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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
27 mg/kg bw/day
Additional information

Data is based on read across from a structurally similar branched triamine C12. Branched triamine C16-18 only differs in the length of the alkyl chain, which is suspected 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.

An oral two-generation reproductive toxicity study with rats, performed in accordance with OECD Guideline 416 (version of 1983) and under GLP is available (Inveresk Research International, 1995). Parental animals received the test substance (as 30.2% aqueous solution) by gavage at dose levels of 0, 10, 30 and 90 mg/kg bw/day (corresponding to 0, 3, 9 and 27 mg/kg bw/day pure substance) 10 weeks prior to mating until weaning of the F1 generation. The treatment of F1 animals commenced from Day 25 after birth and continued to weaning of the F2 generation. The F1 animals were mated 11 weeks after weaning.

At the high dose level most animals of both generations showed signs of reaction to treatment, consisting of dyspnea, piloerection and hunched posture, and many animals also had episodes of post-dosing salivation. For occasional animals, the outline of the spine was prominent. A total of 8 animals died or were killed after showing marked signs of reaction, and a 9th death may also have been related to treatment. In both generations, at the highest dose level, mean weight gain was markedly lower than controls; this effect was apparent for males, and for females in the premating period and during gestation. Food consumption at the high dose level in both generations was slightly lower than in controls. Mating performance, fertility, duration of gestation, litter size and pup survival were considered to be similar in all groups.

Mean seminal vesicle weights in the high dose groups of both generations were significantly lower than controls, however, it was considered that this reduction was an indirect effect of the lower body weights, rather than a direct effect on the seminal vesicles. Mean absolute epidymides and testes weights in the same groups were lower than control, with the value for epidymides for F0 animals and the value for testis for F1 animals attaining statistical significance. However, after adjustment for bodyweight (covariance analysis) these effects were not apparent. Mean prostate weights were essentially similar in all groups of both generations.

In the F2 generation, slightly reduced pup and litter weights and observed clinical signs (2 pups with body tremors) were observed at 27 mg/kg bw/day.

In the current version of the OECD 416 guideline, histopathology of the pups is part of the standard procedure. This study was performed in accordance with the 1983 version of the guideline in which these investigations were not required. However in the subchronic 90-day study in rats histopathological examinations were performed. The lack of effects on reproduction in the 2-generation study along with the supporting data from the 90-day study confidently allows the conclusion that the substance is not a selective reproductive toxicant. The NOAEL for systemic toxicity was set at 9 mg/kg bw/day, while the NOAEL for reproductive toxicity was considered to exceed 27 mg/kg bw/day.


Short description of key information:
Data is based on read across from a structurally similar branched triamine C12. Based on the results of a two-generation oral reproductive toxicity study with rats, branched triamine C12 does not cause adverse effects on fertility. Based on clinical sings of systemic toxicity, combined with decreased food consumption and decreased body weight in high dose animals of the P and F1 generation, a NOAEL for systemic toxicity was set at 9 mg/kg bw/day. As no adverse effects on fertility and reproductive performance were noted at the highest test dose, a NOAEL for reproductive toxicity was set at 27 mg/kg bw/day.

Effects on developmental toxicity

Description of key information
Data is based on read across from a structurally similar branched triamine C12. Based on the results of two developmental toxicity studies with rats and rabbits branched triamine C12 is not a developmental toxicant. The NOAELs for maternal toxicity were set to 7.5 mg/kg bw/day for rats and 9 mg/kg bw/day for rabbits. In rats, an increased incidence of early embryonic deaths and a slightly lower mean foetal weight were observed at the highest dose level of 60 mg/kg bw/day, resulting in a NOAEL for embryotoxicity of 22.5 mg/kg bw/day. In the rabbit study, a marginal increased incidence of resorptions suggesting early embryonic deaths was observed in the high dose group, resulting in a NOAEL for embryotoxicity of 9 mg/kg bw/day. In both cases the observed effects were however considered to be secondary to maternal toxicity.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
22.5 mg/kg bw/day
Additional information

Two developmental toxicity studies based on branched triamine C12 were available for assessment, one with rats (Inveresk Research International, 1994) and one with rabbits (LPT Laboratory of Pharmacology and Toxicology KG, 2005), both performed in accordance with OECD Guideline 414 and under GLP.

In the rat study, groups of 25 female rats were administered the substance (in a form of 30.2% aqueous solution) at dose levels of 0, 25, 75, 200 mg/kg bw/day (corresponding to 0, 7.5, 22.5 and 60 mg/kg bw/day pure substance) by gavage on gestation days 6 -16. Animals were sacrificed on gestation day 20 and assessed for the number of implantation sites, number of corpora lutea, early and late resorptions and gravid uterus weight. Foetuses were counted, sexed, weighed and analysed for external and internal (soft tissue and skeletal) abnormalities. The maternal animals in the rat study showed decreased food consumption and body weight gain at the medium and highest dose level. The NOAEL for maternal effects was set at 7.5 mg/kg bw/day. At the highest dose level an increase in incidence of early embryonic deaths and slightly decreased mean foetal weight was observed, which was considered to be secondary to maternal toxicity. No further developmental toxicity was observed and the NOAEL for teratogenicity/embryotoxicity was set at 22.5 mg/kg bw/day based on secondary effects due to maternal toxicity observed in the foetuses.

In the rabbit study, groups of 20 pregnant females received the substance by gavage at dose levels of 0, 6, 9 and 20 mg/kg bw/day during days 6 -28 of gestation. Animals were sacrificed on gestation day 29. Maternal toxicity was indicated at 20 mg/kg bw/day by the death of two dams and by marginally reduced body weight and food intake during the last days of pregnancy. Necropsy revealed an irritation of the gastrointestinal tract in 5 dams and an increased incidence of resorptions. No substance-related influence was detected on the prenatal foetal development. The incidences of foetal malformations, variations and retardations were similar in all groups. Under the conditions of the study no teratogenic effects (as indicated by the incidences of foetal malformations, variations and retardations) were found up to 20 mg/kg bw/day of the test substance. At 20 mg/kg bw/day there was a marginal increased incidence of resorptions suggesting early embryonic deaths secondary to maternal toxicity. Based on these results the NOAELs for both maternal and embryotoxicity were set to 9 mg/kg bw/day. Under the conditions of this study no teratogenic effects were found related to treatment with the test substance.

Justification for classification or non-classification

Based on the results of the reproduction and developmental toxicity studies with branched triamine C12, there is no need for classification for reproduction/developmental toxicity according to EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Additional information

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