Amines, N-(3-aminopropyl)-N-(C16-18 and C18-unsatd. alkyl)trimethylenedi-

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

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.

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

For details and justification of read-across please refer to the report attached in section 0.2 of IUCLID.

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

not examined

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
At 90 mg/kg bw/day test substance as received (27 mg/kg bw/day pure substance), 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.
At 30 mg/kg bw/day (9 mg/kg bw/day pure substance) occasional animals in both generations showed post dosing salivation; this observation was probably associated with treatment.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
In both generations, at 90 mg/kg/day, mean weight gain was markedly lower than control; this effect was apparent for males, and for females in the premating period and during gestation.

FOOD CONSUMPTION (PARENTAL ANIMALS)
Food consumption in both generations was slightly lower than in controls at 90 mg/kg bw/day (27 mgkg bw/day pure substance).

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Mating performance, fertility, duration of gestation, klitter size and pup survival were considered to be similar in all groups.

ORGAN WEIGHTS (PARENTAL ANIMALS)
Mean seminal vesicle weights at 90 mg/kg bw/day (27 mg/kg bw/day pure substance) in 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.
At 90 mg/kg bw/day, mean epidymides weights in both generations were lower than control, with the value for F0 animals attaining statistical significance. However, after adjustment for bodyweight (covariance analysis) the epididymides weights were similar to control in both generations. Mean epididymides weights at the lower levels were not obviously affected by treatment.
Mean absolute testes weights in both generations at 90 mg/kg/day were slightly lower than control, with the value for F1 males attaining statistical significance. These lower values were considered to reflect the lower body weights, and after adjustment for bodyweight (covariance analysis) mean values were similar to control. Testes weights at 10 and 30 mg/kg/day were similar to control.
Mean prostate weights were essentially similar in all groups of both generations.

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

9 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: Based on observed signs of toxicity and a marked reduction in food consumption and body weight gain of males and of females during the premating and gestation periods at the next dose level.

Remarks on result:

other: Generation: P and F1 (migrated information)

Dose descriptor:

NOAEL

Remarks:

fertility

Effect level:

27 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: No adverse effects on fertility up to the highest tested dose.

Remarks on result:

other: Generation: P and F1 (migrated information)

Clinical signs:

effects observed, treatment-related

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

CLINICAL SIGNS (OFFSPRING)
Two pups at 90 mg/kg bw/day (27 mg/kg bw/day pure substance) showed body tremors in late lactation; these tremors may have been associated with treatment.

BODY WEIGHT (OFFSPRING)
At 90 mg/kg bw/day (27 mg/kg bw/day pure substance), mean litter and pup weights of the F2 pups were slightly lower than controls. Although these differences were probably incidental, the possibility that they were related to treatment could not be entirely discounted. The litter and pup weigts of the F1 pups at 90 mg/kg bw/day (27 mg/kg bw/day pure substance) and of both generations at 10 and 30 mg/kg bw/day (3 and 9 mg/kg bw/day pure substance) were similar to controls.

Dose descriptor:

NOAEL

Remarks:

developmental toxicity / systemic toxicity

Generation:

F2

Effect level:

9 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: Based on slightly reduced pup and litter weights and observed clinical signs (2 pups with body tremors) at the next dose level.

Reproductive effects observed:

not specified

Conclusions:

The study was performed in accordance with the guideline specified. The performance of the 2 generations was very similar. Under the conditions of the study 30 mg/kg/day produced only minor parental toxicity but no reproductive effects. At 90 mg/kg/day there was very marked parental toxicity, a possible minor effect on pup and litter weights, and 2 pups with body tremors. There were no obvious adverse effects on mating and littering performance at any of the levels tested.

Executive summary:

The substance was tested on rats for effects on general reproductive performance over 2 successive generations of animals. Sprague Dawley rats were dosed orally by gavage, once daily at the following dose levels, 0, 10, 30 and 90 mg/kg/day F0 animals were randomised into the 4 treatment groups, each containing 28 males and 28 females From each treatment group, 24 male and 24 female F1 weanlings were selected for rearing to maturity and mating to produce the F2 generation.

The F0 animals were dosed for 10 weeks prior to mating, and then throughout the mating, gestation and lactation periods until sacrifice at the time of weaning of the F1 animals.

The F1 animals were exposed to possible effect of the test material from conception through to weaning Direct treatment of the F1 animals commenced at 25 days of age and continued through to pairing (approximately 11 weeks after weaning), and then throughout the mating, gestation and lactation periods until sacrifice at the time of weaning of the F2 animals.

Clinical observations were performed daily Body weight and food consumption were recorded at various intervals throughout the study Females were allowed to litter normally and observations on the females and litters were recorded.

All F0 and F1 animals were subjected to necropsy, consisting of an external examination, followed by macroscopic examination of the tissues and organs of the cranial, thoracic and abdominal cavities Gross lesions were described and samples taken Applicable organs were weighed.

Only 2 male and 2 female pups that were weaned from each litter under went necropsy.

No pathology was performed as this was available from a 90-day repeat oral dose study.

Toxicity to parent (adult) animals at 90 mg/kg/day was indicated in both generations by a marked reduction in body weight gain of males, and of females during the pre-mating and gestation periods. Food consumption at this level was slightly lower than control.

Additionally most animals in both generations receiving 90 mg/kg/day showed clinical signs of reaction to treatment, principally dyspnoea, piloerection and hunched posture, many animals also had episodes of post dose salivation, and for occasional animals the outline of the spine was prominent. A total of 8 animals (2 F0 males, 3 F0 females, 1 F1 male and 2 F1 females) died or were killed after showing marked signs of reaction, and a ninth death (of an F1 female) may also have been related to treatment.

Mean seminal vesicle weights in both generations at 90 mg/kg/day were significantly lower than control; it was considered that this reduction was an indirect effect of the lower body weights rather than a direct effect on the seminal vesicles.

At 30 mg/kg/day, the only finding that was considered to have been probably associated with treatment was occasional animals in both generations with post dosing salivation; this finding might not be indicative of systemic toxicity.

Mating performance, fertility, duration of gestation, litter size and pup survival were considered to be similar in all groups of both generations.

At 90 mg/kg/day, mean litter weight and pup weights of the F2 pups were slightly lower than control; although these differences were probably incidental, the possibility that they indicated a slight effect of treatment could not be entirely discounted. The litter and pup weights of the F1 pups at 90 mg/kg/day, and of both generations at 10 and 30 mg/kg/day, were similar to control.

Two pups at 90 mg/kg/day showed body tremors in late lactation; these may have been associated with treatment.

At the 10 mg/kg/day dose level no marked toxicity was noted.

This information is used in a read-across approach in the assessment of the target substance. For details and justification of read-across please refer to the read-across report attached to IUCLID section 0.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

27 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Guideline study

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

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.

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.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

For details and justification of read-across please refer to the report attached in section 0.2 of IUCLID.

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
All animals at 200 mg/kg/day test material (corresponding to 60 mg/kg bw/day pure substance) and many at 75 mg/kg/day (corresponding to 22.5 mg/kg bw/day pure subtance) showed reaction to treatment. The principle findings were dyspnoea, salivation with associated brown staining, piloerection and indications of reduced activity (such as hunched, ataxic and cold to touch). Two animals at 200 mg/kg/day were killed prematurely: necropsy findings included intestinal distension, and therefore the similar distension observed for a further animal was also considered to be associated with treatment. The other clinical observations and necropsy findings were considered to be either associated with the above findings or to be incidental.
There was a dose related reduction in weight gain over the dosing period at 75 and 200 mg/kg/day (corresponding to 22.5 and 60 mg/kg bw/day pure substance), which had become apparent by Day 9 of gestation. At 200 mg/kg/day, weight gain over Days 6-17 was significantly lower than control (P<0.0 1) and 5 animals at this level showed weight loss between Days 9 and 13 of gestation. Gain over Days 6-17 at 75 mg/kg/day, although lower than control, was not statistically significant (P> 0.05).
Body weight performance at 25 mg/kg bw/day (corresponding to 7.5 mg/kg bw/day) was essentially similar to control.
There was a reduction in food consumption at 200 mg/kg/day, which persisted throughout the dosing period. At 75 mg/kg/day, food consumption was marginally reduced. At both these levels, food consumption over the dosing period was significantly lower than control (P<0.01).
Food consumption at 25 mg/kg/day was similar to Control.

Dose descriptor:

NOAEL

Effect level:

7.5 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The mean number of implants at 25 and 75 mg/kg/day (corresponding to 7.5 and 22.5 mg/kg bw/day pure substance) was slightly lower than control or at 200 mg/kg/day (corresponding to 60 mg/kg bw/day pure substance). However, this could not be attributed to treatment because the number of implants would have been established prior to commencement of treatment.
The incidence of early embryonic deaths, and hence of total dead implants was greater at 200 mg/kg/day (60 mg/kg bw/day pure substance) than in control. This increase was largely associated with three animals which had large numbers of early deaths. The incidence of dead implants at 25 and 75 mg/kg/day (7.5 and 22.5 mg/kg bw/day pure substance) was similar to control.
Mean foetal weight at 200 mg/kg/day (60 mg/kg bw/day pure substance) was slightly lower than control, with the difference approaching but not achieving statistical significance(P>0.05).
The number and type of major foetal abnormalities were considered to be typical of those seen in historical data. Taken together, the incidences of minor abnormalities and variants were typical of those that would be expected from historical data and were similar in all groups. The group values indicating the state of skeletal ossification were similar in all groups. Slight differences were considered too small to be attributed to treatment.

Dose descriptor:

NOAEL

Effect level:

22.5 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Basis for effect level:

other: embryotoxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

Under the conditions of the study no teratogenic effects (as indicated by the incidences of foetal malformations, anomalies and variants) were found up to 200 mg P4150/kg/day (60 mg a.i./kg/day) of the test substance.

Executive summary:

Based on Guidelines: OECD 414 and EPA-FIFRA 83-3 100 mated female and 60 male rats were used for the study. After mating females were housed singly with separate food and water for each cage. Batches of diet and water were analysed throughout the study. Pairing was on the basis of one male to two females. For each female cohabitation with a male was continuous until mating was detected. A vaginal lavage was examined each morning and the day of detection of sperm in the lavage, or of a copulatory plug in situ was considered to be Day 0 of gestation. On detection of mating, females were randomly assigned to treatment groups. The treatment groups were arranged as follows: Group no. Treatment/dose level mg P4150/kg/day Animal nos. 1 Control 0 1-25 2 Low dose 25 26-50 3 Intermediate 75 51-75 4 High 200 76_100,160* *Replacement animal following death of animal no. 86 Dose levels were determined from the results of a separate dose finding study in rats. In the study, very slight maternal toxicity was demonstrated in mated animals at 100 and 150 mg/kg/day. However, unequivocal toxicity was seen in a supplementary group of unmated animals at 200 mg/kg/day. There was no obvious effect on pregnancy performance or foetal weight in the mated animals. Females were dosed orally by gavage at a volume of 10 ml dosing solution per kg of body weight using a steel dosing cannula. The volume of solution to be administered each day was determined each day by the weight of the animal as measured at the time of administration. The animals were dosed once daily at approximately the same time each day over Days 6— 16 inclusive of gestation. The test material was formulated as a solution in water. Fresh solutions were prepared daily. A 10 ml sample from each concentration was taken on the first and eight day of dosing for analysis for concentration, homogeneity and stability. Clinical observations were recorded for reaction to treatment each day. In addition, all animals were checked for viability at the beginning and end of each day. Individual body weights were recorded on Days 0, 6, 9, 13, 17 and 20 of gestation. The weight of food consumed by each mated female was recorded daily, commencing on Day 3 of gestation. Females were killed by carbon dioxide asphyxiation. Foetuses were killed by chilling at ca 4°C for ca 5 mm before fixation. Animals that died prematurely during the study were examined at necropsy and included examination of the cranial contents. Other necropsies were conducted on Day 20 of gestation but did not include cranial examination. The thoracic and abdominal cavities were inspected, and any lesions were described, samples were taken where necessary. The reproductive tract was weighed intact, with examination of the uterus contents. The number and position of all implants was recorded. Each implant was classified as being live, a foetal death, i.e. death occurred after day 16 of gestation, or an early embryonic death, i.e. only placental remains or a decidual scar visible. The number of corpora lutea graviditatis in each ovary were recorded. Each live foetus within the litter was individually identified and its weight recorded. The foetuses were examined for externally visible abnormalities. Half the foetuses were fixed in methylated ethyl alcohol and examined for occurrence of gross visceral abnormalities. These foetuses were then cleared in potassium hydroxide and glycerol and the skeletons stained with Alizarin Red S for examination for abnormalities and variants, including state of ossification. The other half of the foetuses were fixed in Bouin’s fluid and examined for visceral abnormalities by a free-hand serial sectioning technique from that of (1965) Teratology: Principles and Techniques, The of . The sex of the foetus was determined during the visceral examination. Statistical analysis was used where appropriate. Weight gain was analysed using the Kruskal-Wallis test, with comparisons with the control using a modified Dunn’s procedure. Food consumption was analysed by parametric analysis of variance, with homogeneity of variance checked using Levene’s test and normality of data by the Shapiro-Wilk test. Comparisons with the Control were made using Dunnett’s t-test. For all other parameters, interpretation was based on examination of the individual and group mean values. Maternal toxicity was indicated at 75 and 200 mg P4150/kg/day by reduced body weight gain and food consumption and by clinical reactions to treatment, which in 2 animals at 200/kg/day required premature sacrifice: dyspnoea, salivation with associated brown staining, piloerection and indications of reduced activity (such as hunched, ataxic and cold to touch).. At 200 mg/kg/day, there was an increased incidence of early embryonic deaths: the 3 females with the greatest number of early deaths were all among the 5 females showing weight loss between Days 9 and 13 of gestation, suggesting that the early deaths may have been secondary to maternal toxicity. Mean foetal weight at this level was slightly lower than Control. At 25 and 75 mg/kg/day, there were no obvious effects on pregnancy performance or foetal weight. The incidences of foetal malformations, anomalies and variants were essentially similar in all groups.

This information is used in a read-across approach in the assessment of the target substance. For details and justification of read-across please refer to the read-across report attached to IUCLID section 0.

Reference 2

Endpoint:

developmental toxicity

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Justification for type of information:

For details and justification of read-across please refer to the report attached in section 0.2 of IUCLID.

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Maternal toxicity was indicated at 20 mg/kg/day by the death of two dams, by marginally reduced body weight and food intake during the last days of pregnancy. At 20 mg/kg/day, the body weight was marginally reduced during the last gestion days. There was a reduction in food consumption at 20 mg/kg/day from gestation day 16 onwards, which was up to 36% below the control value (p = 0.05).
Necropsy revealed an irritation of the gastrointestinal tract in 5 dams and an increased incidence of resorptions.

Dose descriptor:

NOAEL

Effect level:

9 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No test 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.

Dose descriptor:

NOAEL

Effect level:

9 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Basis for effect level:

other: embryotoxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

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/day of the test substance.
At 20 mg/kg/day there was a marginal increased incidence of resorptions suggesting early embryonic deaths secondary to maternal toxicity.

Executive summary:

The study was carried out in accordance with OECD Guideline No. 414.

108 mated female rabbits were used for the study. Mating was monogamous and the day of copulation was considered as day 0 of gestation. Females were dosed orally by gavage at a volume of 2 ml dosing solution per kg of body weight once daily from the 6th to the 28th day of pregnancy. On the 29th day of gestation the rabbits were killed by a blow on the neck.

The treatment groups were arranged as follows:

Group no.	Treatment/dose level		Animal Nos.
	mg Lonzabac 12/kg/day
1	Control	0	1-24
2	Low dose	6	25 -48 97-102*
3	Intermediate	9	49 - 72
4	High	20	73-96 103 -108*

* Replacement animals for non-pregnant females. In addition, four females in group 4 had no litters which could be evaluated because of abortions or total resorption of foetuses.

Dose levels were determined from the results of a separate dose-range- finding study. In this study, slight maternal toxicity was demonstrated at 22.5 mg/kg/day. All dams treated with 76.5 mg/kg/day died prematurely.

The following statistical analysis was used:

For numeric values: chi-square test, Dunnett test (for homogeneous variances), Student’s t-test (for heterogeneous variances). For the comparison of classification measurements the Fisher’s exact test was employed.

Analytical determinations of Lonzabac in aqueous solution and in test item-carrier were performed.

This information is used in a read-across approach in the assessment of the target substance. For details and justification of read-across please refer to the read-across report attached to IUCLID section 0.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

22.5 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Guideline study

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

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.