Acute Toxicity in Rodents

Evaluate single-dose or dose-escalation acute toxicity in rodent species. 

Regarding to the acute toxicity, MC-LR is highly toxic (LDjq 25-50 pg kg by i.p. route) the oral LDjq is 5000 pg Kg in mice. Yoshida (1997) has indicated that even by the oral route, micro-cystin-LR displays acute toxicity in rodents. There is no evidence of lydrolysis of microcystins by peptidases in the stomach, and it is apparent that a sigiuficant amount of microcystin-LR passes the intestinal barrier and is absorbed. The i.p. LD q of several of the conunon occurring microcystins (MC-LA,-YR,-YM) are similar to that of MC-LR but for MC-RR is tenfold higher however, because of differences in lipophilicity and polarity between the different microcystins, it cannot be presumed that the i.p LD q will predict toxicity after oral administration. 

In humans, 4-chloro-ort/2o-toluidine induces acute toxicity in the urinary bladder and causes methaemoglobinaemia. In rodents, 4-chloro-ort/zo-toluidine and/or its metabolites bind to macromolecules in liver cells. 

The conduct of animal toxicity studies proceeds concurrently with and in advance of clinical studies. A certain amount of animal toxicity data is required for the IND. This often includes acute toxicity in two rodent species, mutagenicity screening studies, and one-month toxicity studies in a rodent and non-rodent species. After the clinical studies have begun, further animal studies are conducted, usually until the time for the NDA. These would include further mutagenicity studies, reproductive toxicity studies, and long-term toxicity studies, possibly including carcinogenicity studies. 

Acute oral toxicity in rodents exposed to zinc is low, with LD50 values in the range 30-600 mg kg body weight, depending on the zinc salt administered. Acute effects in rodents following inhalation or intratracheal instillation of zinc compounds include respiratory distress, pulmonary edema, and infiltration of the lung by leukocytes. 

V. Because pharmaceuticals are normally tested for toxicity in rodent repeated dose toxicity tests and because there is no longer a requirement for an acute high dose rodent toxicity test, the assessment of genotoxicity (e.g., bone marrow micronucleus test or other tissue/endpoint) should be integrated, if feasible, into the rodent repeated dose toxicity study to optimize animal usage. 

Repeated dose 28-day oral toxicity in rodents (OPPTS 870.3050 or OECD 407) Acute oral toxicity (OPPTS 870.1100/OECD 401, or OECD 425 ["Acute Oral Toxicity Up-and-Down Procedure"])... 

Alkan olamines are only slightly toxic by ingestion (acute oral LD q in rodents = 1.0 5.5 g/kg). 

The LC50 values of methyl parathion have been established in rats. A 1-hour LC50 of 200 mg/m and a 4-hour LC50 of 120 mg/m for males were determined by Kimmerle and Lorke (1968). One-hour LC50 values of 257 mg/m for male rats and 287 mg/m for female rats were determined for 70-80% pure methyl parathion by EPA (1978e) the rats were exposed to aerosols of respirable size. Survivors of toxic doses recovered clinically by 10-14 days postexposure. Sex-related differences in acute mortality of rodents have also been observed after exposure to methyl parathion by other routes (Murphy and Dubois 1958). 

Toxicological Chronic toxicity Carcinogenicity Fertility study (multi-generation) Embryotoxicity (non-rodent) Acute/subacute toxicity in 2nd species Toxicokinetics... 

No studies addressing developmental or reproductive effects following acute inhalation exposure to aniline were located. However, because effects on development and reproduction arise after systemic uptake, oral administration of aniline can be considered for evaluating potential developmental and reproductive toxicity. Aniline (administered as aniline hydrochloride) readily crosses the placental barrier in rodents (Price et al. 1985). 

Toxicokinetics of PCBs in rodents were altered when administered in mixtures (de Jongh et al. 1992). PCBs 153, 156, and 169 produced biphasic elimination patterns in mice when administered in combinations, but single-phase elimination when administered alone. Elimination of all PCBs was more rapid after coadministration. Mixtures of PCBs 153 and 156 raised EROD activity and lengthened retention of each congener in liver however, a mixture of PCB 153 and 169 lowered EROD activity (de Jongh et al. 1992). Selected PCBs of low acute toxicity may increase the toxicity of compounds such as 2,3,7,8-TCDD (Bimbaum et al. 1985). Thus, PCB 153 or 157 at sublethal dosages (20 to 80 mg/kg BW) did not produce cleft palate deformities in mouse embryos. But a mixture of PCB 157 and 2,3,7,8-TCDD produced a tenfold increase in the incidence of palate deformities that were expected of 2,3,7,8-TCDD alone palate deformities did not increase with a mixture of PCB 153 and 2,3,7,8-TCDD. The widespread environmental occurrence of PCB-PCDD and PCB-PCDF combinations suggests a need for further evaluation of the mechanism of this interaction (Bimbaum et al. 1985). 

The traditional acute, subchronic, and chronic toxicity studies performed in rodents and other species also can be considered to constitute multiple endpoint screens. Although the numerically measured continuous variables (body weight, food consumption, hematology values) generally can be statistically evaluated individually by traditional means, the same concerns of loss of information present in the interrelationship of such variables apply. Generally, traditional multivariate methods are not available, efficient, sensitive, or practical (Young, 1985). 

While rDNA techniques offer exciting possibilities, there are many unanswered questions about the potential toxicity that each new product represents. For example, acute clinical toxicities of interferons (IFNs) include flu-like syndrome, fever, chills, malaise, anorexia, fatigue, and headache. Chronic dose-limiting toxicities include neutropenia, thrombocytopenia, impairment of myeloid maturation, reversible dose-related hepatotoxicity, some neurological toxicity (stupor, psychosis, peripheral neuropathy) and gastrointestinal toxicity. Some of these toxicities would be difficult to ascertain in rodents, and, in fact, may be species-specific. 

This approach appears somewhat irrational and without much scientific merit, since many of these new molecules are minimally toxic or nontoxic by this sort of acute evaluation. As in the case of interferons or monoclonal antibodies, the toxic effects observed in humans might not be predicted from safety assessments in rodents. An appropriate test species should be selected. Is the rat or mouse the appropriate species to evaluate a species-specific rDNA protein such as human growth hormone or interferons, or would nonhuman primates be more suitable Does the nonhuman primate really offer any advantages There is some consensus that the nonhuman primate may be a more appropriate species for testing some rDNA human proteins. 

Reproductive Toxicity. No studies were located regarding reproductive effects in humans or animals following inhalation or dermal exposure to di-ft-octylphthalate. No studies were located in humans following oral exposure to this compound. Di-u-octylphthalate caused significant decreases in human sperm motility in vitro (Fredricsson et al. 1993). The results of several acute- and intermediate-duration oral studies in rodents indicate that the potential of di-w-octylphthalate to cause adverse reproductive effects is low. Unlike other phthalate esters such as di(2-ethylhexyl)phthalate, di-w-octylphthalate does not appear to adversely affect testicular function or morphology (Foster et al. 1980 Gray and Butterworth 1980 Heindel et al. 

Guzman, A., Garcia, C., and Demestre, I. Acute and subchronic toxicity studies of the new quinoline antibacterial agent irloxacin in rodents, Arzneim. Forsch., 49(5) 448-456, 1999. 

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