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Description of key information

oral
1 generation study rat: NOAEL > 1000mg/kg bw /day (NOEL < 100mg/kg bw /day) (GLP, OECD 415, BASF 1996)
28-day rat: NOAEL >1000mg/kg bw /day (no treatment associated effects) (GLP, OECD 407, BASF 1991)

Key value for chemical safety assessment

Additional information

Two appropriate GLP guideline studies are available for the assessment of repeated dose toxicity of Keroflux ES 3241.

In a GLP compliant 28 -day study according to OECD 407 with some deviations five Wistar rats per sex per dose received 21 applications with 0, 15, 150 or 1000 mg/kg bw/d of the test substance in olive oil (BASF AG, 1991).

Food consumption and body weight were determined weekly. The state of health was checked each day and once a week the animals were inspected and palpated. The animals were checked for the appearance of clinical signs before and after each test substance administration. At the end of the study, a clinicochemical and hematological examination was carried out. All animals were assessed by gross pathology, followed by a histopathological examination.

No treatment-related changes were found in any dose group. The hematological and clinicochemical examinations of the treated animals revealed no findings which are due to the test substance administered. There were no changes in the absolute and relative organ weights of either male or female animals that showed statistical significance. At necropsy only a few incidental gross lesions in individual animals were noted but this was not associated with any histopathological changes and was considered to be of no toxicological significance. There were no changes in the other parameters measured that could be considered attributable to toxic effects of the test material. Therefore the "no adverse effect level" (NOAEL) is considered to be >= 1000 mg/kg bw/d (BASF AG, 1991).

 

In a GLP compliant one-generation study according to OECD 415, Keroflux ES 3241 was administered by gavage to groups of 25 male and 25 female sexually immature Wistar rats (F0 parental generation) at dosages of 100, 300 or 1000 mg/kg bw/d continuously throughout the whole study period. The test substance was administered to the F0 animals daily for 19 weeks (BASF AG, 1996).

Food consumption of the F0 parents was determined regularly during premating (once weekly), and additionally during gestation and lactation periods. In general, body weights of F0 parents were determined once weekly. However, during gestation and lactation F0 females were weighed on days 0, 7, 14 and 20 of gestation, on the day of parturition, and on days 1, 4, 7, 14 and 21 after birth. Blood and urine samples were taken from 10 F0 animals per sex of each test group towards the end of the study period for clinical pathology examinations. All F0 parental animals were assessed by gross pathology (including weight determinations of several organs) and subjected to an extensive histopathological examination, special attention being paid to the organs of the reproductive system.

Treatment-related effects were observed in the parental (F0) rats and consisted in proliferation of histiocytic cell elements in the marginal and intermdiate sinus in the mesenteric lymph node, forming granulomatous clusters and borad stands of phagocytes. Phagocytes involved in granulomatosis have incorporated in their cytoplasm a vesicluar material that resembles morphologically a lipoid material. This effect was observed in all three treatment groups (male and female). Central necroses was detected in some of of the granulimas. In the liver of the animals from the high-dose group an increased number of focal lympoid cell infiltrates (Kupffer cell granulomas) was observed in males and females (BASF AG, 1996).

Effects observed in rats after repeated oral application of Keroflux ES 3241 to rats match effects named "microgranuloma" and "sinus histiocytes" observed recenty after subchronic anc chronic oral application of minerals of mineral hydrocarbons according to a recently published assessment of a Panel of medical and veterinary pathologists [Carlton WW, Boitnott JK, Dungworth DL, Ernst H, Hayashi Y, Mohr U, Parodi AL, Pattengale PK, Rittinghausen S, Ward JM (2001). Assessment of the morphology and significance of the lymph nodal and hepatic lesions produced in rats by the feeding of certain mineral oils and waxes. Exp. Toxic Pathol; 53: 247 - 255]. The Panel agreed on the following:

Slight reversibility existed for these lesions, however, complete resolution was unlikely as regression of the lesions in the rat would be slow.

Lesions observed in mesenteric lymph nodes and liver of F344 rats exposed to mineral hydrocarbons were different morphologically from changes observed in lymph node, liver of humans that were mineral oil users.

Granulomatous lesions produced in rats are strain specific and depend on strain specific toxicokinetics of the hydrocarbon applied.

Lesions induced by mineraly hydrocarbons, i.e. microgranuloma and sinus histiocytes, are unlike the changes described for mineral hydroxarbon accumulation in human tissue (such as hepatic and associated lymph node) and can be considered inconsequential in humans.

Accumulation of mineral hydrocarbons in humans occur in a high percentage (if not 100%) of human induviduals, do not progress over years and are not associated with any clinicopathologic or clinical abnormalities (CHarlton et al., 2001).

Taking into account the assessment of the Expert Panel on microgranulomas and sinus histiocytes in mesenteric lymph nodes and the liver the effects in the mesenteric lymph nodes and liver in rats exposed orally to Keroflux ES 3241 for 19 weeks are considered not adverse.

Consequently, the NOAEL is considered to be >= 1000 mg/kg bw/d.

Justification for classification or non-classification

Based on the results of the available subacute study, there is no indication given for classification.