Toxicity after repeated application

Pigments are passed via the gastro-intestinal tract and not discharged via the urethra. According to the results of these studies, organic pigments show practically no acute toxicity. 

Publications summarizing the results of studies on the effect of pigments on the skin and mucous membrane (conjunctiva of eyes) of rabbits describe similar observations. These sources refer to pigments as trade products which may contain auxiliaries (Table 37). 

To summarize the results of the two discussed chapters it has been demonstrated that organic pigments exhibit very high LD50 values and only rarely cause irritations of skin or mucous membranes. 

These so-called subacute or subchronic toxicity studies involve the repeated application of a test substance to animals, typically for a period of 30 or 90 days. The time pattern is thus an intermediate one between acute and chronic toxicity. To test a substance for subacute or subchronic toxicity, it is mainly applied by ingestion or inhalation. Not one out of the large number of organic pigments which have thus been tested has demonstrated any irreversible toxic effect. No toxic response was observed in rats which were fed either Pigment Yellow 1 or Pigment Yellow 57 1 for 30 days [22], 

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Toxicology studies are concerned with a variety of aspects, primarily with (1) Acute toxicity, (2) Irritation of skin and eyes, (3) Toxicity after repeated application, (4) Sensitization, (5) Mutagenicity, and (6) Cancerogenicity. 

Applied to the skin of guinea pigs for 24 hours, a 10% solution caused only slight erythema at 10-20ml/kg whereas 5ml/kg caused no effect. There was no evidence of systemic toxicity after topical application. Triphenyl amine was not a skin sensitizer, as determined by repeated application of a 0.1M solution to guinea pigs. 

An example of the application of the model of Boddy is depicted in Figure 13.6, showing the concentrations of active drug in the response and toxicity compartments after repeated administration of an hypothetical drug-carrier conjugate. After the first dose the concentration... 

Nature of effect Route-to-route extrapolation is only applicable for the evaluation of systemic effects. For the evaluation of local effects after repeated exposure, only results from toxicity studies performed with the route under consideration can be used. 

The determination of total amounts in soil is valid for finding whether there are toxic levels of certain metals (e.g. after repeated slurry applications), and comparisons can be made with published tables of maximum recommended levels. Some typical and maximum values are shown in Table 4.5 (ADAS, 1987 DOE/NWC, 1981). Dutch values differ from those developed in the UK in that the intention is to allow the return of contaminated land to any potential use, rather than tailoring the level of remediation to the intended use of the land. The most recent values include general targets and intervention values (httpy/www.athene.freeserve.co.uk/sanaterre/guidelines/dutch.htm). 

Toxicity. The estimated minimum lethal dose is 5 g. A number of deaths have occurred after accidental ingestion and also after chronic application for the treatment of burns. Repeated exposure of neonates and infants to high concentrations of hexachlorophane has been associated with spongy lesions of the brain. Fatalities have been associated with blood concentrations greater than 2pg/ml although recovery has occurred after development of plasma concentrations up to 90 pg/ml. 

Dermal exposure to CR causes a burning sensation and erythema several minutes later. Burning pain goes away after 15 to 30 min, but the erythema lasts up to 2 h (Holland, 1974). CR does not induce inflammatory cell migration to the site of injury, bullous dermatitis, or contact sensitization (Ballantyne, 1977a). Repeated application of CR to the skin (applied 5 days/week for 12 weeks) has little effect (Marrs et al, 1982). Similar to the eye and lungs, CR does not demonstrate significant toxicity to the skin. 

Acute toxic contact dermatitis may be induced by a single application of a toxic material. One local inflammatory skin reaction is characterized by erythema and oedema. This type of reaction occurs following contact with materials such as acids, alkalis, solvents, and cleansers and is rarely associated with topical application of medicinal or cosmetic products. In contrast, irritant contact dermatitis (a superficial non-immuno-logically based reaction) may occur after repeated exposure to many substances, including topical pharmaceutical agents. The reaction is usually localized to the site of exposure and usually diminishes after the stimulus has been removed. Some materials can stimulate an immune response following an initial topical application. Any future exposure may result in an inflammatory immune reaction, an allergic contact dermatitis, or sensitization. 

Very few chronic toxicity studies have been reported. After repeated local applications in animals, sensitization dermatitis may develop. Chronic parenteral administration increases the white blood cell count by 30%. 

Chronic application of 70% DEET solution caused paranoid psychosis, pressurized speech, flight of ideas, and delusions after 2 weeks of daily application for the inappropriate treatment of a skin rash. Repeated application causes erythema. Extensive daily dermal application of 10-15% DEET for 2 days to 3 months has resulted in encephalopathy in children. Toxic encephalopathy has been associated with DEET in children. Signs of toxicity included agitation, weakness, disorientation, ataxia, seizures, coma, and, in three cases, death. As part of the Reregistration Eligibility Decision on DEET released in 1998, however, the US Environmental Protection Agency reviewed all available data on the toxicity of DEET and concluded that... 

Subchronic dermal toxicity is the study of adverse effects occurring as a result of the repeated daily dermal application of a test chemical to animals for a part (not exceeding 10%) of the life span. In the evaluation of a chemical s toxic characteristics, the determination of subchronic dermal toxicity may be performed after initial information on toxicity has been obtained by acute testing. This study provides information on health hazards likely to arise from repeated exposure via the dermal route over a limited period of time. 

Toxicity may occur after ingestion, injection, application to damaged skin (e.g., abrasion, burns, or diaper rash), lavage, or enema. Severe systemic toxicity is most likely to occur from repeated dermal application to damaged skin this has been reported mainly in the treatment of diaper rash in young children. Symptoms include nausea, vomiting, bloody diarrhea, severe colic, and abdominal pain. There may be restlessness, delirium, headache, tremors, and generalized convulsions usually followed by weakness and coma. There is fever and tachypnea followed by Cheyne-Stokes-type respirations and respiratory arrest. 

A similar application of ecotoxicological data is hazard assessment. Unlike risk assessment, hazard assessment is nonprobabilistic and relies upon indices rather than probabilities. One such index is the hazard quotient , which is the ratio of the expected environmental concentration (based upon field surveys or simulation models) divided by a benchmark concentration. The benchmark concentration is derived from some measure of toxicity such as the LC50 or no-observed-effect level. Hazard assessments are often conducted at different levels or tiers of increasing complexity and specificity if a chemical is identified as potentially hazardous by tier (the least complex and specific test), a decision is made to take action or, if more information is needed, to proceed to tier 2 tests. After tier 2 tests, a decision is made whether to take action or proceed to tier 3 tests, and so on. This process is repeated until it is decided that there is enough information to determine whether or not there is significant ecological hazard. If there is, then regulatory action is taken. 

Sulfacetamide is the IV-acetyl derivative of sulfanilamide. The sodium salt of sulfacetamide, because of its effectiveness and low toxicity, continues to be the most widely prescribed sulfonamide in the form of eye-drops and ointment for ophthalmic infections. It was introduced in Europe as "Albucid" in 1938 for various eye and other topical infections. Since its use in the treatment of corneal ulcers (1), sulfacetamide is still popular in ophthalmology. The sodium salt is highly soluble at the physiologic pH of 7.4, and is especially suited, as a 10-30% solution, for repeated topical application in the local management of ophthalmic infections (2-4). It is used mainly in the treatment of acute conjunctivitis and in the prophylaxis of ocular infections after injuries or burns (5). Several reviews on various aspects of sulfacetamide have been published (6-10). 

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