2-methylpentane-1,5-diamine

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

No reproduction toxicity study is available for the submission substance, MPMD.

However, there is a reliable two generation study (feeding study) with the structurally related Hexamethylenediamine (HMD, more details are available in the read-across justification document (see IUCLID section 13.2)).  

In this  two generation study (Schardein, 1985), 26 males and 26 females SD- rats/group received HMD orally in the diet at dosage levels of 0, 50, 150 or 500 mg/kg/day for 56 days prior to mating, then throughout the study in accordance with a respective EPA guideline (similar to OECD test guideline 416) and under GLP conditions.

No adverse effects on reproduction/fertility were obvious in any of the examined generations. The NOAEL was established at the highest dose tested, i.e. 500 mg/kg bw/day.

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

For details on endpoint specific justification please see read-across report in section 13 or find a link in cross-reference “assessment report”.

Reason / purpose for cross-reference:

assessment report

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on significant but slight decreased litter size without any other effects and any historical data.

Remarks on result:

other: read-across from 1,6-Hexanediamine - due to the identical molecular weight of source and target substance, the effect concentrations for the source substance are also valid for the target substance without further adjustment.

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

other: read-across from 1,6-Hexanediamine - due to the identical molecular weight of source and target substance, the effect concentrations for the source substance are also valid for the target substance without further adjustment.

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on slight decreased pups weight observed at high dose. It could be attributed to the un palatability of HMD inducing decrease in food consumption by the F0 and F1 parents.

Remarks on result:

other: read-across from 1,6-Hexanediamine - due to the identical molecular weight of source and target substance, the effect concentrations for the source substance are also valid for the target substance without further adjustment.

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on slight decreased pups weight observed at high dose. It could be attributed to the un palatability of the test material inducing decrease in food consumption by the F0 and F1 parents.

Remarks on result:

other: read-across from 1,6-Hexanediamine - due to the identical molecular weight of source and target substance, the effect concentrations for the source substance are also valid for the target substance without further adjustment.

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Conclusions:

Under the test conditions, there were no adverse effects on reproduction and fertility induced by the test material.
Therefore,
The NOEL (parental) = 500 mg/kg bw/day (any adverse effects were not observed at all dose tested)
The NOEL (Developmental) = 150 mg/kg bw/day, based on slight decreased pups weight at high dose.
The NOEL (Fertility) = 150 mg/kg bw/day, based on slight decreased litter size at high dose.
In addition, these results indicate that the test material does not have significant systemic target organ toxicity.

Executive summary:

The study used as source investigated the effect of 1,6-Hexanediamine on fertility and reproduction in two generations in rats. The study results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (structural analogue) is outlined in the read-across report in section 13 or find a link in cross reference “assessment report”.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

One two-generation study in rats conducted with the structural analogue HMD has a Klimisch Score = 1. The data base is of high quality.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No reproduction toxicity study is available for the submission substance, MPMD.

However, there is a reliable two generation study (feeding study) with the structurally related Hexamethylenediamine (CAS 124-09-4, HMD, more details are available in the read-across justification document (see IUCLID section 13.2)).  

In a this two-generation study (Schardein, 1985), 26 males and 26 females SD- rats/group received HMD orally in the diet at dosage levels of 0, 50, 150 or 500 mg/kg/day for 56 days prior to mating, then throughout the study

in accordance with Series 83 -4 of the Environmental protection Agency Pesticide Assessment Guidelines, Subdivision F., Hazard Evaluation: Human and Domestic Animals, issued November, 1982 (similar to OECD test guideline 416) and under GLP conditions.

The parental rats and pups were observed twice each day for signs of overt toxicity, changes in general appearance and behavior, and mortality. Individual body weights were recorded weekly for the adult rats; In addition, females were weighed on gestation days 0, 6, 15 and 20 and lacation days 0, 4, 7, 14 and 21. Parental food consumption was measured weekly for individual parental rats except during mating. Specific reproductive observations included tabulation of male and female fertility indices, and the length of cohabitation and gestation were recorded. Gross necropsies were performed on F0 and F1 parents as well as F2 pups. The following tissues were taken from F0 and F1 rats for histopathological evaluation: kidneys, liver, lung, ovaries, prostate, seminal vesicles, spleen, testes with epididymis, uterus, and vagina.

The results of this study were:

- Dietary analysis indicated that greater than 90% of the target concentration of hexamethylenediamine were fed to rats in all groups. The actual doses consumed, however, averaged between 123 and 132% of the target doses in these groups.
- No treatment-related mortality was observed in any of the groups. Some deaths occurred, however, they were singular events in specific groups and there was no pattern indicative of a dose-response relationship. Mortality ratios for the F0 males were 0/26, 1/26, 1/26, and 0/26 for the 0, 50, 150, and 500 mg/kg groups, respectively. Mortality ratios for the F0 females were 0/26, 0/26, 0/26, and 0/26 for the 0, 50, 150, and 500 mg/kg groups, respectively. Mortality ratios for the F1 males were 0/26, 0/26, 0/26, and 0/26 for the 0, 50, 150, and 500 mg/kg groups, respectively. Mortality ratios for the F1 females were 1/26, 1/26, 0/26, and 0/26 for the 0, 50, 150, and 500 mg/kg groups, respectively.
- Body weights of male F0 and F1 rats in the 500 mg/kg group were reduced by about 10%, relative to control values, at the end of study weeks 15 and 38. The body weights of females, in contrast, were comparable to control values at these intervals. During gestation, the female weight gain was reduced by about 10% in the high-dose group. Decreased body weight is correlated with a decreased food consumption. Therefore, this effect was likely due to the unpalatability of HMD.

- Fertility was not adversely affected by the dietary administration of hexamethylenediamine over 2 generations. The F0 and the F1 litter size in the 500 mg/kg group was significantly reduced without an increase in the number of dead pups. There were no biological meaningful or statistically significant differences in the number of viable and dead pups on lactation day 1, as compared to control for either generation in the mid and low-dose treatment groups. Pup survival was not significantly reduced in any of the treated groups. At birth, pup body weights were not adversely affected by treatment, but during lactation, reduced weights were apparent in pups of each sex from the high dose group

- No meaningful differences were noted between the control and treated rats of either generation with regard to antemortem observations, copulatory interval, gestation length, nesting and nursing behavior, and appearance of the pups. No treatment related effects were noted on testes weights and no effects were noted by macroscopic or microscopic examination of tissues evaluated.

In conclusion:

Under the test conditions, there were no adverse effects on reproduction and fertility, therefore:

The NOAEL (Parental) = 500 mg/kg bw/day (even if this effect was likely due to the decrease to food consumption as the worst case)

The NOAEL (Developmental) = 500 mg/kg bw/day, since slight decreased pups weight observed at high dose could be attributed to the unpalatability of HMD inducing decrease in food consumption by the F0 and F1 parents.

The NOAEL (Fertility) = 500 mg/kg bw/day, based on significant but slight decreased in litter size without any other effects and any historical data.

Effects on developmental toxicity

Description of key information

Two preliminary OECD TG 414 studies in two species (oral gavage, rats and rabbits) are available for the submission substance. The according main studies enabling to establish respective NOAELs will be submitted at a later point in time during a further update. Thus no final conclusion on developmental toxicity/ teratogenicity can be drawn yet. However, observations from the preliminary studies did not indicate the occurrence of any severe effects on fetal development to be expected in the main studies.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Mode of Action Analysis / Human Relevance Framework

No specific information available.

Justification for classification or non-classification

Based on the above presented data no classification for reproduction toxicity/ developmental toxicity/ teratogenicity is necessary according to Regulation (EC) No 1272/2008.