Reaction product of Propanoic acid, 3-[[bis(2-methylpropoxy)phosphinothioyl]thio]-2-methyl- and tridecanamine, N-tridecyl-, branched and linear

Endpoint summary

Description of key information

The substances causes adverse effects on mesenteric lymph nodes, ileum and liver upon subacute gavage dosing of rats (OECD 407, GLP).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

50 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The substance caused no mortality and no effects on body weight in the 14 -day dose-range finding study performed with four female Wistar rats per dose group (300 and 1000 mg/kg bw in corn oil) (BASF 2016). Increased absolute spleen weights (38% at 300 and 62% at 1000 mg/kg bw) and increased absolute liver weights (61% at high dose) were accompanied by histopathology findings (liver hypertrophy and hematopoiesis in spleen). No effects were observed for the weights of adrenal glands and kidneys. The target organs investigated in the range-finding study were chosen from the known hazard profile of the cationic part of the molecule.

Based on the findings of the dose-range-finding study, the doses of 40, 150 and 450 mg/kg bw were chosen for the main study (OECD 407, GLP).

With regard to clinical examinations, signs of general systemic toxicity were not observed even at a dose level of 450 mg/kg bw/d.

Nearly all animals of test group 3 (450 mg/kg bw/d) ploughed nose-first into bedding after treatment on several days of the study. In addition, all animals in both sexes of test group 3 (450 mg/kg bw/d) showed slight to moderate salivation directly after treatment on several days of the study. This was also observed in animals of test group 2 (150 mg/kg bw/d). From the temporary, short appearance immediately after dosing (or shortly before) it was concluded that both kind of findings were induced by a bad taste of the test substance or local affection of the upper digestive tract. These effects were related to the test substance but assessed as being non-adverse as no treatment-related lesions in the upper digestive tract were observed during pathological examinations.

Regarding clinical pathology, in rats of both sexes of test groups 2 and 3 (150 and 450 mg/kg bw/d) increased neutrophil cell counts indicated an acute inflammatory process. Additionally, in male and female rats of test group 3, total white blood cell (WBC) counts and monocyte counts were increased whereas relative lymphocyte counts were decreased. The increase of monocyte counts confirmed the inflammatory process because these cells act as macrophages.

Additionally, at least in females higher alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities indicated a slight affection of liver cells leading to a leakage enzyme molecules out of the cells.

Regarding pathology, bone marrow (femur and sternum), liver, ileum and mesenteric lymph nodes were target organs.

The increase in liver weight in males and females of test group 3 (450 mg/kg bw/day) was regarded to be treatment-related. Although no histopathologic correlate was seen (the granuloma observed were not regarded to have caused this weight increase), in combination with the altered liver parameters in clinical pathology this finding was regarded to be adverse for female animals of this test group. In males, there was no change in liver parameters in clinical pathology. Therefore, the weight increase was regarded to be treatment-related but not adverse.

The granuloma/granulomatous inflammation observed in several organs (mesenteric lymph nodes, ileum, liver) were regarded to be treatment-related. The most likely way of origin of these findings is the uptake of the test-substance probably mainly in the gastrointestinal tract. It is phagocytosed by macrophages that are either overloaded by the test-substance or are not able to digest it. This leads to a chronic, granulomatous inflammation with foreign body character (represented by the multinuclear giant cells) or single granuloma. This was regarded to be an adverse finding.

The hyperplasia of the bone marrow (femur and sternum) as well as the extramedullary hematopoiesis in the spleen, which leads to an increase of white blood cells, was seen as a secondary reaction to the inflammatory process. It was therefore also regarded to be treatment-related and adverse.

All other findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.

The administration of the test substance by gavage to male and female Wistar rats for 4 weeks caused test substance-related, adverse findings at a dose level of 50 mg/kg bw/d and above taking histopathological findings into account. Therefore, under the conditions of the present study the no observed adverse effect level (NOAEL) was below 50 mg/kg bw/d in male and female Wistar rats.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. There were significant toxic effects at doses of less than 300 mg/kg bw upon subacute oral exposure in rats. These consisted of granulomatous inflammation of mesenteric lymph nodes, ileum and liver in combination with changes in clinical chemistry and white blood cell parameters. As a result the substance is considered to be classified for repeated dose toxicity in Category 2 under Regulation (EC) No. 1272/2008.