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Description of key information

- Repeated dose toxicity, oral: LOAEL = 8 mg/Kg bw for the rat, (OECD 408); study Hazelton (1983)
- Repeated dose toxicity, dermal: no study available
- Repeated dose toxicity, inhalation: NOAEC = 6 mg/m³ (= 1.0 ppm) for the rat, (OECD TG 413); study Monsanto (1983)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEL
8 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
6 mg/m³
Study duration:
subchronic
Species:
rat

Additional information

- Repeated dose toxicity, oral: The LOAEL(rat subchronic) of 8 mg/Kg bw/day is based on the findings in Hazleton (1983) / key (120d study on F344 rats) where increased liver weights were found down to 8 mg/kg/day in males, which is the lowest concentration tested, and at 16 mg/kg/d in females. Liver and kidneys were identified as main target organs reflected by multifocal necrosis, necrosis of individual hepatocytes, the presence of sinusoidal pigment and bile duct chronic inflammation and hyperplasia (liver) and tubular regenerative hyperplasia and hyperbasophilia and megalocytosis (kidneys) at doses of 125 mg/Kg and higher (lower doses not analysed histologically). The histopathologic findings are mirrored by significant effects in clinical chemistry parameters indicative for liver and kidney lesions starting at 16 and 32 mg/Kg respectively.

In contrast to these findings Merrick (1991) / (Sprague Dawley rat, 90 d repeated dose study, gavage, OECD 408) reports cardiopathic effects of 1,2,3-trichloropropene in the rat down to a concentration of 1.47 mg/Kg bw/d but this lesion shows a very uncommon dose response correlation. In addition the complete absence of cardiac effects in a 120 d gavage study (see above), in all subchronic inhalation studies (see chapter 7.5.3) and even in a 2 year chronic gavage study at comparable dose levels (see chapter 7.7: National Toxicology Program (1993) / Rat and Mouse (3 - 30 and 6 - 60 mg/Kg bw/d, respectively)) renders the correlation between the cardiopathic effects and the 1,2,3 -trichloropropane exposition questionable. Beside this unclear finding the study also showed liver effects (raised ALT and AST levels at 117.94 mg/Kg bw in female rats only; raised values in males were compromised by very high ALT and AST levels in male controls, mirrored by uncommon histopathological findings in this control group). Villeneuve (1985) / (rat, repeated dose toxicity, subchronic, 90 d feeding study) is only available as short summary, lacking histopatholigical data but marking also the liver and the kidneys as primary target organs for repeated dose toxicity of 1,2,3-trichloropropane.

So it can be summarized that liver and kidneys are main target organs of subchronic repeated dose toxicity of 1,2,3-trichloropropane with effects down to 8 mg/Kg bw/day in the rat. The cardiopathic findings of (1991) are disregarded. As the noted effects at 8 mg/Kg bw/day are only liver weight changes and as significant changes in clinical chemical parameters are seen only at 16 mg/Kg (and higher) 1,2,3-trichloropropane should be classified as STOT RE2 concerning oral repeated dose toxicity.

As 1,2,3-trichlororpropane will be classified as genotoxic carcinogen and therefore a strict DMEL will be derived, the corresponding risk management measures will surely be sufficient to cover the risk that stems from the oral toxicity of 1,2,3-trichloropropane after repeated exposure for both workers and general public.

 

- Repeated dose toxicity, dermal: No study on dermal toxicity of 1,2,3 -trichloropropane after repeated dermal exposure could be retrieved. Given the low quotient of acute oral to acute dermal toxicity a high bioavailability via the dermal route should be expected, that is nevertheless somewhat lower than via the oral route. As the distribution of 1,2,3-trichloropropane is swift comparable systemic effects as seen in oral repeated dose studies are to be expected also for the dermal route of exposure but a somewhat higher doses. Given the results from skin irritation, very likely no local effects are to be expected at doses that would inflict systemic effects. Therefore 1,2,3-trichloropropane should be classified as STOT RE2 concerning dermal repeated dose toxicity.

As 1,2,3-trichlororpropane will be classified as genotoxic carcinogen and therefore a strict DMEL will be derived, the corresponding risk management measures will surely be sufficient to cover the risk that stems from the dermal toxicity of 1,2,3-trichloropropane after repeated exposure for both workers and general public.

 

- Repeated dose toxicity, inhalation: The NOAEC of 6 mg/m³ (1.0 ppm) is based on the absence of treatment related effects on the nasal tissues in rats as described in DOW HET-K-002524-006 / (F344 rat and B6C3F1 mouse, 14d repeated dose inhalation toxicity lower doses). Histopathologic examinations of the nasal tissues revealed very slight exposure-related changes in the olfactory epithelium of rats in the 3 ppm and 10 ppm groups, as well as in mice in the 10 ppm group. Similar effects on the olfactory epithelium had previously been found in rats and mice exposed to 13 ppm TCP vapors in a previous study; more pronounced effects on nasal tissues occurred in animals exposed t o 40 or 132 ppm (DOW HET-K-002524-004 / (F344 rat and B6C3F1 mouse, 14d repeated dose inhalation toxicity, higher doses)). In the latter study liver weight effects were seen at 780 mg/m³ (132 ppm) in rats. A comparable NOAEC of 9 mg/m³ (1.5 ppm) that is nevertheless based on liver effects can be deduced from Monsanto (1983) / key (Sprague-Dawley rats, 13 wks repeated dose inhalation study) in combination with Rusch (1979) / key (Sprague-Dawley rats, 13 wks repeated dose inhalation study). Both studies have been carried out with the same strain under comparable exposure conditions. In the former study no adverse effects were seen at the high dose of 9 mg/m³ while in the latter liver weights at 5 ppm and corresponding histologic findings were seen in: Histopathological examinations revealed treatment related findings in the liver and lungs of all treated males and lungs and spleen of all treated females. They consisted of mild centrilobular to midzonal hepatocellular hypertrophy (liver), mild to marked peribronchial lymphoid hyperplasia (lung), and mild to marked extramedullary hematopoiesis and the severity of all this effects was raised dose dependently.

So it can be summarized that nasal tissues, liver and kidneys are main target organs of subchronic repeated dose toxicity of 1,2,3-trichloropropane after inhalation with effects 1.0 ppm in the rat. only liver weight changes and as significant changes in clinical chemical parameters are seen only at 16 mg/Kg (and higher) 1,2,3-trichloropropane should be classified as STOT RE1 concerning repeated dose inhalation toxicity.

As 1,2,3-trichlororpropane will be classified as genotoxic carcinogen and therefore a strict DMEL will be derived, the corresponding risk management measures will surely be sufficient to cover the risk that stems from the inhalation toxicity of 1,2,3-trichloropropane after repeated exposure for both workers and general public.


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

Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: liver; respiratory: nose; urogenital: kidneys

Justification for classification or non-classification

Based on the above stated results on oral and dermal repeated dose toxicity 1,2,3-trichloropropane should be classified as STOT RE2 (H373: May cause damage to liver and kidneys through prolonged or repeated exposure via the oral or the dermal route) concerning oral or dermal exposure. Based on the above stated results on repeated dose inhalation toxicity 1,2,3-trichloropropane should be classified as STOT RE1 (H372: Causes damage to nasal tissues, liver and kidneys) through prolonged or repeated exposure via inhalation) concerning repeated inhalative exposure.