidences critical to safety evaluation, even in some of the best controlled assays, those conducted by the National Toxicology Program (NTP). To minimize the impact of these variabilities, dietary control (DC), the control of body weight (BW) growth by nutritionally adequate dietary manipulation, has been suggested for chronic studies. The target BW growth curve for the DC should be fast enough to allow the animal to develop tumors, but slow enough to prevent too great a tumor load in controls. In order to better define these targets in Fischer 344 rats, relationships have been developed between various BWs at different times-on-test, incidences of common tumors in control animals from NTP bioassays initiated from January 1981 and reported by June 1996, as well as survival, with the adjustments for different study types used in the chronic assays. These rat studies were complemented by using a set of similar studies in B6C3F1 mice that appear to have "restricted-like" properties. Data from the experiments using dietary restriction (DR) appeared to be better explained using data derived from these experiments rather than from studies with normal BW growth curves. When the DR data are combined with these "restricted-like" experimental results, the capacity to predict the consequences of DC for tumor incidences is improved.
Final Report On the Safety Assessment of Hc Orange No. 11
Authors: Zondlo Fiume Monice
Published: September 2009

HC Orange No. 1 is used as a colorant in semipermanent hair dyes. The highest concentration reported to be used is 0.15%, but information from manufacturers suggested that higher concentrations may be used in the future. Skin penetration through cadaver skin was 1.28% at 24 hours. In studies using rats, acute oral exposure studies produced little toxicity, and short-term toxicity studies produced reduced body weight and increased liver and kidney weights, relative to controls in animals fed 0.5% HC Orange No. 1. There was no evidence of reproductive or developmental toxicity in rats fed up to 1.25% HC Orange No. 1 or in a multigeneration study using rats in which 0.15% HC Orange No. 1 was painted on the skin. While evidence suggests this ingredient is a mild ocular irritant, no skin irritation, sensitization, or photosensitization was seen in animal or clinical tests. The preponderance of data (four out offive studies) indicate that this ingredient is not genotoxic. Hepatocellular and parathyroid hyperplasia were noted in the dermal carcinogenicity study, but the overall findings were clearly negative. Because the highest concentration tested that produced no significant sensitization in clinical tests was 3%, the Expert Panel concluded that safety could be assured only at levels ≤3%. The Expert Panel recognized that this concentration may be greater than that currently used in hair dye formulations.
Amended Final Report On the Safety Assessment of Pentaerythrityl Rosinate
Authors: Andersen F.A.
Published: September 2009

Pentaterythrityl Rosinate (previously called Pentaerythritol Rosinate) is the ester of rosin acids with the polyol pentaerythritol. It is used as a skin conditioning agent-emollient and viscosity increasing agent-nonaqueous in a few cosmetic formulations. In a previous safety assessment, it was concluded that the available data were insufficient to support the safety of this ingredient in cosmetic products. Additional data needed included: concentration of use, source and method of manufacture, chemistry (ultraviolet [UV] spectral analysis, pH, and impurities), ocular irritation, human dermal irritation and sensitization, and photosensitization (only if Pentaerythritol Rosinate absorbs UVA or UVB light). It was also noted that the carcinogenic potential of this ingredient was still of concern because of the low concentration tested in the available carcinogenicity study. Additional data were received. This ingredient is produced by the fractional distillation of crude tall oil to form rosin, which is then esterified with monopentaerythritol. It is typically used at concentrations of 0. 5-10%. It does not significantly absorb in the UVA or UVB portion of the spectrum. Formulations with 10% Pentaerythrityl Rosinate produced only minimal ocular irritation. Likewise tests of formulations with the ingredient at concentations of 7-9.2% resulted in minimal dermal irritation. The ingredient was nonsensitizing in animal maximization tests. Clinical tests of formulations with the ingredient at concentrations of 7-9.6% resulted in neither irritation nor sensitization. No data, however, were provided on possible impurities. Absent information on the actual chemical structure, the lack of information on impurities was considered significant. On further review, a single carcinogenicity study with negative results reported in the earlier safety assessment was considered inadequate. The absence of genotoxicity data was also considered significant. The lack of impurity and chemical structure information also raised a concern about the need for reproductive and developmental toxicity data. On the basis of this further review, it was concluded that the available data are still insufficient to support the safety of this ingredient in cosmetic products. Additional data needed include: (1) two genotoxicity assays, at least one in a mammalian system; if positive, then a 2-year dermal carcinogenicity study using National Toxicology Program (NTP) methods is needed; (2) dermal absorption; if significantly absorbed, then both a 28-day dermal toxicity study and a reproductive and developmental toxicity study may be needed; and (3) chemical properties, including structure and impurities.
Final Report On the Safety Assessment of Iodopropynyl Butylcarbamate (IPBC)
Authors: Lanigan Rebecca S.
Published: September 2009

Iodopropynyl Butylcarbamate (IPBC) functions as a preservative in a wide variety of cosmetic formulations. Although concentrations as high as 0.1% have been reported, most applications appear to require this preservative at less than 0.0125%. IPBC readily penetrates through the skin. The average acute oral LD50 in rats is 1.47 g/kg. Rats fed IPBC for 4 weeks had increased liver weights and decreased plasma cholinesterase activity, and rats fed IPBC for 13 weeks had transient behavior alteration, increased liver weights, hepatocyte enlargement, stomach lesions, and decreased weight gain. Rats administered IPBC as dusts and liquid aerosols had labored breathing—lung edema, emphysema, and reddened lungs were observed after exposure. Dermal irritation, but no evidence of skin sensitization, was seen in animal studies. At concentrations of 0.5%, IPBC caused iritis and conjunctival irritation in rabbit eyes, but exposure to concentrations up to 0.015% produced only slight conjunctival redness. IPBC was not genotoxic, with or without metabolic activation. No evidence of carcinogenic potential was found in a 104-week chronic oral toxicity study using rats. Reductions in weight gain were observed, along with inflammation of the nonglandular stomach and lesions in the submaxillary salivary gland. In reproductive and developmental toxicity studies using rats and mice, IPBC had no significant effect on fertility, reproductive performance, or on the incidence of fetal malformations. IPBC was found to be mildly irritating, but not sensitizing in clinical testing. At concentrations up to 0.1%, IPBC was not comedogenic in clinical tests. Given the acute inhalation toxicity observed in animals, the potential for mild irritation, and the absence of any data on comedogenicity at concentrations higher than 0.1 % in clinical tests, the Expert Panel concluded that IPBC is safe as a cosmetic ingredient at concentrations ≤0.1 %, but that it should not be used in products intended to be aerosolized.
Final Report On the Safety Assessment of Sodium Alpha-Olefin Sulfonates
Authors: Bindu Nair
Published: September 2009

Sodium C14-16 OlefinSulfonate, Sodium C12-14 Olefin Sulfonate, Sodium C 14-18 Olefin Sulfonate, and Sodium C16-18 Olefin Sulfonate are the Sodium α-Olefin Sulfonates used in cosmetics as surfactant-cleansing agents. The highest concentration reportedly is 16% in shampoos and bath and shower products. These ingredients are a mixture of long-chain sulfonate salts prepared by sulfonation of α-olefins of various carbon chain lengths noted as subscripts. In the manufacture of these ingredients, delta and gamma sultones may be produced. Sodium α-Olefin Sulfonates are poorly absorbed through normal skin, but are significantly absorbed through damaged skin. Acute oral LD50 values were 1.3 2.4g/kg in rats and 2.5-4.3 g/kg in mice. Short-term toxicity studies using rats showed no consistent effects, even with exposures in the 0.5-1.0 g/kg range. Concentrations above 10% produced moderate ocular irritation and a concentration of 5% produced mild ocular irritation in rabbits. In reproductive and developmental toxicity studies, fetal abnormalities were noted, but only at doses that were maternally toxic. Genotoxicity data were mostly negative and oral and dermal carcinogenicity studies were negative. Various animal and clinical studies found irritation and sensitization. Sensitization was attributed to low level gamma sultone residues. Because gamma sultones are demonstrated sensitizers at very low levels, it was concluded that any product containing Sodium α-Olefin Sulfonates should have very little gamma sultone residues. The gamma sultone levels should not exceed 10 ppm for saturated (alkane) sultones, 1 ppm for chloro-sultones, and 0.1 ppm for unsaturated sultones. Sodium α-Olefin Sulfonates are otherwise considered safe for use in rinse-off products. Based on concerns about irritation, were Sodium α-Olefin Sulfonates to be used in leave-on products, it was concluded that concentrations should not exceed 2% for such uses.
Final Report On the Safety Assessment of Polyvinyl Alcohol
Authors: Bindu Nair
Published: September 2009

Polyvinyl Alcohol is a synthetic alcohol used as a binder, film former, and viscosity increasing agent in a wide range of cosmetic formulations at concentrations up to 13%. Typical molecular weights range from 25,000 to 300,000. The acute oral LD50 in rats is reported to be >10 g/kg in one study and >21.5 g/kg in another. Dermal exposures of 5 and 13 weeks (the latter using 13% Polyvinyl Alcohol) produced no significant effects in rats. Various organ lesions and hypertension were noted in rats following repeated subcutaneous or intravenous dosing. Central nervous system depression and anemia, followed by renal damage, was seen in beagle dogs given daily intravenous injections of Polyvinyl Alcohol for a week. Several studies tested the carcinogenicity of subcutaneous implants of Polyvinyl Alcohol sponges or powder. Although the majority of these studies were positive, tumors were localized to the site of implantation. In another study in which Polyvinyl Alcohol was used as the vehicle for another agent and tested itself as the vehicle control, Polyvinyl Alcohol had no effect on the incidence of histiocytic sarcoma. Although no data were available assessing the reproductive or developmental toxicity, these endpoints were not considered to be likely with external exposure to this polymer. Polyvinyl Alcohol was not an ocular irritant in animal or clinical studies, nor was it a sensitizer. Some evidence of dermal irritation in animal and clinical studies was seen, but in the clinical studies it was not considered clinically significant. Based on these data, it was concluded that Polyvinyl Alcohol is safe as used in cosmetic formulations.
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
Authors: Andersen F. Alan
Published: September 2009

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 Safety Assessment for PCA and Sodium PCA
Authors: Andersen F. Alan
Published: September 2009

PCA is the cosmetic ingredient term used for the cyclic organic compound known commonly as pyroglutamic acid. Sodium PCA is the sodium salt of PCA. Both are used as hair and skin conditioning agents. These ingredients are recommended to be used in a concentration range of 0.2-4%. One optical isomer of PCA (the L form) is a naturally occurring component of mammalian tissue. PCA applied to the skin is absorbed to a limited extent. Absorption is in addition to PCA already present in the skin. In short-term and subchronic studies in several animal species, findings were unremarkable except for neurotoxicity in mice when injected interstriatally. No such findings were seen in similar studies using rats or with oral administration using mice. In animal studies, Sodium PCA was nonirritating to the eye and skin at concentrations up to 50%. No evidence of phototoxicity, sensitization, or comedogenicity was found. These ingredients were not genotoxic. In a range of clinical tests, PCA and Sodium PCA were found to be nonirritating and nonsensitizing (with and without UV exposure). Based on the low actual skin penetration of dermally applied PCA and in recognition of the endogenous levels found in the skin, it was considered that reproductive and developmental toxicity data were not critical to completion of the safety assessment. Based on the available data, it was concluded that PCA and Sodium PCA are safe as presently used in cosmetic formulations. These ingredients, however, should not be used in cosmetic products containing nitrosating agents.
Final Report on the Safety Assessment of Propylene Glycol (PG) Dicaprylate, PG Dicaprylate/Dicaprate, PG Dicocoate, PG Dipelargonate, PG Isostearate, PG Laurate, PG Myristate, PG Oleate, PG Oleate SE, PG Dioleate, PG Dicaprate, PG Diisostearate, and PG Dilaurate
Authors: Johnson Wilbur
Published: September 2009

The Propylene Glycol Dicaprylate family of ingredients includes several esters and diesters of Propylene Glycol and fatty acids. These ingredients are used in cosmetic formulations as skin conditioning agents, viscosity increasing agents, and surfactants. Two skin irritation studies (minimal to no irritation) and a comedogenicity study (insignificant comedogen) on Propylene Glycol Dicaprylate/Dicaprate and a skin irritation study (slight) and an acute oral toxicity study (nontoxic) on Propylene Glycol Laurate were available. Available data were also found indicating that Propylene Glycol Dicaprylate/Dicaprate and Propylene Glycol Dipelargonate may enhance the skin penetration of other chemicals. Because of the ability of these Polyethylene Glycol esters and diesters to enhance penetration of other agents, it was recommended that care be taken in using these and other Polyethylene Glycol esters and diesters in cosmetic products. Previous Cosmetic Ingredient Review safety assessments of related ingredients, including Polyethylene Glycol, Polyethylene Glycol Stearate, Coconut Oils and Acids, Isostearic Acid, Lauric Acid, Myristic Acid, Oleic Acid, and Caprylic/Capric Triglyceride, were summarized. Included were mutagenicity, chronic toxicity, and skin irritation and sensitization data. Based in part on the limited data available on the ingredients included in the report, but more so on the previous reviews of chemically similar moieties, it was concluded that Propylene Glycol Dicaprylate, Propylene Glycol Dicaprylate/Dicaprate, Propylene Glycol Dicocoate, Propylene Glycol Dipelargonate, Propylene Glycol Isostearate, Propylene Glycol Laurate, Propylene Glycol Myristate, Propylene Glycol Oleate, Propylene Glycol Oleate SE, Propylene Glycol Dioleate, Propylene Glycol Dicaprate, Propylene Glycol Diisostearate, and Propylene Glycol Dilaurate are safe for use as cosmetic ingredients in the present practices of use.
Final Report on the Safety Assessment of Ascorbyl Palmitate, Ascorbyl Dipalmitate, Ascorbyl Stearate, Erythorbic Acid, and sodium Erythorbate
Authors: Andersen F. Alan
Published: September 2009

Ascorbyl Palmitate, Ascorbyl Dipalmitate, Ascorbyl Stearate, Erythorbic Acid, and Sodium Erythorbate are related ingredients that function as antioxidants in cosmetic formulations. Ascorbyl Palmitate, Ascorbyl Dipalmitate, and Ascorbyl Stearate are esters and diesters of ascorbic acid with long-chain fatty acids. Erythorbic Acid is a stereoisomer of ascorbic acid and Sodium Erythorbate is the sodium salt of Erythorbic Acid. Although all of these ingredients are used, uses of Ascorbyl Palmitate and Erythorbic Acid predominate, with combined uses in over a thousand cosmetic formulations at low concentrations. Ascorbyl Palmitate is used at concentrations between 0.01 and 0.2% , and Erythorbic Acid is used at concentrations of 0.5-1% . Ascorbyl Palmitate has vitamin C activity approximately equal to that of L-ascorbic acid, whereas Erythorbic Acid has only 5% activity. The esters are likely to penetrate the skin readily, but the acid and its salt are not likely to penetrate. These ingredients exhibit low acute oral toxicity in animals. In chronic feeding studies, decreased body weight gain, the formation of oxalate stones in the bladder, and hyperplasia were seen in rats fed high levels of Ascorbyl Palmitate. Ascorbyl Palmitate (10%) and Ascorbyl Dipalmitate (100%) were not irritating to the intact skin of albino rabbits. Ascorbic Acid (30 % ) itself caused barely perceptible erythema and Sodium Erythorbate powder caused no irritation to the intact and abraded skin of rabbits. In animal studies, Ascorbic acid was not a sensitizer, and Erythorbic Acid (10%) applied topically to porcine skin reduced ultraviolet B (UVB)-induced phototoxicity. In clinical studies, Ascorbyl Palmitate caused no dermal irritation or sensitization. These ingredients are minimally irritating to the eye. Sodium Erythorbate did not cause fetal or maternal toxicity or developmental toxicity in rats and mice fed high levels. Although these ingredients were generally negative in a wide range of genotoxicity tests, Erythorbic Acid and Sodium Erythorbate did produce isolated positive genotoxicity test results. As antioxidants, these ingredients have been studied in animals after initiation with various carcinogens. In some cases reductions in tumor incidence were seen, in others no effect was noted. In no case did treatment with these ingredients increase tumor incidence. The highest use concentrations of Erythorbic Acid and Sodium Erythorbate are in oxidative hair dyes, where they are completely consumed in the chemical reaction that takes place at mixing. The fatty acid esters of ascorbic acid are used at lower concentrations in leave-on formulations. In consideration of these uses and based on the available safety test data, Ascorbyl Palmitate, Ascorbyl Dipalmitate, Ascorbyl Stearate, Erythorbic Acid, and Sodium Erythorbate are safe for use as cosmetic ingredients in the present practices of use.