Toxicity reproductive studies

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

RTI. 1992. Research Triangle Institute. Two-generation reproductive toxicity study of tributyl phosphate administered in the feed to CD (Sprague-Dawley) rats. RTI Project No. 60C-4652. 

OECD, Organization for Economic Cooperation and Development, Guideline 416, Two Generation Reproduction Toxicity Study, 2001b. 

Developmental and reproductive toxicity studies regarding animal exposure to phosgene were not available. 

CBER (2000). Guidance for Industry — Consideration for Reproductive Toxicity Studies for Preventive Vaccines for Infectious Disease Indications. 

Ema M (2008) Two generation reproductive toxicity study of the flame retardant HBCD in rats. Reprod Toxicol 25 335-351... 

Meeks RG, Stump DG, Siddiqui WH, Holson JF, Plotzke KP, Reynolds VL (2007) An inhalation reproductive toxicity study of octamethylcyclotetrasiloxane (D-4) in female rats using multiple and single day exposure regimens. Reprod Toxicol 23 192-201... 

Wolfe GW, Layton KA (2003) Multigeneration reproduction toxicity study in rats (unaudited draft) diethylhexylphthaiate muitigenerational reproductive assessment when administered to Sprague-Dawley rats in the diet. The Immune Research Corporation (Gaithersburg, Maryland), TRC Study no 7244-200... 

One-Generation Reproduction Toxicity Study (Original Guideline, adopted 26 May 1983)... 

In the first step of the hazard assessment process, aU effects observed are evaluated in terms of the type and severity (adverse or non-adverse), the dose-response relationship, and NOAEL/LOAEL (or alternatively BMD) for every single effect in aU the available studies if data are sufficient, and the relevance for humans of the effects observed in experimental animals. In this last step of the hazard assessment, all this information is assessed as a whole in order to identify the critical effect(s) and to derive a NOAEL, or LOAEL, for the critical effect(s). It is usual to derive a NOAEL on the basis of effects seen in repeated dose toxicity studies and in reproductive toxicity studies. However, for acute toxicity, irritation, and sensitization it is usually not possible to derive a NOAEL because of the design of the studies used to evaluate these effects. For each toxicological endpoint, these aspects are further addressed in Sections 4.4 through 4.10. 

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... 

The developmental neurotoxicity test (OECD TG 426 Draft, US-EPA OPPTS 870.6300) can be conducted as a separate study, incorporated into a reproductive toxicity study and/or adult neurotoxicity study, or added onto a prenatal developmental toxicity study. 

WHO/IPCS (1994, 1999) stated that a minimum data set considered adequate for an assessment will vary according to the purpose of the assessment. The major deficiencies in a toxicity database, other than those related to the pivotal study, which increase the uncertainty of the extrapolation should be recognized by the use of an additional UF. Since the quality and/or completeness of different databases vary, the additional UF will also vary. For example, a value of 1 would be applied to a database that was considered complete for the evaluation of the compound under consideration, but a factor of 1-100 might be necessary for limited databases. If minor deficiencies in the data exist with respect to quality, quantity, or omission, then an extra factor of 3 or 5 would be appropriate. An extra factor of 10 would be appropriate where major deficiencies in the data exist, e.g., a lack of chronic toxicity studies and reproductive toxicity studies. It was pointed out that inadequacies of the pivotal study could also be considered as a subset of inadequacies of the database and that the total factor for limitations of the pivotal study plus adequacy of the overall database should not exceed 100 since such a database is generally not acceptable for development of a TDI. 

In conclusion, the uncertainty related to the confidence in the database should be taken into account by the use of an assessment factor. Since the quality, completeness, and/or consistency of different databases vary, the assessment factor will also vary and can only be assigned on the basis of expert judgment, preferably made transparent through the application of a set of criteria. In any case, the size of the factor should be considered in terms of other information in the database. The default value should be 1 in case of a high-confidence database, and a factor of 10 would be appropriate where major deficiencies in the data exist, e.g., a lack of chronic and reproductive toxicity studies when setting a tolerable intake. 

Box 3.2 shows the toxicity package t)q)ically generated before a Phase I trial. These trials are usually conducted in males, and thus do not require formal reproductive toxicity studies. In the United States, women can be included in early trials without any animal reproductive toxicity if special precautions are taken to ensure that pregnancy does not occur. A histopathological assessment of the effects of the test compound on the male reproductive tract is made in the repeat-dose toxicity tests. 

Before the ICH guidelines (see below), reproductive toxicity studies were divided into three segments which, in Europe, were designed as follows ... 

The following points should be considered when evaluating the data from reproductive toxicity studies. 

Toxicity studies are costly in terms of both animals and resources, as indicated in Table 3.7. For a product developed for chronic oral therapy, approximately 4000 rats, 1300 mice, 100 rabbits, 50 guinea pigs and 160 dogs, a total of over 5000 animals, is used. If the foetuses and offspring from the reproductive toxicity studies are... 

Tyl W, et al Three generation reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley rats. Toxicol Sci 68 121, 2002... 

Leuschner J Reproductive toxicity studies of D-camphor in rats and rabbits. Arzneimit-telforschung 47(2) 124—8,1997... 

Neeper-Bradley TL, Tyl RW, Fisher LC, et al Reproductive toxicity study of inhaled paradichlorobenzene (PDCB) vapor in CD rats. Teratology 39 470-471, 1989 (abst)... 

Nemec MD, Topping DC, Tyler TR, et al Inhalation 2 -generation reproductive toxicity study of methyl isobutyl ketone in rats. Toxicologist 60(1) 250, 2001... 

Reproductive toxicity studies have shown developmental toxicity at doses causing no or mild maternal toxicity. A transient decrease in pup weight, delayed physical development, and... 

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