Lethality data

One group of investigators reported that the dermal LDjg for trichloroethylene in rabbits is more than 29 g/kg but did not report any other details (Smyth et al. 1969). No other dermal lethality data were available. 

A comparison of RD, (respiratory depression) and LC, values of HC1 demonstrates that the mouse is also more sensitive than the rat to both the sensory irritant and also to the lethal effects of HC1. However, it has been claimed that the mouse may still be 7 to 10 times less sensitive than man and that a correction factor is required to extrapolate mice lethality data to man (4). The correction factor is based on the observation that HC1 (or smoke from PVC) is about 7 to 10 times more... 

Considerable controversy continues to exist as to what concentration of HC1 is hazardous to man. Although numerous studies of the acute effects of HQ have been conducted with rodents, it is questionable whether lethality data from rodents can be directly extrapolated to man because of anatomical differences in the respiratory tract... 

Acute lethality data are summarized in Table 1 1 and discussed below. 

Acute lethality data for several laboratory species are summarized in the following sections. Lethal concentrations for various species are shown in Table 2 4. Cumulative exposures (C t) exhibit notable variability even within species. 

Lethality data are available for several animal species including rats, mice, monkeys, dogs, and cats. Cumulative exposures producing lethality range from 525 to 11,520 ppm-min, with the highest value representing a 24-h exposure to only 8 ppm. 

For AEGL-3, the 1-h LC50 of 82 ppm for squirrel monkeys (Haun et al. 1970) was reduced by a factor of 3 to estimate a lethality threshold (27.3 ppm). Temporal scaling to obtain time-specific AEGL values was described by C% t=k (where C=exposure concentration, t=exposure duration, and k=a constant). The lethality data for the species tested indicated a near linear relationship between concentration and exposure duration (n=0.97 and 0.99 for monkeys and dogs, respectively). The derived exposure value was adjusted by a total uncertainty factor of 10.2 An uncertainty factor of 3 was applied for... 

Acute lethality data for inhalation exposure to monomethylhydrazine are available for monkey, dog, rat, mouse, and hamster. Based upon the available data, hamsters appear to be the most resistant species, and the squirrel monkey and beagle dog are the most sensitive. The lethality of monomethylhydrazine appeared to follow a linear relationship for exposures up to 1 h. Most animal data focus on lethality as the toxicity endpoint with very limited exposure-response information available regarding nonlethal effects. The most significant effect reported in the acute exposure studies was the notable hemolytic response that was reversible upon cessation of exposure. However, the preponderance of the data suggest that there is little margin between exposures associated with nonlethal, reversible effects and those that result in death. 

Because a regression analysis of lethality data for squirrel monkeys and dogs showed an approximately linear response (n = 0.97 and 0.99, respectively, see Appendix B), the lethality threshold estimate (27.3 ppm) was linearly scaled (C1 xt=k) t° the AEGL time periods using the methods often Berge et al. (1986) (Appendix A). 

Time scaling 2.73 ppmx60 min=163.8 ppm-min C1xt=k (ten Berge et al. 1986) (27.3 ppm)1 60 min=163.8 ppm-min regression analysis of the squirrel monkey lethality data suggested a near linear... 

Test Species/Strain/Sex/Number Squirrel monkeys, 2-4 males/group Exposure Route/Concentrations/Durations Inhalation exposure at 300,340, or 376 ppm for 15 min 130, 150, or 170 ppm for 30 min 75, 85, or 90 ppm for 60 min Effects Data specifically identifying serious, irreversible effects consistent with the AEGL-2 definition were not available. The lethality data are shown in the summary table for AEGL-3. 

Data Adequacy Adequate lethality data were available for several species including nonhuman primates. Although the variability in response to the lethal effects of monomethylhydrazine among all species tested appeared to be relatively small (2- to 3-fold difference), the squirrel monkey appeared to be somewhat more sensitive. The AEGL values for monomethylhydrazine reflect the steep exposure-response relationship suggested by available data. ... 

TABLE 4-3 Summary of Lethality Data for Dimethylhydrazine in Laboratory Species... 

Inhalation lethality data are available for several laboratory species, including dogs, rats, mice, and hamsters. Most of the available data, however, were collected using 1,1-dimethylhydrazine as the test material. Independent studies and reports confirm a steep exposure-response relationship for the dimethyl... 

Fowles, J.R., G.V.Alexeeff, and D.Dodge. 1999. The use of benchmark dose methodology with acute inhalation lethality data. Regul. Toxicol. Pharmacol. 29 262-278. 

Rat and mouse lethality data from the well-conducted study of Zwart et al. (1990) also suggest that Haber s law is valid for phosgene. The study by ten Berge et al. (1986) has shown that the concentration-exposure-time relationship for many irritant and systemically acting vapors and gasses can be described by the relationship Cnxt=k. When the 10- to 60-min rat LC50 data are utilized in a linear regression analysis a value of the exponent, n, of 0.93 is obtained. The mouse 10- to 60-min lethality data yield a value of 1.3 for n. 

Many lethality data exist for a variety of species (mouse, rat, guinea pig, rabbit, cat, dog, goat, sheep, and monkeys). However, in most cases, experimental parameters are poorly described, and the quality of the data is questionable for AEGL derivation. The mouse and rat LC50 studies of Zwart et al. (1990) are the exception and are appropriate for AEGL-3 derivation. 

Few data were located. Lethality data were available for only one species, the rat. In studies that addressed sublethal effects, narcosis was induced at approximately the same concentration in the monkey, dog, rat, and mouse. 

Acute inhalation lethality data for the rat, mouse, and rabbit for exposure times of 10 s to 12 h were located. A single inhalation study with the dog did not give an exposure duration. The data are summarized in Table 5-4. Data from studies with nonlethal concentrations are summarized in Table 5-5. Barcroft (1931) reported LC50 values and times to death for eight species of animals, the times to death at a constant concentration. Due to experimental design constraints, the LC50 values are not reported here, but relevant data are discussed in the section on relative species sensitivity (Section 4.4.1). 

Scaling C2xt=k (this document based on regression analysis of incapacitation and lethality data for the monkey)... 

Using Range-Finding Lethality Data in Drug Development ... 

Death. Occupational mortality studies of pesticide workers exposed to heptachlor have not revealed an excess number of deaths in these cohorts compared to the general U.S. population. This may possibly be explained as a healthy worker effect. The ERA has described human case reports in which convulsions and death were reported following suicidal ingestion of technical-grade chlordane, which typically contains 6-30% heptachlor, but these effects cannot be attributed to heptachlor or heptachlor epoxide. There are no controlled, quantitative human data for any route of exposure. Acute lethality data were located for animals exposed via the oral and dermal routes. Both heptachlor and heptachlor epoxide may be considered very toxic via the oral route on the basis of acute animal data in rats and mice. Intermediate oral exposure to these compounds also caused up to 40% and 100% mortality in rats and mice, respectively. There appear to be differences in sensitivity in males and females in some species with the males being most sensitive. Heptachlor epoxide is more toxic than heptachlor. Heptachlor may be considered very toxic to extremely toxic via the dermal route on the basis of acute lethality data in rats and mice. The severity of acute effects may possibly depend upon the extent of formation of heptachlor epoxide and the species tested. 

Schafer and Bowles 1985), lethal doses for intermediate duration exposure (4 weeks) of 54 mg/kg/day in rats and 390 mg/kg/day in mice (NTP 1983), and nonlethal and lethal doses for chronic exposure in rats (2 and 5 mg/kg/day, respectively) and mice (10 and 52 mg/kg/day, respectively) (NTP 1983). The animal lethality data are discussed below and summarized in Table 2-1. 

In one series of studies (NTP 1987), the lethality data for 1,4-dichlorobenzene, when administered for 14 days by gavage in com oil to Fischer 344 rats and B6C3Fi mice, were rather inconsistent. In one of these studies, no 1,4-dichlorobenzene-related deaths occurred in rats of either sex that received doses up to 1,000 mg/kg/day however, in the second rat study, 4 of 5 females (80%) at 1,000 mg/kg/day died, and all rats dosed at >2,000 mg/kg/day died. In one 14-day study in mice, no 1,4-dichlorobenzene-related deaths occurred in either sex at levels up to 1,000 mg/kg/day however, in a second 14-day mouse study, 70% of mice at 1,000 mg/kg/day died, and all mice that received 4,000 mg/kg/day died within 4 days. At... 

Acute lethality data indicate that DMEP exhibits slight to moderate toxicity. The oral LDso in rats ranged from 3.2 to 6.4g/kg. Exposure of rats to 1595 ppm for 6 hours caused deaths of all animals, whereas 770 ppm for 6 hours was not lethal. The dermal LDso in guinea pigs was greater than lOml/kg, suggesting very little absorption. 

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