Oral Toxicity Studies

In the stomach, the chemicals contact other already-existing materials (stomach contents), secretions, (e.g., pepsin, gastric lipase, rennin), and hydrochloric acid. The effect of pH in the stomach, and the influence of pH on the ionization of weak organic acids and bases, plays a major role in the bioavailability of the chemical within the organism. 

Following oral administration, absorption of chemicals from the gut necessarily involves translation of the chemical either to the lymphatic system or portal circulation. Those environmental chemicals, which enter the portal circulation, are transported directly to the liver. 

The oral route is the preferred exposure, provided that the test chemical is not absorbed from the GI tract. Animals must receive the test chemical in their diet, dissolved in drinking water, or given by gavage or capsule for the length of time specified in the section on the study duration. 

Ideally, daily dosing on a 7-day-per-week basis should be used because dosing in gavages or as capsules on a 5-day-per-week basis may permit recovery or toxicity withdrawal in the nondosing period, thus affecting the result and evaluation. However, based primarily on practical considerations, dosing on a 5-day-per-week basis is considered acceptable. 

The most common and easiest manner of exposure to an environmental chemical is through accidental or intentional skin contact. To pass into the skin, the candidate chemical must either traverse the epidermal cells or enter through the follicles. The epidermal cells are the major pathway of potential to chemicals, since these constitute a larger surface area. 

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Health and Safety Factors. Results of acute oral toxicity studies of 2-pyrrohdinone on white rats and guinea pigs show the LD q to be 6.5 ml,/kg. Skin patch tests on 200 human subjects indicate that 2-pyrrohdinone is a skin kritant, but there is no indication of sensitising action. It is a mild eye irritant (79). 

Appel MJ, Waalkens-Berendsen DH (2004b) Trichlorooctyl-stennane [CAS 3093-25-6] Sub-chronic (13 week) oral toxicity study in rats, including a reproduction/developmental screening study. Zeist, TNO Nutrition and Food Research Institute, July (TNO Report No. V3963). 

Chronic-Duration Exposure and Cancer. No data were located regarding chronic-duration exposure of humans or animals to americium. Chronic-duration inhalation and oral MRLs were not derived for americium due to the lack of human or animal data. To generate appropriate data for deriving chronic-duration inhalation and oral MRLs for americium, at least one comprehensive chronic-duration inhalation and one chronic-duration oral toxicity study of at least one animal species exposed to several dose levels would be needed. Such studies could be designed to also generate data regarding potential age-related differences in toxicity. However, since americium is not found naturally, and is produced and used... 

Single-dose oral toxicity studies in rats, mice, and cattle indicate that signs of diisopropyl methylphosphonate intoxication include decreased activity, ataxia, tympanitis, and prostration within 1-4 hours after dosing (Hart 1976 Palmer et al. 1979). Mink that received 1,852 mg/kg/day diisopropyl methylphosphonate in their feed displayed aggressive behavior. However, it was concluded that this behavior was probably due to hunger resulting from the unpalatability of the feed (Aulerich et al. 1979). 

Acute-Duration Exposure. Acute oral LD50 data are available for mice and rats (Hart 1976) and for ducks (Aulerich et al. 1979). Acute oral toxicity studies, including histopathological observations, are available for ducks, mice, rats, dogs, and mink (Aulerich et al. 1979 Hardisty et al. 1977 Hart 1976, 1980). Limited acute dermal toxicity are available for rats (Hart 1976). These data suggest a relatively low toxicity. However, a clear relationship between dose and effect has not been elucidated. Inhalation data of any kind were not identified, and dermal data were very limited. 

Bucci TJ, Parker RM, Wustenberg W. 1992. A 90-Day oral toxicity study and a 5-day metabolism study of diisopropyl methylphosphonate (DIMP) in mink. Jefferson, AR Pathology Associates, Inc. NTIS No. AD-A257-397. 

Bucci TJ, Wustenberg W, Perman V, et al. 1994. Subchronic oral toxicity study of diisopropyl methylphosphonate in mink. Fundam Appl Toxicol 22(2) 220-230. 

FMC. 1990a. Non-definitive acute oral toxicity study of Durad 110 in rats. Study No. 190-1143. FMC Corporation, Princeton, NJ. 

Humiston CG, Frauson LO, Quast JF, et al. 1975. A 90-day oral toxicity study incorporating acrylonitrile in the drinking water of rats. Dow Chemical Company, Health and Environmental Research, Toxicology Research Laboratory, Midland, Ml. 

Haggerty, G.C., Miller, G., Port, C. and Gad, S. (1989). Four-week oral toxicity study of diclofenac in the ferret. Presented at the National Meeting of the American College of Toxicology, Williamsburg, Virginia. 

They can be either single endpoint (such as lethality and pyrogenicity) or shotgun (also called multiple endpoint, including such test systems as a 13-week oral toxicity study). 

Gerhart JM. 1986. Ninety-day oral toxicity study of copper cyanide (CuCN) in Sprague-Dawley Rats. Prepared for The Dynamac Corporation, Rockville, MD by IIT Research Institute, Chicago, IL. IITRI Project No. L06183, Study No. 3. 

The JECFA classified chlorophyll under List A which means that the colorant has been fully cleared and its use is not limited toxicologically since when used with good manufacturing practice does not represent a hazard to health. A subchronic oral toxicity study showed no adverse effects.26... 

FURUKAWA, F., KASAKAWA, K., NISHIKAWA, A., IMAZAWA, T. and HIROSE, M. A 13-week subchronic oral toxicity study of chlorophyll in F 344 rats. Bull. Nat. Inst. Health Sciences, 1998, 116, 107-12. 

Jonker D, Woutersen RA, Van Bladeren PJ, et al. 1990. 4-Week oral toxicity study of a combination of eight chemicals in rats Comparison with the toxicity of the individual compounds. Food Chem Toxicol 28(9) 623-631. 

Because bromomethane tends to volatilize and exists mainly as a gas at room temperature, only two oral toxicity studies have been performed (Boorman et al. 1986 Danse et al. 1984). Both studies were performed by administering bromomethane dissolved in oil to rats and both studies reported that irritation of the stomach was the chief effect. The 13-week study by Danse et al. (1984) identified a NOAEL of 0.4 mg/kg/day and a LOAEL of 2 mg/kg/day. An intermediate-duration oral MRL of 0.003 mg/kg/day was derived from the NOAEL (0.4 mg/kg/day) by adjusting for intermittent exposure (5 days/week) and dividing by an uncertainty factor of 100 (10 for extrapolation from animals to humans, and 10 for human variability). 

No information is available on acute oral exposure of humans or animals to bromomethane. Extrapolation from acute inhalation data is probably not appropriate, since some of the effects (both inhalation and oral) are due to point-of-contact irritation. However, acute oral toxicity studies are probably not essential, since oral exposure of humans to acutely toxic levels of bromomethane is not likely to occur due to the high volatility of the compound. 

Buck WB, Radeleff RD, Jackson JB, et al. 1959. Oral toxicity studies with heptachlor and heptachlor epoxide in young calves. J Econ Entomo 52(6) 1127-1129. 

API. 1979d. Rat acute oral toxicity study API 78-3 2 Home heating oil (10% cat). Washington, DC American Petroleum Institute. Project no. 1443-E. 

Repeated Dose 28-day Oral Toxicity Study in Rodents (Updated Guideline, adopted 27 July 1995)... 

The combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG 422) is, for the repeated dose toxicity part, concordant with the standard 28-day oral toxicity study (OECD TG 407) except for use of pregnant females and longer exposure duration (about 6 weeks for males and approximately 54 days for females) in the combined study compared to the standard 28-day study. 

Repeated dose 28-day oral toxicity study in rodents... 

Four-Week Oral Toxicity Study in Female Rats with Mixtures of Nephrotoxicants Having Similar Modes of Action... 

Acute oral toxicity studies do not contribute to the assessment of reproductive toxicity as they lack organ weight measurements and histopathology. In a way this is unfortunate because the study design itself, a single high dose followed by a 2-week observation period, might be suited for early detection and preliminary characterization of testicular toxicants. 

Barnes . 1988. 90-day oral toxicity study in dogs. Project No. 882012. Unpublished report dated August 4, 1988 from Ciba-Geigy Ltd. Basel, Switzerland. EPA-40815004. 

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