Dinitro-o-cresol final screening assessment: appendix 2
Appendix 2: summary of health effects information for DNOC
| Endpoint | Lowest effect levelsa/Results |
| 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; Ambrose 1942; Spencer et al. 1948; Dow Chemical Co. 1950; King and Harvey 1953a; McGirr and Papworth 1953; Burkatskaya 1965b; Ben Dyke et al. 1970; Dow Chemical Co. 1992; 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; Spencer et al. 1948; Burkatskaya 1965b; Ben Dyke et al. 1970; Jongerius and Jongeneelen 1991; Dow Chemical Co. 1992; 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) lowest observed effect Level (LOEL) (rat) = 7.24 mg/kg-bw per day: decreased body weight gain (6-week study) (Broadmeadow 1988) [Additional studies: Dow Chemical Co. 1940,; Spencer et al. 1948; Quinto et al. 1989; Dow Chemical Co. 1992; 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 no-observed-effect concentration (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 incidence 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.b 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, 1991b) 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, 1991b, 1991d; 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) |
- LC50 = the concentration estimated to be lethal to 50% of the organisms; LD50 = the dose estimated to be lethal to 50% of the organisms; LOEC = lowest-observed-effect concentration; LOEL = lowest-observed-effect level; NOEC = no-observed-effect concentration.
- It was indicated in the IPCS (2000) review that studies by Nehéz et al. involved testing of a commercial product (Krezonit E) that contains 50%DNOC; therefore, results of these assays may relate to other components in the product.
| Endpoint | Lowest effect levelsc/Results |
| 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 per day for 39 days (data presented for two subjects, total number examined unclear) (Dodds and Robertson 1933) [Additional study: Plotz 1936] |
- LC50 = the concentration estimated to be lethal to 50% of the organisms; LD50 = the dose estimated to be lethal to 50% of the organisms; LOEC = lowest-observed-effect concentration; LOEL = lowest-observed-effect level; NOEC = no-observed-effect concentration.
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