Developmental studies

The data in animals are insufficient to derive an acute inhalation MRL because serious effects were observed at the lowest dose tested (Hoechst 1983a). No acute oral MRL was derived for the same reason. The available toxicokinetic data are not adequate to predict the behavior of endosulfan across routes of exposure. However, the limited toxicity information available does indicate that similar effects are observed (i.e., death, neurotoxicity) in both animals and humans across all routes of exposure, but the concentrations that cause these effects may not be predictable for all routes. Most of the acute effects of endosulfan have been well characterized following exposure via the inhalation, oral, and dermal routes in experimental animals, and additional information on the acute effects of endosulfan does not appear necessary. However, further well conducted developmental studies may clarify whether this chemical causes adverse developmental effects. 

Robertson, D., Anderson, L, and Bachmann, M., Pigment-deficient mutants genetic, biochemical and developmental studies, in Maize Breeding and Genetics, Walden, D., Ed., John Wiley Sons, New York, 1978, 461. 

Szabo K. and Mendoza A. (1988). Developmental studies on the rat vomeronasal organ vascular pattern and neuroepithelial differentiation. I. Light microscopy. Brain Res 467, 253-258. 

No fetal effects were noted in a dose range-finding developmental study in which pregnant Sprague-Dawley rats were exposed to 150 ppm hydrogen sulfide on gestation days 6-20, despite body weight loss in the dams (Saillenfait et al. 1989). 

Developmental Toxicity. No information is available on developmental effects of acrylonitrile in humans by any route of exposure. Acrylonitrile is teratogenic and embryotoxic in rats both by the oral and inhalation routes of exposure. Developmental studies on other animal species have not been conducted. Because species differences for acute acrylonitrile toxicity and metabolism have been demonstrated, additional developmental studies in other species using various dose levels would be valuable in evaluating the potential for acrylonitrile to cause developmental effects in humans. Because the available oral study was conducted by gavage, additional studies are needed to determine if these effects will occur following ingestion of drinking water or food. 

It is needless to say that the above developmental studies must be accompanied by intensive efforts of collecting many strains from various habitats and selecting potentially prospective strains among them. 

Neurotoxicity. No information is available on neurotoxic effects of hexachloroethane in humans following any route of exposure. Acute inhalation exposure in rats caused staggering gait after exposure to high concentrations (5,900 ppm) (Weeks et al. 1979). The usefulness of this data is limited since this concentration was lethal. Tremors have been reported at 260 ppm but not 48 ppm following inhalation exposure of rats in a developmental study and in a study of 6-weeks duration (Weeks et al. 1979). The lack of tremors at 48 ppm in the developmental study serves as the basis for the acute inhalation MRL, and the lack of tremors at 48 ppm in the 6-week study serves as the basis for the intermediate inhalation MRL. One study that evaluated spontaneous motor activity and avoidance behavior in rats during 6 weeks of exposure to 260 ppm hexachloroethane vapors did not reveal adverse effects of hexachloroethane on these neurobehavioral functions (Weeks et al. 1979). 

Stelzner DJ. The relationship between synaptic vesicles, Golgi apparatus, and smooth endoplasmic reticulum A developmental study using the zinc iodide-osmium technique. Z Zellforsch 1971 120 332-345. 

Sangster AG, Hodson MJ, Parry DW, Rees JA. A developmental study of silicifi-cation in the trichomes and associated epidermal structures of the grass Phalaris canariensis L. Ann Bot 1983 52 171-197. 

Woodmansee, K.B., Zabel, C.J., Glickman, S.E., Frank, L.G. and Keppel, G. (1991) Scent marking (pasting) in a colony of immature spotted hyenas (Crocuta crocuta) A developmental study. J. Comp. Psychol. 105, 10-14. 

As part of a developmental study on oral exposure to -hexane, pregnant 60-90-day-old outbred albino mice (CD-I) received -hexane (99%) once daily at doses up to 2,200 mg/kg/day on gestation days 6-15 by cottonseed oil gavage. One of 14 mice died after receiving 10 daily doses of 2,200 mg/kg/day (Marks et al. 1980). In a second study where doses were given 3 times a day, 2 of 25 died at 2,830 mg/kg/day,... 

After extensive developmental studies, [35] the final crucial element in our most recent synthesis of epothilone B involves an asymmetric catalytic reduction of the C3 ketone of 67 proceeding via a modified Noyori procedure (Scheme 2.8, 67—>68). In the event, Noyori reduction of ketone 67 afforded the desired diol 68 with excellent diasteresdectivity (>95 5). The ability to successftdly control the desired C3 stereochemistry of the late stage intermediate 68 permitted us to introduce the Cl-C7 fragment into the synthesis as an achiral building block. 

It is unknown whether infants or children are more susceptible than adults to the adverse effects of phenol as stated above, developmental studies are inconclusive. Most of the information available on the toxic effects of phenol in infants and children comes from the use of phenol in medical treatments. Phenol was once used as an antiseptic in wound dressing products and there are several reports of deaths in children and infants following overzealous application of such... 

An acute-duration oral MRL was not derived for phenol. The lowest LOAEL was a serious effect reported in a developmental study (Narotsky and Kavlock 1995). Dyspnea, rales, and a 20% decrease in maternal body weight gain were reported in pregnant rats treated by gavage with phenol in water at a dose of 40 mg/kg/day on gestation days 6-19. A significant decrease in the number of livebom pups was observed at 53.3 mg/kg/day and was associated with severe respiratory effects. This study is limited in that the number of dams with respiratory effects was not stated. 

Of 50 adult rats used in a reproductive/developmental study, 22% of those that received 6 mg/kg/day heptachlor in the diet developed lens cataracts 4.5-9.5 months following exposure. In addition, 6-8% of the pi offspring and 6% of the p2 offspring of these rats also developed cataracts 19-21 days after birth (Mestitzova 1967). The author of this study eliminated the possibility of a vitamin B deficiency or a recessive genetic trait as the cause of the cataracts. She could not rule out the possibility of altered vitamin B metabolism caused by heptachlor. 

Developmental Toxicity. It is not known whether 1,2-diphenylhydrazine crosses the placenta, but there is no reason to assume that it (or its metabolites) would not do so. Developmental studies in mammals would provide information on possible fetotoxic and teratogenic effects of... 

Renwick et al. (2000) have performed an analysis of the need for an additional UF for infants and children. They considered that the proposal to introduce an additional 10-fold factor when exposure of infants and children is anticipated implies either age-related differences between species or differences within humans, which exceed those present in adults. Alternatively, the extra factor could be related to deficiencies of current testing methods or concerns over irreversibility in developing organ systems. They concluded that the available data did not provide a scientific rationale for an extra factor due to inadequacy of inter- and intraspecies UFs. Justification for the factor therefore must relate to the adequacy and sensitivity of current methods or concern about irreversible effects in the developing organism. They also pointed out that when adequate reproduction, multigeneration, or developmental studies are conducted, there will be no need for an additional 10-fold factor. 

In rat developmental studies, fetal effects including delayed ossification and decreased locomotor activity occurred at doses that also caused maternal toxicity. Cadmium sulfate injected into the lingual vein of female hamsters on day 8 of pregnancy caused a high incidence of resorption and malformed offspring. Acute necrosis of rat testes followed large doses orally or parenterally, but testicular effects have not been reported thus far in humans." ... 

Naphthalene was not teratogenic in a number of developmental studies, although a trend toward dose-related malformations was seen in rats administered up to 450mg/kg/day on gestation days 6-15. °... 

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