Subchronic

Toxicity studies on trifluoroethanol show acute oral LD q, 240 mg/kg acute dermal LD q, 1680 mg/kg and acute inhalation L(ct) Q, 4600 ppmh. Long-term subchronic inhalation exposure to 50—150 ppm of the alcohol has caused testicular depression in male rats, but no effects were noted at the 10 ppm level (32). Although the significance of the latter observations for human safety is unknown, it is recommended that continuous exposure to greater than 5 ppm or skin contact with it be avoided. 

PVDE is a nontoxic resin and may be safely used in articles intended for repeated contact with food (190). Based on studies under controked conditions, including acute oral, systemic, subchronic, and subacute contact implantation and tissue culture tests, no adverse toxicological or biological response has been found in test animals (191,192). PVDE is acceptable for use in processing and storage areas in contact with meat or poultry products prepared under federal inspection and it complies with the 3-A sanitary standards for dairy equipment. 

J. M. Smith and co-workers, "Methyl Methacrylate Subchronic, Chronic and Oncogenic Inhalation Safety Evaluation Studies," Mbstracts of the Eighteenth Mnnual Meeting of the Society of Toxicology, New Orleans, La., 1979. 

In additional EPA studies, subchronic inhalation was evaluated ia the rat for 4 and 13 weeks, respectively, and no adverse effects other than nasal irritation were noted. In the above-mentioned NTP chronic toxicity study ia mice, no chronic toxic effects other than those resulting from bronchial irritation were noted. There was no treatment-related increase ia tumors ia male mice, but female mice had a slight increase in bronchial tumors. Neither species had an increase in cancer. Naphthalene showed no biological activity in other chemical carcinogen tests, indicating Htde cancer risk (44). No incidents of chronic effects have been reported as a result of industrial exposure to naphthalene (28,41). 

Some nonmalignant respiratory effects have been observed in experimental animals during acute or subchronic exposures. Soluble and moderately soluble compounds were more toxic than were insoluble compounds and produced different effects. Sulfate and subsulftde produced fibrosis whereas nickel oxide did not. 

Inhalation is the chief route of worker exposure. Comparative data from acute or subchronic inhalation exposures with rats (98) indicate that nitromethane and nitroethane are the least toxic of the nitroparaffins by this route and do not induce methemoglobin formation. The nitropropanes are less well tolerated 2-nitropropane is more toxic than 1-nitropropane and is more likely to cause methemoglobinemia. 

Subchronic effects of overexposure have been studied in feeding tests of PPS powder at dietary levels of up to 5%. No detrimental effects in laboratory animals were observed (157). 

Undiluted DMAMP, AMP-95, and AB cause eye bums and permanent damage, if not washed out immediately. They are also severely irritating to the skin, causing bums by prolonged or repeated contact. Of these three aLkanolarnines, only AMP has been studied in subchronic and chronic oral studies. The principal effect noted was the action of AMP on the stomach as a result of its alkalinity. The no-observed-effect level (NOEL) in a one-year feeding study in dogs was 110 ppm in the diet. In general, the low volatility and appHcations for which these products are used preclude the likelihood of exposure by inhalation. 

A commercially interesting low calorie fat has been produced from sucrose. Proctor Gamble has patented a mixture of penta- to octafatty acid ester derivatives of sucrose under the brand name Olestra. It was approved by the FDA in January 1996 for use as up to 100% replacement for the oil used in preparing savory snacks and biscuits. Olestra, a viscous, bland-tasting Hquid insoluble in water, has an appearance and color similar to refined edible vegetable oils. It is basically inert from a toxicity point of view as it is not metabolized or absorbed. It absorbs cholesterol (low density Hpoprotein) and removes certain fat-soluble vitamins (A, D, E, and K). Hence, Olestra has to be supplemented with these vitamins. No standard LD q tests have been performed on Olestra however, several chronic and subchronic studies were performed at levels of 15% in the diet, and no evidence of toxicity was found. No threshold limit value (TLV), expressed as a maximum exposure per m of air, has been estabhshed, but it is estimated to be similar to that of an inert hpid material at 5 mg/m. ... 

Subchronic exposures involve consecutive daily exposures to the test material for a period amounting to usually no more than 10—15% of the lifespan of the test species. 

Subchronic Studies. Although short-term repeated exposure studies provide valuable information about toxicity over this time span, they may not be relevant for assessment of ha2ard over a longer time period. For example, the minimum and no-effects levels determined by short-term exposure may be significantly lower if exposure to the test material is extended over several months. Also, certain toxic effects may have a latency which does not allow their expression or detection over a short-term repeated-exposure period for example, kidney dysfunction or disturbances of the blood-forming tissues may not become apparent until subchronic exposure studies are undertaken. 

Chronic Toxicity Studies. With the exception of tumorigenesis, most types of repeated exposure toxicity are detected by subchronic exposure conditions. Therefore, chronic exposure conditions are usually conducted for the following reasons if there is a need to investigate the tumorigenic potential of a material if it is necessary to determine a no-effects or threshold level of toxicity for lifetime exposure to a material and if there is reason to suspect that particular forms of toxicity are exhibited only under chronic exposure conditions. 

A number of antioxidants have been accepted by the FDA as indirect additives for polymers used in food appHcations. Acceptance is deterrnined by subchronic or chronic toxicity in more than one animal species and by the concentration expected in the diet, based on the amount of the additive extracted from the polymer by typical foods or solvents that simulate food in their extractive effects. Only materials of insignificant risk to the consumer are regulated by the FDA for use in plastics contacted by food stuffs. 

Subchronic OralToxicity Test with Coumarin in Rat, National Toxicology Program, Washington, D.C., 1981. 

Testing to identify hazards should be tiered, starting with short-term screening, followed by subchronic and chronic tests. 

Subchronic study Rats/mice/dogs/rabbits 6 months Target organs, delayed effects... 

Acceptable Intake for Subchronic Exposure (AIS) An estimate similar in concept to the subchronic RfD. but derived using a less strictly defined methodology. Subchronic RfDs have replaced AISs as the Agency s preferred alues for use in e ahiating potential noncarcinogenic health effects resulting from subchronic exposure to a chemical. 

A UF of 10 is used when a NOAEL derived from a subchronic instead of a chronic study is used as the basis for a chronic RfD. 

Development of subchronic RfDs parallels the development of chronic reference doses in concept the distinction is one of e.xposurc duration. Appropriate studies are evaluated and a subchronic NOAEL is identified. The RfD is derived from the NOAEL by the application of the UFs and MF, as outlined above. When experimental data arc available only for shorter e.xposurc durations than desired, an additional uncertainly factor is applied. This is similar to the application of the uncertainly factor for duration differences when a chronic RfD is estimated from subchronic animal data. On the other hand, if subchronic data are missing and a chronic oral RfD derived from chronic data exists, the chronic oral RfD is adopted as the subchronic oral RfD. Ill this instance, there is no application of an uncertainly factor to account for differences in exposure duration. 

To assess die overall potential for non carcinogenic effects posed by several exposure pathways, the total haziird index for each exposure duration (i.e., chronic, subchronic, and shorter-term) should be calculated separately. This equation is described below ... 

Note that die total exposure hazard index is calculated separately for clironic, subchronic, and shorter-term exposure periods. 

---