Irritation tests in animals

Atkinson KA, Fentem JH, Clothier RH, and Balls M (1992) Alternatives to ocular irritation testing in animals. Lens and Eye Toxicity Research 9(3—4) 247-258. 

Irritation Tests in Animals Draize-Type Tests... 

Enslein, K. An overview of structure-activity relationships as an alternative to testing in animals for carcinogenicity, mutagenicity, dermal and eye irritation, and acute oral toxicity. Toxicol Industrial Health 1988 4 479-98. 

Objective irritation is defined as nonimmunologically mediated, localized inflammation of the skin, usually resulting from contact with a substance that chemically damages the skin.2,9 The exact mechanism is unknown, and it is likely that both endogenous and exogenous factors are involved. In vivo predictive testing in animals (e.g., modified Draize test, repeated application patch tests,... 

In vivo skin irritation test (3 animals total)... 

The basic ocular irritation test in the rabbit will be described in detail in another section, but it is important to point out that the number of test animals can be reduced from the usual six at each exposure level to two or, at most, three animals per dose without sacrificing much accuracy. Many test series have shown 88-91% accuracy with two animals per treatment group. The agent, instilled in the pouch formed by the lower eyelid, is held in place for 1 s and then released. The treated eye is not washed, allowing the animal s own tear secretions to flush out the material. The untreated eye serves as a control. Both eyes are examined at 1, 24, 48, and 72 h after treatment, the irritation (or damage) to the cornea, the conjunctiva, and the iris being scored numerically in a subjective manner. The test is open in that the experiment can be terminated at 72 h if there is no evidence of irritation, but observed effects can be assessed for a longer time period. 

Ocular Effects. Exposure to high levels of 1,1,1-trichloroethane vapor is associated with mild eye irritation in humans (Stewart et al. 1961) and mice (Evans and Balster 1993). Tests in animals suggest that 1,1,1-trichloroethane applied directly to the eye is likely to cause only mild eye irritation in humans (Duprat et al. 1976 Krantz et al. 1959 Marzulli and Ruggles 1973 Torkelson et al. 

ACUTE HEALTH RISKS based on testing in animals, may cause irritation of skin, respiratory distress, diarrhea, kidney impairment, muscle tremor, seizure, and possible effects on the gastrointestinal tract. 

ACUTE HEALTH RISKS irritation to mucous membranes can cause skin irritation can cause allergic skin reaction can cause allergic respiratory reaction lachrymator - causes severe eye irritation can cause pulmonary edema, based on testing in animals may be fatal if ingested. 

ACUTE HEALTH RISKS irritation of eyes, skin, and respiratory tract cough headache abdominal pains sore throat lowering of consciousness based on testing in animals, may cause lacrimation, dyspnea, pulmonary edema, narcosis, and injury to liver and kidneys. 

Nitrobenzene (CAS 98-95-3) Irritating upon direct contact sensitization dermatitis may occur. Well absorbed by all routes. Causes methemoglobinemia (see p 251), Symptoms include headache, cyanosis, weakness, and gastrointestinal upset. May injure liver. Injures testes in animals. Limited evidence for adverse effects on fetal development in animals. 1 ppm, S,A3 200 ppm 3 2 1 Pale yellow to dark brown viscous liquid. Shoe pollsh-llke odor Is a good warning property. Vapor pressure Is much less than 1 mm Hg at 20 C (58°F). Combustible. Thermal-breakdown products Include oxides of nitrogen. 

K. Enslein, Toxicol. Industr. Health, in press. An Overview of Structure-Activity Relationships as an Alternative to Testing in Animals for Carcinogenicity, Mutagenicity, Dermal and Eye Irritation, and Acute Oral Toxicity. 

Diesel exhaust is a mixture of gases and particulates produced during the combustion of diesel fuel. The very small particles are known as diesel particulate matter (DPM), which consists primarily of solid elemental carbon (EC) cores with organic carbon (OC) compounds adhered to the surfaces. The organic carbon includes polyaromatic hydrocarbons (PAH), some of which cause cancer when tested in animals. Workers exposed to diesel exhaust face the risk of health effects ranging from irritation of the eyes and nose, headaches and nausea, to respiratory disease and lung cancer. 

Obviously, in the past, the difficulty has been that the tannins studied have been difficult to purify and to characterize chemically. This was not the case with the most recent work (59), and precise characterization of structure will be possible in the future. In addition, these studies must include tests in animal models that are recognized as being useful models in place of humans. The differention of a true toxic effect from an irritant one will not be easy. Also, the tumors produced must be examined by an expert pathologist to prove carcinogenicity. 

Open application tests are normally used to study new chemicals when their irritation potential in man has never been tested. For such unknown compounds, open applications follow in vitro tests and tests in animals. The characteristic of open application tests is that products are applied on skin and not covered. Any adverse reaction occurring on the skin is seen immediately, and the test products are removed and rinsed off before excessive skin damage appears. This type of application is usually used for a safety evaluation in order to determine if a neat product/material is likely to cause serious skin irritation in the case of undesired, accidental contact. 

SM is widely known for its vesicating properties. There are no documented studies that conform to any standard regulatory test method for dermal irritation/corrosivity. However, there is sufficient information from observations and tests in humans to establish SM as a primary irritant, and further tests in animals are not required. 

This section includes some of the most promising methods that may replace animals in the eye irritation test in the future (Table 9.1.5). 

Health and Safety Factors. Boron trifluoride is primarily a pulmonary irritant. The toxicity of the gas to humans has not been reported (58), but laboratory tests on animals gave results ranging from an increased pneumonitis to death. The TLV is 1 ppm (59,60). Inhalation toxicity studies in rats have shown that exposure to BF at 17 mg/m resulted in renal toxicity, whereas exposure at 6 mg/m did not result in a toxic response (61). Prolonged inhalation produced dental fluorosis (62). High concentrations bum the skin similarly to acids such as HBF and, if the skin is subject to prolonged exposure, the treatment should be the same as for fluoride exposure and hypocalcemia. No chronic effects have been observed in workers exposed to small quantities of the gas at frequent intervals over a period of years. 

Poly(tetramethylene ether) glycols were found to have low oral toxicity in animal tests. The approximate lethal oral dose, LD q, for Terathane 1000 has been found to be greater than 11,000 mg/kg (272). No adverse effects on inhalation have been observed. The polymer glycols are mild skin and eye irritants, and contact with skin, eyes, and clothing should be avoided. Goggles and gloves are recommended. In case of contact with the skin, wash thoroughly with water and soap. If swallowed, no specific intervention is indicated, because the compounds are not hazardous. However, a physician should be consulted (260). 

---