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State of the Science Report for DNOC
Exposure Assessment, Hazard Characterization and Risk Evaluation
The upper-bounding estimate of exposure to DNOC for the general population is 0.06 µg/kg-bw per day for the 0- to 6-month (formula-fed) age group, based on very limited data from Canadian surveys of drinking water and soil (Ontario Ministry of Environment and Energy, 1994; City of Toronto Water and Wastewater Services Division, 2002a,b,c,d) and an estimated concentration of DNOC in air in Switzerland (Leuenberger et al., 1988) (see Table 1). No quantitative data on levels of DNOC in food were identified. Confidence in the database for estimating exposure is considered moderate, since there is information for conservative estimation of exposure through drinking water and air, the likely principal media of exposure. The levels of DNOC in drinking water were below the detection limit; thus, estimates based on the detection limit likely overestimate exposure. The concentration of DNOC in air was estimated from rain samples but is considered to be conservative, as it is higher than levels measured in automobile exhaust, a source of DNOC (Tremp et al., 1993).
A health assessment of DNOC was published by the International Programme on Chemical Safety (IPCS) in 2000 (see Table 2 for an overview of the toxicological database, in which confidence is considered to be high, in view of the wide range of toxicity studies available). Although IPCS did not select a critical study for use as a basis of a tolerable intake or guidance value, the Lowest-Observed-Effect Level (LOEL) identified in that review that is considered to be the critical effect level is 2.5 mg/kg-bw per day in a 90-day rat dietary exposure study, with resulting dose-related decreases in blood pyruvate and triiodothyronine levels (Den Tonkelaar et al., 1983). Although several lower effect levels were reported in the IPCS assessment, there was less confidence in these studies due to the fact that insufficient details were available; however, these lower values were generally within an order of magnitude of the effect level considered to be critical. Similarly, in very early clinical investigations of the potential application of DNOC in the treatment of obesity, effects associated with increases in basal metabolic rate were observed in individuals administered doses in the range of this critical value. DNOC was not carcinogenic in the only long-term study identified (Broadmeadow, 1991), and the weight of evidence for genotoxicity was considered to be equivocal by IPCS (2000), as positive results were observed in some but not all in vivo assays in which rodents were administered doses generally greater than the critical effect level for non-neoplastic effects. Similarly, the results of modelling of in vivo and in vitro genotoxicity endpoints are also equivocal.
Comparison of the critical effect level with the upper-bounding estimate of exposure results in a margin of exposure of approximately 41 700. Based on the level of confidence in the available database and the conservative nature of this evaluation, including the use of an upper-bounding exposure estimate and lowest effect level, this margin is considered adequate to account for the uncertainties in the database.
| Route of exposure | Estimated intake (µg/kg-bw per day) of DNOC by various age groups | ||||||
|---|---|---|---|---|---|---|---|
| 0-6 months1 | 0.5-4 years 3 | 5-11 years4 | 12-19 years5 | 20-59 years6 | 60+ years7 | ||
| Formula fed2 | Not formula fed | ||||||
| Air8 | 1.4 × 10-2 | 3.0 × 10-2 | 2.4 × 10-2 | 1.4 × 10-2 | 1.1 × 10-2 | 9.9 × 10-3 | |
| Drinking water9 | 4.3 × 10-2 | 1.6 × 10-2 | 1.8 × 10-2 | 1.4 × 10-2 | 8.1 × 10-3 | 8.5 × 10-2 | 8.9 × 10-3 |
| Food10 | NA11 | NA | NA | NA | NA | NA | |
| Soil12 | 4.0 × 10-4 | 6.5 × 10-4 | 2.1 × 10-4 | 5.1 × 10-5 | 4.2 × 10-5 | 4.2 × 10-5 | |
| Total intake | 5.7 × 10-2 | 3.0 × 10-2 | 4.9 × 10-2 | 3.8 × 10-2 | 2.1 × 10-2 | 2.0 × 10-2 | 1.9 × 10-2 |
1 Assumed to weigh 7.5 kg, to breathe 2.1 m3 of
air per day, to drink 0.8 L of water per day (formula fed) or 0.3
L/day (not formula fed) and to ingest 30 mg of soil per day (EHD,
1998).
2 For formula-fed infants, intake from water is synonymous
with intake from food. No data on concentrations of DNOC in formula
were identified for Canada.
3 Assumed to weigh 15.5 kg, to breathe 9.3 m3 of
air per day, to drink 0.7 L of water per day and to ingest 100
mg of soil per day (EHD, 1998).
4 Assumed to weigh 31.0 kg, to breathe 14.5 m3 of
air per day, to drink 1.1 L of water per day and to ingest 65 mg
of soil per day (EHD, 1998).
5 Assumed to weigh 59.4 kg, to breathe 15.8 m3 of
air per day, to drink 1.2 L of water per day and to ingest 30 mg
of soil per day (EHD, 1998).
6 Assumed to weigh 70.9 kg, to breathe 16.2 m3 of
air per day, to drink 1.5 L of water per day and to ingest 30 mg
of soil per day (EHD, 1998).
7Assumed to weigh 72.0 kg, to breathe 14.3 m3 of
air per day, to drink 1.6 L of water per day and to ingest 30 mg
of soil per day (EHD, 1998).
8 Leuenberger et al. (1988) estimated an ambient air
concentration of 0.05 µg/m3 using measured concentrations
of DNOC from a rainwater sample (15 nM) taken at Dübendorf,
Switzerland, in 1985 and using a reference rain/air partition coefficient
(5.6 × 104 ). Canadians are assumed to spend 3
hours outdoors each day (EHD, 1998). Data available from which
the critical data were selected included Tremp et al. (1993). In
the absence of data, the estimated ambient air concentration (0.05 µg/m3)
was also used for indoor air. Canadians are assumed to spend 21
hours indoors each day (EHD, 1998). Ambient air was assumed to
be representative of exposure to indoor air, since there was no
indication of additional sources of DNOC in indoor environments.
9 The detection limit (0.4 µg/L) for DNOC in 19
samples of tap water from Toronto, Ontario, in 2002 was used as
a surrogate for the level of DNOC in Canadian drinking water (City
of Toronto Water and Wastewater Services Division, 2002a,b,c,d).
Data available from which the critical data were selected included
Hallberg (1989), City of Toronto (1990) and Spliid and Koppen (1998).
10 No quantitative data were identified for concentrations
of DNOC in food items. A detection limit of 1000 µg/g was
used for a study by Schmidt (1970) that measured for DNOC in potatoes.
However, this value was not used in the intake estimate due to
the age of the study and because DNOC is not expected to contaminate
foods based on its application method. Data available from which
the critical data were selected included DeVault (1985).
11 NA = not available.
12 The Ontario Ministry of Environment and Energy (1994)
did not detect DNOC in 161 soil samples collected from Ontario.
The method detection limit of 100 ng/g was used in the intake estimate
as a surrogate for the level of DNOC in Canadian soil. Data available
from which the critical data were selected included Webber (1994)
and Migaszewski (1999).
| Endpoint | Lowest effect levels1/Results |
|---|---|
| Laboratory animals and in vitro | |
| Acute toxicity | Lowest oral LD50= 16 mg/kg-bw (Jongerius and Jongeneelen, 1991) (range: 16 mg/kg-bw to 100 mg/kg-bw) [Additional studies: Dow Chemical Co., 1940, 1950, 1992; Ambrose, 1942; Spencer et al., 1948; King and Harvey, 1953a; McGirr and Papworth, 1953; Burkatskaya, 1965b; Ben Dyke et al., 1970; Driscoll, 1995a] Lowest dermal LD50= 187 mg/kg-bw (Arustamyn, 1972) (range: 187 mg/kg-bw to >2000 mg/kg-bw) [Additional studies: Dow Chemical Co., 1940, 1992; Spencer et al., 1948; Burkatskaya, 1965b; Ben Dyke et al., 1970; Jongerius and Jongeneelen, 1991; Driscoll, 1995b] Lowest inhalation LC50= 40 mg/m3 (Burkatskaya, 1965a) (range: 40 mg/m3 to 230 mg/m3) [Additional studies: King and Harvey, 1953b; Dey-Hazra and Heisler, 1981] |
| Short-term repeated-dose toxicity | Lowest oral (diet) LOEL (rat) = 7.24 mg/kg-bw per day: decreased body weight gain (6-week study) (Broadmeadow, 1988) [Additional studies: Dow Chemical Co., 1940, 1992; Spencer et al., 1948; Quinto et al., 1989; Takahashi et al., 1999] Lowest inhalation LOEC (cat) = 2 mg/m3: mortality (30-day study) (Burkatskaya, 1965a) |
| Subchronic toxicity | Lowest oral (diet) LOEL (rat) = 2.5 mg/kg-bw per day: change in blood pyruvate and thyroid hormone levels (13-week study) (Den Tonkelaar et al., 1983) [Additional studies: Til, 1980; Kelly 1995] Lowest inhalation NOEC (cat) = 0.2 mg/m3: "no severe adverse effects" (90-day study) (Burkatskaya, 1965a) |
| Chronic toxicity/ carcinogenicity | Lowest oral (diet) non-neoplastic LOEL (male rat) = 4.12 mg/kg-bw per day: increased food consumption (104-week study) (Broadmeadow, 1991) No increase in tumour incidences was observed at dose levels up to 5 mg/kg-bw per day in a 104-week study using rats exposed through the diet (Broadmeadow, 1991). [N.B.: It is not clear based on the secondary account of this study if the substance was tested up to the maximum tolerated dose.] |
| Genotoxicity and related endpoints: in vivo | Positive: mouse, bone marrow (micronuclei; 20 mg/kg-bw or 10 mg/kg-bw intraperitoneally [i.p.].after 1 year); rat, bone marrow (chromosomal aberrations; 7.5-30 mg/kg-bw i.p.); rat, hepatocytes (DNA unwinding; 1-9.3 mg/kg-bw i.p.); mouse (dominant lethal assay; 8-15 mg/kg-bw i.p.; and chromosomal aberration in F1 embryo; 5-10 mg/kg-bw i.p.) (Nehéz et al.,1 1978, 1981, 1984; Grilli et al., 1991; Hrelia et al., 1994) Negative: rat and mouse, bone marrow (chromosomal aberrations; 4-16 mg/kg-bw oral and 3-12 mg/kg-bw i.p., respectively); mouse, bone marrow (micronuclei; 20 mg/kg-bw i.p.); rat, hepatocytes (unscheduled DNA synthesis; 28-70 mg/kg-bw oral) (Kirkland, 1984, 1986; Marzin, 1991c; Fellows, 1998) |
| Genotoxicity and related endpoints: in vitro | Positive : Proteus mirabilis (DNA repair), Salmonella typhimurium TA98, TA100, TA1535, TA1537, TA1538 (mutagenicity), Drosophila (sex-linked recessive lethal), mouse lymphoma (mutagenicity), human lymphocytes (chromosome damage), Chinese hamster V79 cells (mutagenicity) (Adler et al., 1976; Nehéz et al., 1977, 1978; Muller and Haberzetti, 1980; Martin, 1981; Nishimura et al., 1982; Sundvall et al., 1984; Marzin, 1991a,b) Negative : S. typhimurium TA98, TA100, TA100NR, TA1535, TA1537 (mutagenicity), mouse lymphoma (mutagenicity), human lymphocytes (chromosome damage, sister chromatid exchange and unscheduled DNA synthesis), Chinese hamster ovary cells (chromosome damage) (Martin, 1981; Somani et al., 1981; Nishimura et al., 1982; Garner, 1984; Sundvall et al., 1984; Marzin, 1991a,b,d; Hrelia et al., 1994) |
| Developmental toxicity | Lowest oral (gavage) LOEL (rabbit) = 25 mg/kg-bw per day: external or visceral malformations or skeletal variations, including microphthalmia or anophthalmia and hydrocephaly or microcephaly (gestation days 6-18) (Allen et al., 1990a) [Additional studies: Nehéz et al., 1981; Dickhaus and Heisler, 1984] Lowest dermal LOEL (rabbit) = 30 mg/kg-bw per day: total resorptions in two females (gestation days 6-18) (Allen et al., 1990b) |
| Reproductive toxicity | Lowest oral (diet) LOEL (rat) = 1.73-2.24 mg/kg-bw per day: decreased group mean litter size in F0 generation on days 14 and 21 of lactation (two-generation reproductive study) (Coles and Brooks, 1997) |
| Immunotoxicity | Highest oral (diet) NOEL (rat) = 20 mg/kg-bw per day (3-week study) (Vos et al., 1983) |
| Humans | |
| Clinical study | Increase in basal metabolic rate and symptoms of toxicity (sweating, lethargy, headache, altered sleep patterns) at 3 mg/kg-bw for "several" days. Slight increase in basal metabolic rate but no symptoms of toxicity were noted in one patient administered 0.5 and then 1 mg/kg bw/day for 39 days. (data presented for two subjects, total number examined unclear) (Dodds and Robertson, 1933) [Additional study: Plotz, 1936] |
1 LC50 = median lethal concentration; LD50 = median lethal dose; LOEC = lowest-observed-effect concentration; LOEL = lowest-observed-effect level; NOEC = no-observed-effect concentration.
