Two-generation study

The two-generation study in mink (Bucci 1997) has been completed and will hopefully help resolve the differences between the federal agencies recommendation and those of the state of Colorado. 

Rusch, G.M., R.-J.Millischer, C.de Rooij, A.J.Brooker, E.Hughes, and D.Coombs. 1995. Inhalation teratology and two-generation studies with 1,1-dichloro-l-fluoroethane (HCFC-141b). Fd. 

A two-generational study in pregnant rats exposed to 538 ppm 1,4-dichlorobenzene via inhalation produced decreased survival and decreased body weights in Fj pups (Tyl and Neeper-Bradley 1989). Murthy et al. (1987) reported morphologically abnormal sperm in rats exposed to 800 mg/kg/day by intraperitoneal injection. There are no studies that report transgenerational effects of exposure to... 

In order to fully assess the hazardous properties of a substance with respect to reproductive toxicity, the key data requirements are a two-generation study and a prenatal developmental toxicity (teratogenicity) smdy in two species (EC 2003). 

With respect to endocrine dismption, the two-generation study (OECD TG 416, US-EPA OPPTS 870.3800, EU Annex V B.35) is currently the most complete study available. Both in this study and in the developmental toxicity study (OECD TG 414, US-EPA OPPTS 870.3700, EU Annex V B.31), additional endocrine-sensitive parameters may be studied on a case-by-case basis when endocrine disruption is an issue of concern. 

In a 6-month study of rats, oral doses of 2.7 or 25mg/kg/day caused no hepatic changes. A two-generation study of reproduction and fertility in rats used oral doses of 2, 7, or 25mg/kg/day." Maternal toxicity was observed. Decreases in dam weight, number of corpora lutea, number of implantations, and number of neonates was attributable to the toxic effects in the dams. There were no findings in the Fi generation. 

Riley AJ, Nessel CS, McKee RH, et al Assessment of the reproductive toxicity potential of gasoline vapor in a two-generation study in rats. Toxicologist 54(1) 395, 2000... 

Reproductive effects were not observed in two-generation studies of rats treated with up to 15,000ppm MBT in the diet. ... 

Mercieca MD, Rodwell DE, Hinderer RK, et al Mercaptobenzothiazole (MBT) A two-generation study using Sprague-Dawley rats. Toxicologst 11(1) 112, 1991... 

Reproductive Effects. No reproductive effects have been reported in humans exposed to cresols. Although several studies in animals, including two- generation studies in rats and mink, examined the reproductive effects of cresols, no such effects were seen even at parenterally toxic doses. These results suggest that cresols do not have reproductive effects in animals or humans. 

Key words Pesticides, Prenatal toxicity study, Two-generation study. Regulatory toxicology. Hazard identification, Risk assessment... 

Reproductive toxicity, including prenatal toxicity in two species (rat, rabbit) and a two-generation study in rats... 

The two-generation study should allow the evaluation of two different sets of reproductive parameters, fertility of the parent FO animals as well as development and fertility of FI offspring. Table 2... 

In a two-generation study in rats, chlorobenzene in concentrations up to 450 ppm did not adversely affect reproductive performance or fertility (Nair et al. 1987). This value has been presented in,... 

Reduced fertility has been found for a number of chemicals, but often at relatively high exposure levels. However, it has to be considered that the rat is the most commonly used experimental animal and that a male rat can generally still produce normal progeny after having its sperm production reduced to 10% of the normal level (Aafjes et al., 1980). Thus, fertility data from rat studies alone can be a rather insensitive end-point. Human males may not have a similar sperm reserve capacity as rodents, and therefore the two-generation study has recently been updated to include assessment of sperm quality. It is unknown whether female rats (compared with human females) are also less sensitive to effects on fertility, but the two-generation study has recently been updated in that aspect by the inclusion of assessment of estrous cyclicity. 

Effects manifesting during the ageing process are not included in any guideline for reproductive toxicity. For example, the reproductive span of females is limited from the time of sexual maturation to reproductive senescence. The time of sexual maturation may be assessed in the two-generation study, but reproductive senescence is not assessed. Consequently, effects on the reproductive span of females are not covered in the reproductive toxicity test guidelines. 

The postlactational ovary should contain primordial and growing follicles as well as the large corpora lutea of lactation. In the two-generation study, the histopathological examination includes assessment of qualitative depletion of the primordial follicle population in the parental animals. A quantitative evaluation of primordial follicles should be conducted for FI females the number of animals, ovarian section selection, and section sample size should be statistically appropriate for the evaluation procedure used. Examination should include enumeration of the number of primordial follicles, which can be combined with small growing follicles, for comparison of treated and control ovaries. 

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