Toxicity studies

Toxicity studies (108—110) estabUshed tolerance levels and degrees of irritations, indicating that the eye is the area most sensitive to fluorine. Comprehensive animal studies (111—113) deterrnined a rat LC q value of 3500 ppm-min for a single 5-min exposure and of 5850 ppm-min for a 15-min exposure. A no-effect concentration corresponded to a concentration-time value of ca 15% of the LC q levels. 

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. 

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. 

The self-ignition temperature of PVF film is 390°C. The limiting oxygen iadex (LOI) for PVF is 22.6% (98), which can be raised to 30% ia antimony oxide-modified film (99). Hydrogen fluoride and a mixture of aromatic and aUphatic hydrocarbons (100) are generated from the thermal degradation of PVF. Toxicity studies, ie, survival and time to iacapacitation, of polymers, ceUulosics (101,102), and airplane iaterior materials (103) expose... 

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). 

Toxicological Information. The toxicity of the higher olefins is considered to be virtually the same as that of the homologous paraffin compounds. Based on this analogy, the suggested maximum allowable concentration in air is 500 ppm. Animal toxicity studies for hexene, octene, decene, and dodecene have shown Httle or no toxic effect except under severe inhalation conditions. The inhalation LD q for 1-hexene is 33,400 ppm for these olefins both LD q (oral) and LD q (dermal) are >10 g/kg. 

The three peroxodisulfates are ah. toxic and irritating to skin, eyes, and mucous membranes. Pubhshed toxicity studies are as foUow (28) ... 

P. G. Watanabe, D. G. Pegg, J. D. Burek, H. O. Yakel, and L. W. Rampy, M 90-Day Bepeated Inhalation Toxicity Study of Cumene Hydroperoxide in Bats, Toxicology Research Laboratory, EPA Document No. 868600016, Eiche No. OTS0510168, Dow Chemical USA, Midland, Mich., 1979. 

Sediment Toxicity. Because of their low solubiUty ia water and lipophilic nature, phthalates tend to be found ia sediments. Unfortunately httle work has previously been carried out on the toxicity of phthalates to sediment dwelling organisms. Eor this reason ECPI has commissioned some sediment toxicity studies designed to measure the effect of DEHP and DIDP ia a natural river sediment on the emergence of the larvae of the midge, Chironomus riparius. 

The compound is an intermediate in several synthetic reactions and recently has found extensive use in experimental toxicity studies in animals. It has been shown to cause methemoglobinemia its metaboHsm in humans has been discussed (189,190). 

Health and Safety Factors. Results of acute oral toxicity studies of 2-pyrrohdinone on white rats and guinea pigs show the LD q to be 6.5 ml,/kg. Skin patch tests on 200 human subjects indicate that 2-pyrrohdinone is a skin kritant, but there is no indication of sensitising action. It is a mild eye irritant (79). 

In 1969, a chronic toxicity study on a cyclamate saccharin (10 1) blend indicated bladder cancer problems in rats. Cyclamate was soon banned by the FDA, but saccharin remained an approved sweetener. In 1977, the FDA proposed a ban on saccharin because of the discovery of bladder tumors in some male rats fed with high doses of saccharin. Because no other nonnutritive sweetener was available at that time, the proposed ban faced strong opposition. 

Acute Toxicity. ThioglycoHc acid, its esters and 3-mercaptopropionic acid are considered moderately toxic on the basis of acute toxicity studies. These are presented in Table 4. 

Considerable caution is necessary in making quantitative comparisons between different materials, even when considering the same toxic end point. This can be conveniendy illustrated using, as an example, death in response to a single exposure, ie, acute lethal toxicity. Studies to determine acute lethal toxicity by a particular route are usually conducted as described below. 

Acute Toxicity Studies. These studies should provide the following information the nature of any local or systemic adverse effects occurring as a consequence of a single exposure to the test material an indication of the exposure conditions producing the adverse effects, in particular, information on dose—response relationships, including minimum and no-effects exposure levels and data of use in the design of short-term repeated exposure studies. 

Acute toxicity studies are often dominated by consideration of lethaUty, including calculation of the median lethal dose. By routes other than inhalation, this is expressed as the LD q with 95% confidence limits. For inhalation experiments, it is convenient to calculate the atmospheric concentration of test material producing a 50% mortaUty over a specified period of time, usually 4 h ie, the 4-h LC q. It is desirable to know the nature, time to onset, dose—related severity, and reversibiUty of sublethal toxic effects. 

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. 

M One-Year Inhalation Toxicity Study ofMntimonj Trioxide in the Rat (with a One-year Recovery Period), Bio /dynamics Incorporated, East Millstone, N.J. submitted to Antimony Oxide Industry Association (AOIA), Feb. 9, 1990. 

A further complication of these reactions is that many nonhemoglobin proteins contain reactive groups and may also be modified to produce new, potentially toxic, contaminants. It has been difficult to produce a pure modified hemoglobin for toxicity studies because most processes start with relatively cmde stroma-free hemoglobin. 

Polymers. Studies to determine possible exposure of workers to residual epichl orohydrin and ethylene oxide monomers in the polymers have been done. Tests of warehouse air where Hydrin H and Hydrin C are stored showed epichl orohydrin levels below 0.5 ppm. Air samples taken above laboratory mixing equipment (Banbury mixer and 6" x 12" mill) when compounds of Hydrin H or C were mixed gave epichl orohydrin levels below detectable limits, and ethylene oxide levels less than 0.2 ppm, well below permissible exposure limits (46). A subacute vapor inhalation toxicity study in which animals were exposed to emission products from compounded Parel 58 suggests that no significant health effects would be expected in workers periodically exposed to these vapors (47). 

Two-generation mammalian reproductive toxicity study or a less comprehensive test. 

Hazard identification, step one, means identification of new chemicals or other factors that may cause harmful health effects. Previously, novel hazards were usually observed in case studies or after accidents or other excessive exposures, usually in occupational environments. Today, thorough toxicity studies are required on all pesticides, food additives, and drugs. New chemicals also have to be studied for their potential toxic effects. Thus, earlier hazards were in most cases identified after they had caused harmful effects in humans. Today, most chemical products have been evaluated for their toxicity with experimental animals. Therefore, hazard identification has become a preventive procedure based on safety studies conducted before a chemical compound or product reaches the market, and before individuals are exposed to it. ... 

TABLE 5.24 Toxicity Studies for Safety Evaluation of Drugs, Pesticides, Food Additives, and Other Chemicais Utilizing Experimental Animals and Other Systems Required by Health Authorities... 

It is essential to determine the concentration of each isomer and define limits for all isomeric components, impurities, and contaminants of the compound tested preclin-ically that is intended for use in clinical trials. The maximum level of impurities in a stereoisomeric product used in clinical studies should not exceed that in the material evaluated in nonclinical toxicity studies. This point is expanded in the ICH impurities guideline (Section 13.5.3). 

A one-year toxicity study on rats (oral) did show a somewhat lowered weight increase combined with a reduced food consumption, but only for the... 

A chronic toxicity study for DOSS was performed using beagle dogs [72]. The dogs showed no toxic effects over a one-year period. Not even an effect on gastric mucosa was found (in contradiction to an earlier study [101] see also [102]). 

S3A Note for Guidance on Toxicokinetics The Assessment of Systemic Exposure in Toxicity Studies... 

Safety pharmacology studies may also be conducted in conjunction with the toxicity studies. These focus on identifying secondary pharmaceutical side effects that may occur, when the drug is administered in the therapeutic range. Emphasis is placed on identifying effects on vital systems, particularly the central nervous, cardiovascular and respiratory systems. 

GL37 Safety repeat dose chronic toxicity Studies to evaluate the safety of residues of veterinary drugs in human food Repeat-dose Chronic Toxicity Testing... 

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