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Effects on fertility

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

In a two generation study (OECD TG 416, IBR, 1988) with integrated teratological investigation, dose levels of 10, 60, 120 mg/kg 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine were administered once daily by oral gavage to male and female rats. Following a 10-weeks pre-mating treatment period for male animals and a 2 -weeks treatment period for females, this generation of animals (F0) was mated to produce the F1 generation. After gestation, delivery of F1, and a 3-week lactation period, F0 females were mated for a second time. F0 -generation males were sacrificed after this second mating period and F0 -generation females were sacrificed for hysterectomy after 20 gestation days.

24 males and 24 femals of F1 generation were selected per dose-group to form the basis of next generation. Treatment was installed at the age of 4 weeks.

The results of the present study indicate that a daily oral treatment with 10 mg/kg of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine to rats over two generations did not adversely affect maternal or fetal litter development in any stage of the study. Thus a 10 mg/kg dose-level revealed a clear no-effect level (NOAEL) for 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine.

Dose levels of 60 mg/kg (group II) and 120 mg/kg (group III) led to dose-related maternal and paternal reduced increase of weight gains and reduced food consumption. Some mortalities (3 males and 4 females in parental F0- generation and 2 males and 3 females in the F1 -generation of the highest dose group) most likely are due to the test compound administration. At this high (slight toxic) dose level pregnancy rate was distinctly reduced among F0 -females (probably due to pre-implantation loss), which was found to be significantly increased among high dosed females in the teratology segment (120 mg/kg). Above all no adverse effect on litter development, e.g. malformations, behaviour dysfunctions or increased death rates were noticed in any phase of the study. Only liver-(and kidney) weights increased in both, F1- and F2- pups and F2 -pups showed a slight tendency towards decreased weight gains in the highest dose group.


Short description of key information:
The results of the two generation study (IBR, 1988) indicate that a daily oral treatment with 10 mg/kg of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamin to rats over two generations did not adversely affect maternal or fetal litter development in any stage of the study. Thus a 10 mg/kg dose-level revealed a clear no-effect level (NOAEL) for 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine.

Effects on developmental toxicity

Description of key information
Under the conditions of a oral two generation study with integrated teratological investigation with rats, 2,2,4(or  2,4,4)-trimethylhexane-1,6-diamine was not teratogenic up to the highest test concentration of 120 mg/kg bw. In a second oral teragonicity study, a daily exposition to a 0.05 %  2,2,4(or  2,4,4)-trimethylhexane-1,6-diamine concentration in drinking water did not exert signs of maternal toxicity and a 0.25 % concentration did not adversely affect fetal development of New Zealand White-rabbits.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
120 mg/kg bw/day
Additional information

In a two generation study with integrated teratological investigation, dose levels of 10, 60, 120 mg/kg 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine were administered once daily by oral gavage to male and female rats. Following a 10-weeks pre-mating treatment period for male animals and a 2 -weeks treatment period for females, this generation of animals (F0) was mated to produce the F1 generation. After gestation, delivery of F1, and a 3-week lactation period, F0 females were mated for a second time. F0 -generation males were sacrificed after this second mating period and F0 -generation females were sacrificed for hysterectomy after 20 gestation days. 24 males and 24 femals of F1 generation were selected per dose-group to form the basis of next generation. Treatment was installed at the age of 4 weeks.

The results of the present study indicate that a daily oral treatment with 10 mg/kg of 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine to rats over two generations did not adversely affect maternal in any stage of the study. Therefore, under the conditions of this oral teratogenicity study with rats, the NOAEL for maternal toxicity was determined to be 10 mg/kg bw.

Dose levels of 60 mg/kg (group II) and 120 mg/kg (group III) led to dose-related maternal and paternal reduced increase of weight gains and reduced food consumption. Some mortalities (3 males and 4 females in parental F0- generation and 2 males and 3 females in the F1 -generation of the highest dose group) most likely are due to the test compound administration. At this high (slight toxic) dose level pregnancy rate was distinctly reduced among F0 -females (probably due to pre-implantation loss), which was found to be significantly increased among high dosed females in the teratology segment (120 mg/kg). No external abnormalities were found in the fetuses from the dosed groups of the teratology study (1 small hematoma in a control fetus). One cystic dilated renal pelvis each in one low- (10 mg/kg bw) and one mid-dose (60 mg/kg bw) fetus was considered to be within the normal rate of spontaneously occurring anomalies. Skeletal examination revealed a comparable development stage for all test groups and variations (wavy ribs) at incidences often seen in this strain of rats.

Above all no adverse effect on litter development, e.g. malformations, behaviour dysfunctions or increased death rates were noticed in any phase of the study. Only liver-(and kidney) weights increased in both, F1- and F2- pups and F2 -pups showed a slight tendency towards decreased weight gains in the highest dose group.

Therefore, under the conditions of this oral two generation study with integrated teratological investigation with rats,

2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine was not teratogenic up to the highest test concentration of 120 mg/kg bw.

In a second oral teratogenicity study 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine was administered daily via drinking water to pregnant rabbits during the organogenetic phase of gestation (Day 6 - 18), concentrations of 0.01 %, 0.05 % and 0.25 % were used, a concurrent control group received tap water only.

The only sign of maternal response to treatment were reduced bodyweights and reduced water consumption in the high dose group. Maternal uterine and intrauterine parameters (e.g. number and weight of fetuses, number of resorptions, implantations, corpora lutea and weights of placentae or uteri) did not reveal significant differences between groups. The index of resorptions and thus the postimplantion-loss index was slightly increased for dose group III - females. This was, however, only due to two dams showing 6 or 5 early resorptions. Since the difference to the controls did not attain statistical significance, this increase is considered to be coincidental and not treatment related.

Examination of fetuses (external, skeletal and visceral) demonstrated one malformed fetus in dose group I only. Therefore no treatment related effect was indicated from data obtained during this study.

Under the experimental conditions of this study, a daily exposition to a 0.05 % 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine concentration in drinking water did not exert signs of maternal toxicity and a 0.25 % concentration did not adversely affect fetal development of New Zealand White-rabbits.

Justification for classification or non-classification

Regarding toxicity to reproduction (embryotoxicity and fertility) the substance 2,2,4(or 2,4,4)-trimethylhexane-1,6-diamine is not classified according to the criteria of EC Directive 67/548/EEC and EC Regulation 1272/2008.

Additional information