Reproductive or Developmental Toxicity

Teratogenic effects observed during studies of reproductive or developmental toxicity are reportable, and so are other adverse effects on the developing organism and the test animals reproductive systems. 

Although liver and kidney weight changes are not generally reportable if they are less than 10 percent of body weight, this rule does not apply to developmental toxicity studies, and liver and kidney weight changes are reportable if observed in these studies.  

These effects are reportable even if they are reversible, and whether they are observed prenatally or postnatally. Reproductive or developmental toxicity is reportable whether or not there is maternal toxicity. Similarly, maternal toxicity observed during a reproductive or developmental toxicity study is reportable in the absence of reproductive or developmental toxicity.  

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The priority effects are carcinogenicity, mutagenicity, reproductive or developmental toxicity, endocrine disruption and neurotoxicity. Human toxicity is broader than priority effects, including acute toxicity, systemic toxicity (organ effects), immune system effects and skin/eye/respiratory damageaswellasthepriority effects. And toxicity as T includes both human toxicity and ecotoxicity. 

Additionally, there are specialized studies designed to address endpoints of concern for almost all drugs (carcinogenicity, reproductive or developmental toxicity) or concerns specific to a compound or family of compounds (local irritation, neurotoxicity, or immunotoxicity, for example). When these are done, timing also requires careful consideration. It must always be kept in mind that the intention is to ensure the safety of people in whom the drug is to be evaluated (clinical trials) or used therapeutically. An understanding of special concerns for both populations should be considered essential. 

Dourson et al. (1996) noted that if data are only available from one chronic study on which to base the estimation of a sub-threshold dose, the question could be asked whether data from chronic studies in other species or data from different types of bioassays (e.g., reproductive or developmental toxicity) would yield lower NOAELs. The uncertainty related to this issue must therefore be addressed and, according to the authors, the default approach to address this uncertainty is to apply a 3- or 10-fold UF, based on the assumption that the critical effect can be discovered in a reasonably small selection of toxicity studies. With a reference to some analyses performed within this area, the authors suggested the use of a UF to account for missing bioassays however, the quantification of this UF was considered to require additional work. 

Hemminki, K., Paasivirta, J., Kurkirinne, T. Virkki, L. (1980) Alkylation products of DNA bases by simple epoxides. Chem.-biol. Interact., 30, 259-270 Hine, C.H., Kodama, J.K., Wellington, J.S., Dunlap, M.K. Anderson H.H. (1956) The toxicology of glycidol and some glycidyl ethers. Arch. ind. Health, 14, 250-264 Hooper, K., LaDou, J., Rosenbaum, J.S. Book, S.A. (1992) Regulation of priority carcinogens and reproductive or developmental toxicants. Am. J. ind. Med., 22, 793-808 Hussain, S. (1984) Dose-response relationships for mutations induced in E. coli by some model compounds. Hereditas, 101, 57-68... 

No inhalation MRLs were derived for DEHP due to inadequate data for this route of exposure. As summarized in Section 2.2, the inhalation database for DEHP is essentially limited to two studies in rats that found some reversible effects in the lungs and liver following exposure for 28 days and no evidence for reproductive or developmental toxicity (Klimisch et al. 1991 Merkle et al. 1988). 

Data sets that are insufficient for evaluating reproductive or developmental toxicity do not arise solely from studies that are unreliable and therefore unworthy of consideration. Information from in vitro or nontraditional in vivo studies, for example, frequently provides enough experimental evidence to corroborate other evidence for an adverse effect. Alone, however, those studies might not provide enough evidence to be considered sufficient to identify an adverse effect. 

Even a single exposure, no matter the duration, might result in reproductive or developmental toxicity. Agents that show accumulation with repeated exposures or that have a long half-life will result in greater exposures over time. The pattern of exposure is extremely important in predicting outcome, and it is usually difficult to extrapolate results from one pattern to another unless pharmacokinetic data are available to illuminate the differences. In the case of intermittent exposures, peak exposures and averages over time should be considered. 

Reproductive or developmental toxicity endpoints must be interpreted in the context of general toxicity that could also occur in the same animals. Toxic effects reported from other studies can be particularly valuable because excessive toxicity could significantly confound the interpretation of a reproductive or developmental toxicity study. Observations from studies of other toxicity endpoints might either strengthen or weaken the conclusions to be drawn from a reproductive or developmental study and provide information about target organs that should be evaluated further in developing animals. 

Acute toxicity data also can suggest the extent of absorption through different routes of exposure. If, for example, systemic toxicity or death can occur as a result of significant absorption of the chemical through dermal exposure, it must be assumed that dermal exposure also can cause reproductive or developmental toxicity. 

Assessments of risk for reproductive or developmental toxicity that... 

Data for assessing reproductive or developmental toxicity are derived both from observations of humans and from experimental animal studies. It is beyond the scope of this document to enumerate the kinds of data that can permit a complete assessment of reproductive and developmental toxicity that covers all situations. The definition of a sufficient data set changes as scientific knowledge accumulates on specific agents and as the understanding of the predictive capabilities of animal models and other procedures improves. Appendix C and Appendix D of this document describe studies that commonly provide such information and offer guidance in their interpretation. 

At least one well-conducted study must show reproductive or developmental toxicity in a mammalian species. When the study data are insufficient, improper study design or execution, inadequate doses or duration of exposure, poor survival, or too few animals to achieve statistical power are often the cause. At present, no nonmammalian or in vitro systems are considered to be predictive of human responses, and are not accepted by... 

When assessing manifestations of toxicity, evaluators might base their conclusions about relevance on the mechanism that produces a toxicological effect however, a basic default assumption is that any manifestation of reproductive or developmental toxicity is relevant to humans unless the mechanism by which it occurs is impossible in humans. For example, if a toxic effect occurs in animals through an inhibition of folic acid synthesis, that effect would not be considered relevant for humans because humans do not synthesize folic acid. It is unusual, however, to have such detailed knowledge about mechanisms of toxicity from experimental animal studies. 

Assume that susceptibility to reproductive or developmental toxicity may be greater than susceptibility to any known toxicity of the agent, and apply additional uncertainty factors to reflect the lack of data. 

The approach described in this chapter results in limitations that would be unnecessary if the exposure under consideration were known to be safe. The most effective way to reduce uncertainty is to develop data to characterize the toxicity of the agents the Navy must use. Applying additional uncertainty factors to exposure limits can lead to unnecessarily conservative limits, which can lead the Navy to curtail the use of agents that may have been acceptable if adequate data were available. Such circumstances may increase costs. Obtaining a sufficient data set on the safety of a particular exposure might, therefore, provide substantial savings without increasing the risk of reproductive or developmental toxicity. 

No human studies have been conducted to assess female reproductive or developmental toxicity caused by exposure to JP-8 or any other kerosene-based fuel. 

Data on comparative pharmacokinetics are sparse there are no data to support a conclusion that adverse reproductive or developmental toxic effects in rats or mice are not predictive of some adverse effect in humans. Thus, it is accepted by default that animal data are relevant to humans. 

Data on the toxicity and disposition of HFC-134a suggest that it is a compound with little or no reproductive or developmental toxicity except at very high exposure concentrations that induce narcosis. However, data are needed from postnatal evaluations and from a multigeneration study with 6 hr/d exposure. The similarities in pharmacokinetics between humans and laboratory animals provide confidence that the data are relevant for predicting human risk. 

Usefulness in Identifying Exposures that Pose a Substantial Risk of Reproductive or Developmental Toxicity in Humans... 

IARC working groups are composed of individuals with expertise related to cancer. There usually is a member with expertise on reproductive and developmental toxicity who prepares that section, but the working group is not constituted to provide a peer review of reproductive or developmental toxicity. 

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