Regulation and Risk Assessment of 1,4-Dioxane - Environmental Investigation and Remediation - page 309

statistically derived median single lethal dose for 50% of animals tested (LD 50 ) by the oral/ingestion,
inhalation/breathing, and dermal/skin exposure routes. The lethal dose varies by species, strain, age,
and sex of the laboratory animal tested. For example, rat pups, rat dams (females), and male rats may
each have their own LD 50 , whereas mice, guinea pigs, and rabbits may have considerably larger or
smaller LD 50 values. The species exhibiting the greatest sensitivity to the toxin is usually selected as
the human surrogate from which estimates of toxic effect levels for humans can be extrapolated.
Subacute assays assess the toxic effects in an animal population from daily exposure to the toxi-
cant over about 10% of the animal's lifetime. Subacute toxicity assays identify many different toxic
endpoints, such as dysfunction of different organs (Kamrin, 1988). The highest dose at which none
of the animals in a test population displays a toxic effect (NOAEL) is typically divided by 100 to
rel ect greater variation among human populations.
Carcinogenic chemicals are distinguished by their capacity to produce neoplasms (“new
growths,” or tumors) in the receptor. Any one of the following four types of evidence is generally
used to classify a chemical as carcinogenic:

1. The exposed population develops tumors not seen among animals in the control population

2. There is an increased incidence of tumors in the exposed population of the same type that
also commonly occurs at a low incidence rate among the control population

3. Tumors develop earlier in the exposed population than in the control population

4. Tumors in the exposed population multiply more quickly than in the control population
(Williams and Weisburger, 1986)

The carcinogenic agent that actually converts a normal cell to a neoplastic (tumor) cell and i nally
into an overt neoplasm may be either (1) the original chemical that enters the body by ingestion,
inhalation, dermal exposure, or other means or (2) a metabolic by-product that results in organ-spe-
cii c exposure, for example, in the liver. The route of exposure may control the carcinogenicity of a
compound. For example, a compound may not be carcinogenic when absorbed into the bloodstream
through the lungs, but could be carcinogenic when metabolized following ingestion. Carcinogens are
classii ed by the weight of evidence for their likelihood to initiate or promote cancerous tumors.
Table 6.24 lists the oral and inhalation rat LD 50 values for selected solvent-stabilizer compounds.
Although it is preferable to compare RfDs or RfCs, these are generally not available for the list of
stabilizer compounds included in Table 6.24. The reader is cautioned that NOAELs for different
species, routes of exposure, toxicity endpoints, exposure durations, and study designs cannot be
directly compared; the values are provided to list available information for these compounds.

TABLE 6.24
Relative Risk Thresholds of Solvent Stabilizers Compounds

Carcinogenicity,
Mutagenicity, and
Genotoxicity

Stabilizer Oral Rat LD 50 Inhalation LC 50 NOAEL

Epichlorohydrin 40 mg/kg [1]

90 mg/kg [2]

LC 50 rat inhalation
500 ppm for 4 h [1]

3.4 mg/m 3 6 h/day; 5
day/week [3]

IRIS B2—probable human
carcinogen [4]; coni rmed
animal carcinogen [5]; IARC
group 2A probably
carcinogenic to humans [6]

Acetonitrile 175 mg/kg [7] LC 50 rat inhalation [1]

330 ppm for 90 days

100 ppm maternal
rat [8]

A4: Not classii able as a
human carcinogen [9]

continued