Dermal LD50 Values Research Articles

Chemical Permeation Enhancers for Topically-Applied Vitamin C and Its Derivatives: A Systematic Review

This paper reports the permeation-enhancing properties and safety of different chemical permeation enhancers (CPEs) on the topical delivery of vitamin C (VC) and its derivatives. A literature search using search keywords or phrases was done in PubMed®, ScienceDirect, and MEDLINE databases. The calculated Log P (cLog P) values were referenced from PubChem and the dermal LD50 values were referenced from safety data sheets. Thirteen studies described the permeation-enhancing activity of 18 identified CPEs in the topical delivery of VC. Correlation analysis between ER and cLog P values for porcine (r = 0.114) and rabbit (r = 0.471) showed weak and moderate positive correlation, while mouse (r = −0.135), and reconstructed human epidermis (r = −0.438) had a negative correlation. The majority (n = 17) of the CPEs belonged to Category 5 of the Globally Harmonized System of Classification or low toxicity hazard. CPEs alone or in combination enhanced permeation (ER = 0.198–106.57) of VC in topical formulations. The combination of isopropyl myristate, sorbitan monolaurate, and polyoxyethylene 80 as CPEs for VC resulted in the highest permeation enhancement ratio.

4,4’- Isopropylidenediphenol – inhalable fraction. Documentation of proposed values of occupational exposure limits (OELs)

4,4’- Isopropylidenediphenol – inhalable fraction. Documentation of proposed values of occupational exposure limits (OELs)

Derivation of avian dermal LD50 values for dermal exposure models using in vitro percutaneous absorption of [14C]-atrazine through rat, mallard, and northern bobwhite full thickness skin

Understanding dermal exposure is important for higher-tier avian ecological risk assessments. However, dermal exposure and toxicity are often unknown for avifauna. The US EPA's Terrestrial Investigation Model (TIM) uses a method to estimate avian dermal LD50 values (and ultimately dermal exposure) that frequently results in unusually high dermal exposure and low dermal LD50 estimates. This is primarily a result of using organophosphate and carbamate toxicity data to develop the oral-dermal relationship. An estimated dermal LD50 is necessary to generate a dermal route equivalency factor that normalizes potency relative to oral toxicity within the dermal pathway dose equation. In this study, atrazine dermal absorption experiments were conducted with mallard, northern bobwhite, and rat skin. These data were used to derive an avian-mammal dermal route equivalency factor for atrazine and introduce a new approach for estimating dermal LD50 values and ultimately predicting exposure via the TIM dermal pathway. Compared to the default TIM method, this new approach yielded TIM output with lower mean total dose, lower dermal fraction of total dose, greater oral fraction of total dose, and reduced model predicted mortality for atrazine. In addition, the new approach was compared with other methods for estimating avian dermal LD50 values such as those proposed for use with mammalian data and physico-chemical properties and a triazine-specific oral-dermal equation using mammalian LD50 data. The three alternative approaches resulted in output similar to one another and different from the default TIM methods. These results indicate that a dermal route equivalency factor derived from empirical data provides a higher avian dermal LD50 estimate that is consistent with other methods. In addition, the use of this dermal route equivalency factor results in greatly reduced modeled atrazine risk to birds than previously reported in US EPA risk assessments using TIM.

Safety assessment and toxicological profiling of a novel combinational sunprotective dermal formulation containing melatonin and pumpkin seed oil

Ultraviolet (UV) radiation exposure has been known to cause irreparable damages to human skin. The daunting risk of UV radiation exposure faced by military personnel led to the development of a sunscreen formulation which has superior sun protection factor combined with the ability to counteract reactive oxygen species. The present work deals with the preclinical safety evaluation of the sunscreen formulation comprising of four US FDA approved UV filters; namely avobenzone, octinoxate, oxybenzone, titanium dioxide along with melatonin and pumpkin seed oil, via OECD protocols of assessing acute oral and dermal toxicity; skin sensitizing; skin irritating; ocular irritating and genotoxic potential. Both oral and dermal LD50 values were found to be ˃2000 mg/kg body weight in adult Wistar albino rats using acute dermal and oral toxicity tests. The sunscreen formulation was found to be non-sensitizing to the skin of guinea pigs and non-irritating to both skin and eyes of rabbits. The sunscreen formulation was also found to be non-mutagenic which was affirmed by a battery of genotoxicity and muagenicity assays. The results obtained from this preclinical study indicated that the sunscreen formulation is non toxic and safe in animal models. This study along with additional preclinical evaluations may serve as a basis for considering the formulation as a potential candidate for further trials to establish its efficacy, tolerability and applicability.

Can acute dermal systemic toxicity tests be replaced with oral tests? A comparison of route-specific systemic toxicity and hazard classifications under the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)

Acute systemic toxicity data (LD50 values) and hazard classifications derived in the rat following oral administration and dermal application have been analysed to examine whether or not orally-derived hazard classification or LD50 values can be used to determine dermal hazard classification. Comparing the oral and dermal classifications for 335 substances derived from oral and dermal LD50 values respectively revealed 17% concordance, and indicated that 7% of substances would be classified less severely while 76% would be classified more severely if oral classifications were applied directly to the dermal route. In contrast, applying the oral LD50 values within the dermal classification criteria to determine the dermal classification reduced the concordance to 15% and the relative ‘under-classification’ to 1%, but increased the relative ‘over-classification’ to 84%. Both under- and over-classification are undesirable, and mitigation strategies are discussed. Finally, no substance with an oral LD50 of >2000mg/kg was classified for acute systemic toxicity by the dermal route, suggesting that dermal testing for acute systemic toxicity of such substances adds nothing to the hazard characterisation and should be removed from routine regulatory data requirements.

Final Report on the Amended Safety Assessment of Diisopropyl Dimer Dilinoleate, Dicetearyl Dimer Dilinoleate, Diisostearyl Dimer Dilinoleate, Dioctyl Dimer Dilinoleate, Dioctyldodecyl Dimer Dilinoleate, and Ditridecyl Dimer Dilinoleate

Diisopropyl Dimer Dilinoleate, Dicetearyl Dimer Dilinoleate, Diisostearyl Dimer Dilinoleate, Dioctyl Dimer Dilinoleate, Dioctyldodecyl Dimer Dilinoleate, and Ditridecyl Dimer Dilinoleate are diesters of their respective alcohols and dilinoleic acid. They function as skin-conditioning agents in a variety of cosmetic products at concentrations around 10%, but may be used at concentrations up to 53% in lipsticks. These ingredients do not absorb radiation in the ultraviolet (UV) UVA or UVB range and the only impurities expected are <0.5% dilinoleic acid, <0.1% isopropyl alcohol or <1% isostearyl alcohol, and/or small amounts of dilinoleic acid and cetearyl alcohol or octyldodecanol, depending on which diester is used. The potential skin penetration of these ingredients was evaluated using an estimate of the octanol/water partition coefficient (logP of 17.7) based on the structure of Diisopropyl Dimer Dilinoleate. This is consistent with the insolubility of these ingredients in water. Safety test data on dilinoleic acid (no adverse effects) were considered relevant because dilinoleic acid is a component of these diesters and a likely breakdown product. The acute oral and dermal LD50 values for rats of Diisopropyl, Diisostearyl, and Dioctyldodecyl Dimer Dilinoleate were >5.0 g/kg. In a subchronic feeding study, macrophage aggregation was seen in the mesenteric lymph node at the lowest dose level (0.1% in the diet). These ingredients did not produce skin or ocular irritation in animal tests, nor were they comedogenic. Ames testing, clastogenesis in human lymphocytes in culture, and L5178Y mouse lymphoma cell forward mutations were all negative, indicating no dilinoleic acid genotoxicity. No carcinogenicity or reproductive/developmental toxicity data were available; however, structural alerts that would suggest a mutagenic or carcinogenic risk are absent. Significant reproductive/developmental toxicity or other systemic toxicity is not expected with these ingredients because they remain on the skin surface. In clinical studies, cosmetic formulations containing these ingredients did not produce skin irritation or sensitization, although one report of sensitization to dilinoleic acid appeared in the case literature. The Panel did note that the concentration of use of Diisopropyl Dimer Dilinoleate was reportedly as high as 53% in lipsticks, but that the highest concentration tested for irritation/sensitization is 27%. Given the size of these molecules, their relative insolubility in water, their lipophilic nature, and the absence of any significant case reports of allergic reactions, a use concentration of 53% is not likely to be associated with any adverse effects. Accordingly, these diesters were considered safe as used in cosmetic products.

Epoxy Compounds: Aromatic Diglycidyl Ethers, Polyglycidyl Ethers, Glycidyl Esters, and Miscellaneous Epoxy Compounds

Epoxy Compounds: Aromatic Diglycidyl Ethers, Polyglycidyl Ethers, Glycidyl Esters, and Miscellaneous Epoxy Compounds

The dermal acute toxic class method: test procedures and biometric evaluations.

A dermal acute toxic class (ATC) method is presented with the use of significantly fewer animals in comparison with the classical dermal 50% lethal dose (LD50) test. The principle of the dermal ATC method is based on the oral and the inhalation ATC method. The method was developed for three fixed starting doses. Depending on the dermal LD50, the slope, the classification system and the starting dose on average 40 to 90% fewer animals will be used in comparison to at least 30 animals with the dermal LD50 test. The method was biometrically evaluated by using the Probit model for dose-response relationships. At present, there are eight different international classification systems based on dermal LD50 values. The test procedures and the calculations of the classification probabilities demonstrate that the dermal ATC method is a reliable alternative to the dermal LD50 test with the use of significantly fewer animals. Classification probabilities are presented for all classification systems currently in use, and expected numbers of experimental and of moribund/dead animals are demonstrated for the system of chemicals in the European Union for all three starting doses. The conclusion is justified that, similarly to the inhalation ATC method, there is no need to validate the dermal ATC method with the use of experimental animals.

Acute, Pharmacokinetic, and Subchronic Toxicological Sudies of 2,4-Dichlorophenoxyacetic Acid

The single-dose oral LD50 values in Fischer 344 rats for technical-grade 2,4-dichlorophenoxyacetic acid (2,4-D), es ters, and salts ranged from 553 mg/kg (isobutyl ester in females) to 1090 mg/kg (dimethylamine salt in males). The LDH values for the acid, esters, or salts, when expressed as acid equivalents, were consistent which suggests that the acute toxicity was due to 2,4-D per se. Acute dermal LD50 values in rabbits for the acid, esters, and salts were greater than 2000 mg/kg. Overall, these results indicate that the acute oral and dermal toxicity of 2,4-D are low. Pharmacokinetics were evaluated in male Fischer 344 rats given single oral doses of 10, 25, 50, 100, or ISO mg 2,4- [14CJD/kg The amount of 2,4-D in the plasma, kidney, and urine 6 hr postdosing indicated that the urinary elimination of 2,4-D was saturated in male rats given oral doses in excess of 50 mg/ kg. Subchronic dietary studies in male and female Fischer 344 rats used dose levels of 0, 15, 60, 100, or 150 mg/kg/thy of purified or technical-grade 2,4-D acid for 13 weeks. Body weight gains were decreased for both sexes at the higher dose levels of purified and technical-grade 2,4-D acid. Kidney weights were increased in all treated male rats and in females given the higher three dose levels of purified 2,4-D. Treatment-related cytoplasmic alterations were present in the renal proximal tubules of most rats given 60mg/kg/thy and higher of purified or technical-grade 2,4- D; a few females given 15 mg/kg/thy also had slight alterations in the cytoplasm of the proximal tubules. A dose-related degenerative change was identified in the descending proximal renal tubules of all male rats given the highest three dose levels of either test material and some given 15 mg/kg/thy. Dose levels of 100 or 150 mg/kg/thy of either compound for both sexes produced minimal swelling and increased staining homogeneity in the liver cells and were associated with a slight elevation of liver weight and serum glutamic pyruvic transaminase activity. Higher dose levels of technical-grade and purified 2,4-D decreased total serum tetraiodothyronine levels in female rats, however, the morphology of the thyroid gland was normal. The no-observed-effect level (NOEL) was less than 15 mg/kg/day for both purified and technical-grade 2,4-D acid.

Application of a dermal self-exposure model to worker reentry.

The dermal toxicity of five commonly used organophosphate insecticides was investigated with a mouse intermittent self-exposure model. Blood cholinesterases were monitored on d -3 and -1 before exposure and for 4--6 d during exposure to foliar residues. Responses were much greater in unmuzzled than in muzzled animals due to oral contamination. After two 10-h exposures, muzzled mice showed log-linear cholinesterase responses across a wide range of foliar pesticide concentrations. Foliar pesticide levels that caused 50% depression in plasma or red blood cell cholinesterase were determined with log-probit dose-response analysis. The greatest cholinesterase responses for both emulsifiable concentrate and encapsulated formulations were found with diazinon, followed by parathion and methyl parathion. Azinphos-methyl and mevinphos produced no significant responses in muzzled mice at maximal foliar concentrations. Symptomatology, food consumption, and body weight provided less sensitive indicators of response than cholinesterases. No consistent relation existed between the mouse intermittent self-exposure toxicities and mouse dermal LD50 values. Use of data from acutely exposed animals to predict the hazard of intermittent foliar exposure appears inadvisable.

Acute dermal toxicities of various organophosphate insecticides in mice.

Dermal LD50 values for five organophosphate insecticides were determined in mice by application of solutions to hind feet. Values were simultaneously generated for the ED50 (milligrams per kilogram) for both cholinesterase and acetylcholinesterase. Lethality was greatest with mevinphos, followed by parathion, methyl parathion, diazinon, and azinphosmethyl. LD50 values were higher than reported values for mice treated on shaved back skin. Cholinesterase ED50 values roughly agreed with LD50 values for mevinphos, parathion, methyl parathion, and azinphos-methyl, but diazinon appeared much more inhibitory of blood than neuronal cholinesterase. Red blood cell and plasma cholinesterase activities were equally sensitive for all but mevinphos and diazinon.

Acute toxicity of a homologous series of branched-chain primary alcohols.

Animal studies have been carried out on a series of highly branched primary aliphatic alcohols. The alcohols were amyl, hexyl, isooctyl, 2-ethylhexyl, isononyl, decyl, tri-decyl, and hexadecyl. The tests included oral and dermal LD50, eye and skin irritation, and 6-hour vapor exposure. Oral LD50 values in rats ranged from 1.5 to greater than 8.4 gm/kg and did not show a consistent increase with increased molecular weight. Signs of effect were associated with central nervous system depression. Dermal LD50 values in rabbits were all greater than 2.6 or 3.2 gm/kg, the highest dose tested, although percutaneous absorption was seen. Skim irritation was slight to severe and generally inversely related to molecular weight. The C5 through C13 alcohols produced moderate to severe eye irritation; the C16 alcohol produced only slight irritation. Inhalation toxicity was low, with systemic effects seen only with amyl, 2-ethylhexyl, and isononyl alcohols. Some eye, nose, throat, or respiratory tract irritation was seen...

The Acute Toxicity of Pesticides to Rats

Abstract 1. 1. LD50 values for 42 pesticides and 2 metabolites of DDT administered in a single dose by the oral or dermal route to Sherman strain adult rats have been determined. 2. 2. A comparison of laboratory results and use experience indicates that there is a much closer relationship between dermal LD50 values and the occurrence of occupational poisoning than between oral LD50 values and occupational poisoning. 3. 3. The carbamate pesticide Isolan was observed to be different from other compounds tested in that it was considerably more toxic by the dermal route than by the oral route to rats.