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Description of key information

Data is based on read across from a structurally similar branched triamine C12. A NOAEL of 7 mg/kg bw/day was established in a 90-day repeated dose toxicity study with rats, based on tubular nephropathy in the kidney and the appearance of foamy macrophages in mesenteric lymph nodes at the next dose level. In a 90-day study with dogs, a NOAEL of 20 mg/kg bw/day was established, based on decreased body weight, increased absolute and relative gall bladder weight and increased potassium and ALAT and ASAT activities in plasma. In a combined chronic repeated dose toxicity/carcinogenicity diet study with rats a NOAEL of 4 mg/kg bw/day was established, based on increased ASAT activity, increase of lymphohistiocytic inflammatory reactions in the kidney, skeletal muscle and heart, and foamy macrophages in the mesenteric lymph nodes and alveoli of the lungs at the next dose level.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
4 mg/kg bw/day
Study duration:
chronic
Species:
rat

Additional information

Data is based on read across from astructurally similar branched triamine C12.Branched triamine C16-18 only differs in the length of the alkyl chain, which issuspected to influence bioavailability, but not chemical reactivity and route of metabolisation, aspects that influence specific mechanisms of toxicity. For these reasons, many of the studies can best be performed on the substance with the shortest chain length within a group of structurally similar substances, as this is considered to result to the lowest NOAEL or most likely able to show specific effects..

Oral: The 90-day feeding study in rats, performed in accordance with EU Method B.26 and under GLP (CIT, 2003) resulted in a NOAEL of 100 ppm of the test substance in diet, which corresponded to ca. 7 mg/kg bw/day ingested substance (7 mg/kg bw/day for male and 8 mg/kg bw/day for female rats). Groups of 10 male and 10 female rats received 0, 100, 300 and 900 ppm of the test substance in diet for 90 days (corresponding to actual ingested doses of 7, 20 and 57 mg/kg bw/day for males and 8, 22 and 65 mg/kg bw/day for females). Animals were observed for clinical signs of toxicity, body weight changes and food consumption. In addition functional battery observations and haematological, clinical chemistry and

ophthalmological examinations were performed. All animals were sacrificed and subjected to gross necropsy and histopathological examinations.

The critical effects were tubular nephropathy of the kidney, associated with increased relative kidney weight, and the appearance of foamy macrophages in the mesenteric lymph nodes.

The 90-day dog study (LPT Laboratory of Pharmacology and Toxicology KG, 2004), in which animals received the test substance at dose levels of 0, 200, 500 and 1500 ppm in diet (corresponding to actual ingested doses of 0, 8.0, 20.0 and 55.1 (males) and 52.6 (females) mg/kg bw/day , resulted in a NOAEL of 500 ppm (20 mg/kg bw/day of ingested substance) in both males and females. At this dose level increased plasma ALAT and ASAT activities were noted; however, in the absence of pathological changes or signs of systemic toxicity they were considered to be non-adverse. At the next higher level of 1000 ppm (corresponding to 55.1 mg/kg bw/day and 52.6 mg/kg bw/day for female dogs) reduction in food consumption with a decrease in body weight was observed, as well as increased absolute and relative weight of the gall bladder, increased potassium and increased ALAT and ASAT activity in plasma.

Results from the rat and dog studies indicate species differences. In the rat study effects on the kidney were clearly present, while such effects were not observed in dogs. This is possibly related to higher metabolic rate in smaller animals, leading to higher uptake and renal excretion rates, and a subsequent higher concentration of the substance in the renal tubuli.

A combined chronic/carcinogenicity study in rats by dietary administration is currently running (LPT Laboratory of Pharmacology and Toxicology KG, 2008-2009). The chronic 1-year toxicity results from this study indicate a NOAEL of 4 mg/kg bw/day, reached from dosing mostly at a dietary concentration of 100 ppm. Based on dietary concentrations, the NOAEL from the chronic study is comparable to the NOAEL of the 90-day study. The next highest level in this study is spaced a factor 2 higher at 8 mg/kg bw/day and represents the LOAEL, at which signs of toxicity were a higher ASAT activity, increase of lymphohistiocytic inflammatory reactions in the kidney, skeletal muscle and heart, and foamy macrophages in the mesenteric lymph nodes and alveoli of the lungs. Additionally, an enlarged pituitary gland was observed in a few females without a histopathological correlate.

Dermal: In accordance with Column 2 of REACH Annex VIII, a repeated dose toxicity study using the most appropriate route of administration with regard to possible human exposure needs to be conducted. Data on repeated dose toxicity by oral route are available. As the substance is corrosive, and its dermal uptake is low (< 1% in 24 hr), dermal exposure is considered to be not relevant and the performance of a dermal repeated dose toxicity study is not indicated.

Inhalation: In accordance with Column 2 of REACH Annex VIII, a repeated dose toxicity study using the most appropriate route of administration with regard to possible human exposure needs to be conducted. Data on repeated dose toxicity by oral route are available. As the substance is not volatile (at 25 ºC vapour pressure is 0.00014 Pa), the inhalation route of exposure is considered not likely and the conductance of an inhalation repeated dose toxicity study is not indicated.

Justification for classification or non-classification

Data is based on read across from astructurally similar branched triamine C12 which is considered to be predictive, and even worst case for Branched triamine C16-18.

Based on the results of the 90 -day oral repeated dose toxicity studies with rats showing kidney pathology (Tubular nephropathy of the kidneys) at levels between 10 - 100 mg/kg bw/d (21 mg/kg bw), the substance needs to be classified as R48/22: danger of serious damage to health by prolonged exposure according to EU Directive 67/548/EEC. According to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 the substance needs to be classified as Category 2, STOT, H373.

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