Developmental toxicity study

No acute oral MRL was derived for methyl parathion because data regarding the most sensitive effect that was observed after acute oral exposure are conflicting. Increased pup mortality and altered behavior occurred in offspring of rats exposed to 1 mg/kg/day methyl parathion during, but no effects on pup survival or on sensitive electrophysiological indices of neurotoxicity were seen at virtually the same dose, 0.88 mg/kg/day, in a similar developmental toxicity study. 

Developmental Effects. Evidence from human studies on congenital anomalies as an end point (Emhart et al. 1985, 1986 McMichael et al. 1986 Needleman et al. 1984) indicate no association between prenatal exposure to low levels of lead and the occurrence of major congenital anomalies. This conclusion is further supported by developmental toxicity studies conducted in rats and mice these studies provide no evidence that lead compounds (acetate or nitrate) are teratogenic when exposure is by natural routes (i.e., inhalation, oral, dermal). Intravenous or intraperitoneal injection of lead compounds (acetate, chloride, or nitrate) into pregnant rats, mice, or hamsters, however, has produced malformations in several studies reviewed by EPA (1986a). 

Developmental toxicity of dimethylhydrazines has been demonstrated in rats following parenteral administration of maternally toxic doses during gestation. No developmental toxicity studies were available that employed inhalation. 

Guidance for Industry Considerations for Developmental Toxicity Studies for Preventive and Therapeutic Vaccines for Infectious Disease Indications. U.S. Department of Health and Human Services, Food and Drug Administration Center for Biologies Evaluation and... 

EPA, U.S. Environmental Protection Agency, Prenatal Developmental Toxicity Study, Health Effects Test Guidelines, OPPTS 870.3700, EPA 712-C-98-207,1998a. http //www. epa.gov/opptsfrs/OPPTS Harmonized/870 Health Effects Test Guidelines/Series/870-6300.pdf... 

OECD, Organization for Economic Cooperation and Development, Guideline 414, Prenatal Developmental Toxicity Study, 2001a. 

McCarty JD, Freeman C, Watt BA (2002) Comparison of dietary and oral gavage administration of bifenthrin in developmental toxicity studies in Sprague-Dawley rats. Toxicologist 66(1-S) 320... 

Results from developmental toxicity studies indicate that HFC-134a does not cause terata in rats or rabbits (Collins et al. 1995 Alexander et al. 1996). 

The AEGL-3 value is supported by additional animal data, which result in a higher value. The highest nonlethal concentration for the rat was a 4-h exposure at 359,300 ppm (Silber and Kennedy 1979a). Adjustment by interspecies and intraspecies UFs of 3 each (for a total of 10) results in an AEGL-3 value of approximately 36,000 ppm. Developmental toxicity studies in which exposures were repeated for 9-13 d (Hodge et al. 1979 Lu and Staples 1981 Collins et al. 1995) also support this value (i.e., no effects following daily exposures to concentrations <30,000 ppm). 

Neeper-Bradley TL. 1989a. Developmental toxicity study of commercial hexane vapor in CD(Sprague-Dawley) rats. Prepared by Bushy Run Research Center (Export, PA) for the American Petroleum Institute (API), Project Report 52-605, October 27, 1989. 

Developmental toxicity screening study (OECD 421) Developmental toxicity study (OECD 414)... 

In vivo mutagenicity studies Further repeat-dose study in the rat Second developmental toxicity study Two-generation fertility study in the rat Chronic fish toxicity study Biodegradation simulation studies... 

Developmental toxicity studies in two species (if not part of the Annex VI data)... 

By the time Phase III testing is completed, some additional preclinical safety tests must also generally be in hand. These include the three separate reproductive and developmental toxicity studies (Segments I and III in the rat, and Segment II in the rat and rabbit) and carcinogenicity studies in both rats and mice (unless the period of therapeutic usage is intended to be very short). Some assessment of genetic toxicity will also be expected. 

Reproductive Performance and Developmental Toxicity Studies. These will be dictated by the product, clinical indication and intended patient population. 

Regulatory guidelines require that there be maternal toxicity at the highest dosage level in embryo-fetal developmental toxicity studies. It is important to avoid excessive toxicity in these studies since it is known that marked maternal toxicity can cause secondary developmental toxicity (see discussion in Section 8.4.3, Association between Developmental and Maternal Toxicity ). This secondary developmental toxicity is irrelevant to the assessment of the developmental hazard of the test agent and thus simply confounds the interpretation of the data. 

Thus, in any case where developmental toxicity occurs at dosage levels with only moderate to severe maternal toxicity, the possibility of the developmental toxicity being secondary to the maternal toxicity can be considered. That is not to say, however, that it can be concluded that the developmental toxicity is secondary any time there is coincident maternal toxicity. To the contrary, it is usually very difficult to establish a causal relationship. Superficially similar types of maternal toxicity do not always cause the same pattern of developmental toxicity (Chemoff et al., 1990). This may be because the developmental toxicity is secondary to matemotoxicity, but, since typical developmental toxicity studies include only a very cursory evaluation of maternal toxicity, the developmental toxicity may be secondary to an aspect of matemotoxicity that is not even being measured. 

Clark, R.L., Antonello, J.M., Wenger, J.D., Deyerle-Brooks, K. and Duchai, D.M. (1991). Selection of food allotment for New Zealand white rabbits in developmental toxicity studies. Fund. Appl. Toxicol. 17 584-592. 

Food and Drug Administration (1984). Final Report of Task Force on Reproductive and Developmental Toxicity. Review of Current Recommendations and Requirements for Reproductive and Developmental Toxicity Studies, Department of Health and Human Services, Washington, D.C., 24 pp. 

Wise, L.D., Clark, R.L., Minsker, D.H. and Robertson, R.T. (1988). Use of hematology and serum biochemistry data in developmental toxicity studies. Teratology 37 502-503. 

Common Study Protocols. The dog is the most commonly used nonrodent species in safety assessment testing (i.e., acute, subchronic, and chronic studies). The exception to this is its use in developmental toxicity and reproductive studies. For developmental toxicity studies, the dog does not appear to be as sensitive an indicator of teratogens as other nonrodent species such as the monkey (Earl et al., 1973) or the ferret (Gulamhusein et al., 1980), and, for reproductive studies, the dog is not the species of choice because fertility testing is difficult to conduct (due to prolonged anestrus and the unpredictability of the onset of proestrus) and there is no reliable procedure for induction of estrus or ovulation. 

Results of developmental toxicity studies (see Section 2.22.6) in rodents suggest endrin can adversely affect pregnancy outcomes. There was reduced survival of pups in hamsters exposed to a single dose of 5 mg/kg (38% mortality, 3% in untreated controls) during the eighth gestation day (Ottolenghi et al. 

Prenatal Developmental Toxicity Study (Updated Guideline, adopted 22 January 2001)... 

Other types of reproductive toxicity studies, e.g., the prenatal developmental toxicity study, the reproduction/developmental toxicity screening study, and the developmental neurotoxicity study (Section 4.10.3) may give some indications of general toxicological effects arising from repeated exposure over a relatively limited period of the animal s life span as clinical signs of toxicity and... 

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