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Description of key information

The test substance, Tar, brown-coal, low-temp., was tested for subchronic toxicity using the  Method B.26 Sub-Chronic Oral Toxicity Test: Repeated Dose 90-day Oral Toxicity Study in Rodents, Council Regulation (EC) No. 440/2008, Published in O.J. L142, 2008. 
The values (NOAEL and LOAEL) were established mainly on the basis of changes in red blood cell component, biochemical parameters related to kidney function and histopathology and function of the liver.
No other studies on repeated dose toxicity (dermal or inhalation) of the substance are available.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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

Additional information

Wistar rats of SPF quality were used for testing. The test substance was administered in olive oil by stomach tube; oral application of rats was made daily. The study includes four main groups and two satellite groups of animals. Each main group consisted of 10 males and 10 females; each satellite group consisted of 6 males and 6 females.Main groups contained 3 treated groups (doses 50, 200, 800 mg/kg of body weight /day) and one control group (vehicle only). The satellite groups contained one control group (vehicle only) and one treated group (800 mg/kg/day).

No mortality occurred after test substance treatment. Ophthalmoscopic examination revealed no changes in treated groups of animals. The test substance had negative effect on growth increments in both sexes. It was connected with damage of liver metabolism and it was confirmed by the histopathological examination of liver – damage to liver cells. These irreversible changes were recorded at all treated groups of males and in females at the middle and highest dose levels. Weight of liver was dose-dependently increased in both sexes. Biochemical examination also showed significant damage of liver at the middle and highest dose level: increased values of cholesterol, total protein (inc. albumin) and changed activity of liver enzymes. Observed anaemia may be secondary to liver damage. Parameters of blood coagulation were statistically significantly altered in males at the middle and highest dose level and all dose levels of females. These changes were not fully reversible. Biochemical examination revealed negative irreversible influence of the test substance treatment also on kidneys - increased value of creatinine in both sexes, disbalance in ions (sodium, chloride) and minerals (phosphorus and calcium) were measured in both sexes, markedly it occurred at the middle and highest dose levels. The weight of kidneys was significantly irreversibly increased in both sexes at the highest dose level. Urinalysis revealed changes with toxicological importance. Treatment related histopathological findings in kidneys were recorded only in females at the highest dose level – initial glomerulonephrosis and presence of hyaline casts. Significantly increased concentration of glucose in blood is related probably to total stress of organism. The macroscopic findings in genital organs together with decreased organ weights showed negative irreversible atrophic effect of the test substance treatment in both sexes at the highest dose level. Atrophic changes caused an inhibition of oestral cycle in females. Thyroid gland of part of males at the middle and highest dose levels and females at the highest showed highest frequency of retracted colloid in follicles which was more basophilic in comparison to control animals. The cause of this finding is not clear but its relation to the test substance treatment is probable. In females presence of cysts in thyroid gland was recorded only at the middle and highest dose level and in recovery females and this affection was accompanied by the test substance treatment. Hematopoietic and lymphatic organs showed changes with toxicological significance. Abdominal lymph nodes were haemorrhagic with accompanied erythrocytosis and presence of hemosiderin, thymus was reduced and atrophied. Increased presence of rubiginous pigment (probably haemosiderin) in red pulp of spleen of females at the highest dose level was recorded together with increased extramedullary haematopoiesis. Well-differentiated squamous cell carcinoma was revealed in the lungs of one male from the high dose group. This tumor is reported in rats and its relation to the test substance administered could not be unambiguously excluded.

The value of LOAEL (Lowest Observed Adverse Effect Level) was established as 50 mg/kg/day. The value of NOAEL (No Observed Adverse Effect Level) is lower than 50 mg/kg/day. The values were established mainly on the basis of changes in red blood cell component, biochemical parameters related to kidney function and histopathology and function of the liver. The effects of test substance to the liver were of major significance.


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

Justification for classification or non-classification

According to the Regulation (EC) No.1272/2008 the data from the study „Tar, brown-coal, low-temp. - Repeated Dose 90-day Oral Toxicity Study“ (Study No. 73/10/8, VUOS Report No.11-308, 2011) are of acceptable quality for classification for STOT RE (Specific Target Organ Toxicity – Repeated Exposure).

The determined value of NOAEL (<50 mg/kg body weight/day) was used for comparison with classification criteria.

In accordance with guidance values for STOT RE (Regulation (EC) No 1272/2008 the value (dose/concentration) for STOT RE Category 1 by oral route is C ≤ 10 mg/kg body weight/day, the range (dose/concentration) for STOT RE Category 2 by oral route is 10 < C ≤ 100 mg/kg body weight/day for oral route exposure.

The test substance, Tar, brown-coal, low-temp, meets criteria for classification for specific target organ toxicity-repeated exposure category 2 - STOT RE 2; H373 May cause damage to liver and kidneys through prolonged or repeated exposure (Xn; R48/22Harmful: danger of serious damage to health by prolonged exposure if swallowed -according to DSD criteria).