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Administrative data

Description of key information

The subchronic NOEL in rat was 250 mg/kg/day and in mice, 500 mg/kg/day (NTP, 1986, KSs) Overall, results from repeat dose studies indicate that the liver is a target organ in rodents with a chronic oral NOAEL of 62-125 mg/kg/d in rats and a chronic LOAEL of 125 mg/kg/d in mice (no NOAEL established). There were no adverse systemic organ effects in rats and mice following subchronic exposure to 150 ppm DCP (NOAEL), whereas red blood cell parameters (regenerative anemia) were altered in rabbits with a LOAEL of 150 ppm in males and a NOAEL of 150 ppm in females. Body weight was slightly, but statistically significantly decreased in rats only (NOAEL 15 ppm) in one sub-chronic inhalation study, with site-of-contact (irritative) changes present in stomach (mouse, NOAEL/LOAEL 125 mg/kg/d after oral gavage, dependent on sex) and nasal tissue (rat, NOAEL 15 ppm after inhalation; rabbits, NOAEL 500 ppm).

Key value for chemical safety assessment

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

Oral:

The oral repeat dose toxicity of DPC has been investigated extensively by NTP (1986) in a series of GLP-compliant studies using male and female F344 rats and B6C3F1 mice. The results indicate that the liver is a target organ after gavage administration, with a chronic NOAEL of 125 mg/kg bw/day in female rats (males unaffected) and a chronic LOAEL of 125 mg/kg bw/day in male mice (females unaffected). Acanthosis of the stomach (indicative of persistent local irritation) was noted in mice (rats unaffected) with a chronic NOEL of 125 mg/kg bw/day in males and a chronic LOEL of 125 mg/kg bw/day in females. Body weight was decreased 14-24% in rats (chronic NOEL (males) = 62 mg/kg bw/day, chronic NOEL (females) = 125 mg/kg bw/day) whereas mice were unaffected (chronic NOEL = 250 mg/kg bw/day, both sexes). The overall NOAEL values following chronic administration of DPC were 62 and 125 mg/kg bw/day for male and female rats respectively. No chronic NOAEL was derived for mice of either sex; the LOAEL was 125 m/kg bw/day.

Inhalation:

The effects of repeated (13 week) inhalation exposure to DCP were investigated in rats, mice, and rabbits (Dow, 1988). These GLP key studies evaluated macroscopic and microscopic effects following repeated exposures to 15, 50, and 150 ppm for rats and mice and 150, 500, and 1000 ppm in rabbits. Nasal respiratory changes, considered site-of-contact effects, were identified in rats and slight reductions in body weight were also reported (NOEL of 15 ppm for both). No effects were identified in mice (NOEL of 150 ppm). Results from rabbits demonstrated slight changes in red blood cell parameters, which were indicative of a macrocytic normochromic, regenerative anemia (LOEL of 150 ppm for males; NOEL of 150 ppm for females), and site-of-contact effects in nasal tissue (NOAEL of 500 ppm).

In rat JBRC subchronic inhalation study (Umeda et al., 2010, SS), DPC induced inflammation, hyperplasia of the respiratory epithelium, and atrophy of the olfactory epithelium at 125 ppm, the lowest dose (study LOAEC for males and females, all animals per group affected) and above. Inflammation of the respiratory epithelium significantly increased in the male rats exposed to 1000 and 2000 ppm. At the higher exposures, haemolytic anaemia and lesions of liver and adrenal gland in females were observed. In a mouse JBRC subchronic inhalation study (Matsumoto et al., 2013, SS), no NOAEC was also established. Respiratory metaplasia, atrophy and necrosis of the olfactory epithelium occurred in both sexes exposed to ≥300 ppm DPC. Anaemia was seen in all DPC-treated male mice, and in ≥300 ppm treated females. Liver and spleen effects as well as other significant toxicity were reported in both sexes.


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: nose

Justification for classification or non-classification

DPC can result in some tissue effects upon repeated administration via oral (liver) or inhalation (nasal cavity, body weight) routes.

The 90-day NOEL for oral toxicity in mice is 500 mg/kg bw/day and in rat, 250 mg/kg/day (NTP, 1986; KSs), which is above the cut-off value of 100 mg/kg bw/day established for a 90-day study). Thus, classification is not warranted according to Directive 67/548/EEC, EU CLP (Regulation (EC) No. 1272/2008) and UN GHS. 

The 90-day inhalation NOAEL for rats was 15 ppm, based on local effects (minimal nasal hyperplasia response) at 50 ppm; the 90-day inhalation NOEL in mouse was 150 ppm, the highest dose tested. Despite the rodent NOAEL values falling below the cut-off limit of 250 ppm established for classification as harmful by EU Directive 67/548/EEC and UN GHS, the classification is considered to be not warranted, as the effects are not considered to reflect major functional changes in any organ system or severe organ damage. Furthermore, based on the fact that no effects were identified in mouse, and the understanding that typically such mild nasal hyperplasia effects are considered adaptive and reversible, the site-of-contact effects are not considered to present a risk of serious damage to health. Thus, classification for repeated dose inhalation toxicity is not warranted in accordance with Directive 67/548/EEC, EU CLP (Regulation (EC) No. 1272/2008), and UN GHS.