N,N'-[(methylimino)dipropane-1,3-diyl]dioleamide

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

A NOAEL for reproductive toxicity of 1000 mg/kg bw/day was established for N, N’-[(methylimino)bis(trimethylene)] bis(oleamide) based on read-across information from an OECD 422 guideline study with the test substance N,N’[(methylimino)bis(trimethylene)]bis(stearamide).

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Refer to attached document

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: no effects

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: no effects

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Conclusions:

A NOAEL for reproductive toxicity of 1000 mg/kg bw/day was established for N, N’-[(methylimino)bis(trimethylene)] bis(oleamide) based on read-across information from an OECD 422 guideline study with the test substance N,N’[(methylimino)bis(trimethylene)]bis(stearamide).

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Read-across from a study according to OECD 4422 Guideline with GLP

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

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

Toxicity to reproduction: other studies

Additional information

Available information from an OECD 422 guideline study with the test substance N,N’[(methylimino)bis(trimethylene)]bis(stearamide) were used to evaluate effects on toxicity to reproduction of N, N’-[(methylimino)bis(trimethylene)] bis(oleamide).

 

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening study according to OECD guideline 422, N-N’-[(methylimino)bis-(trimethylene)]bis-(stearamide) was administered to 10 Sprague-Dawley rats /sex/ at dose levels of 0, 100, 300 and 1000 mg/kg bw/day by gavage.

Males were treated for 2 weeks prior to pairing and during pairing with females until the day before necropsy, for a total of 34/35 days. Pregnant females were treated for 2 weeks prior to pairing, during pairing, post-coitum and post-partum periods until Day 13 post-partum (for at least 51 days). The non-pregnant females were dosed up to the day before necropsy (post-coitum from Days 26/28). Females which did not mate were sacrificed after approximately 8 weeks of treatment.

Additionally a recovery group was included (5 rats/sex) for control and high dose with a 4 week treatment-free period in order to assess any delayed toxicity or recovery from any adverse effects observed during the dosing phase. Recovery males were treated for up to 4 consecutive weeks and killed after 4 weeks of recovery period. Recovery females were treated for up to 6 weeks, when most of the main group females were killed. The females were sacrificed after 4 weeks of recovery period.

Based on the results of the present study, the NOAEL for general toxicity was considered to be 1000mg/kg/day for both males and females. Details are reported in section 7.5 of IUCLID dataset.

 

The concurrent decrease of T4 and TSH observed in mid- and high dose males of main group is usually associated with secondary hypothyroidism (due to pituitary impairment). However, since no changes of pituitary were recorded at histopathological examination in high dose males, no clear conclusion could be drawn for these findings.

In the recovery group Thyroid hormones determination revealed no significant differences between control and high dose animals that could be considered related to treatment.

 

Seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and to the integrity of the various cell types within the different stages. Regular layering in the germinal epithelium was noted.

 

The oestrous cycle cyclicity of the treated females monitored during the pre-mating period, for a total of 14 days, was not affected by treatment. The mean number of oestrous cycles observed in treated animals and control group were comparable.

An increased incidence in mean number of days for the pre-coital interval was observed in the treated groups compared to controls. The mean pre-coital interval was 3.2 days in the control group, 4.5 days in the low dose group, 7 days in the mid-dose group and 4.8 days in the high dose group. In particular, in the mid- and high dose groups the numbers of females conceiving after 5 days were more than 50% of animals. A reduction in the number of copulation plugs was also observed. The fertility index in treated animals was reduced compared to controls without dose relation. In the absence of dose relationship and without a statistically significance, the relation remained unclear.

 

Two control, 4 low dose, 2 mid-dose and 3 high dose females which showed evidence of copulation were found not pregnant at necropsy. One mid-dose and one high dose females showed no evidence of copulation and were found not pregnant at necropsy (did not mate).

One low dose dam lost its litter on the day of parturition (Day 0 post-partum), one high dose female showed dystocia and was humanely killed.

The total number of pregnant females/group was: 8 in the control, 4 in the low dose, 7 in the mid-dose and 6 in the high dose groups.

The number of females with live pups on Day 14 post-partum was: 8 in the control, 3 in the low dose, 7 in the mid-dose and 5 in the high dose groups.

 

Implantation, pre-birth loss data and gestation length of females were unaffected by treatment.

Furthermore litter data and sex ratios were unaffected by treatment. Clinical signs of pups were unaffected by treatment. No nipples were found in male pups on Day 13 post-partum.

No effects on anogenital distance were seen between control and treated pups.

No necropsy findings were described in in decedent pups and in any pups sacrificed on Days 4 and 14 post-partum.

 

No changes were seen in pups sacrificed on Days 4 and 14 post-partum in T4 and TSH (T3 of all treated pups were found below the limit of quantification). No significant differences were noted in thyroid weight between control and pups of treated groups.

 

Based on the results of the present study, the NOAEL for general toxicity was considered to be 1000mg/kg/day for both males and females.

The NOAEL reproductive toxicity of females and pups was 1000 mg/kg/day.

The NOAEL reproductive toxicity of males was 1000 mg/kg/day, even if an increased incidence in the precoital interval was observed in all treated animals.

The cause of this effect was unclear and conclusion cannot be achieved, considering that this test (as indicated in the guideline) is designed to generate limited information and does not provide complete information on all aspects of reproduction.

Justification for classification or non-classification

Reproductive toxicity of N, N’-[(methylimino)bis(trimethylene)] bis(oleamide) was assessed based on data from a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening study with the read-across substance ,N’[(methylimino)bis(trimethylene)]bis(stearamide).

The no-observed-adverse-effect-level (NOAEL) for systemic toxicity and also for reproductive/ developmental toxicity was considered to be 1000 mg/kg/day, the highest tested dose.

Considering the available data it can be concluded, that according to GHS Regulation EC No 1272/2008 classification for reproductive toxicity is not warranted for N, N’-[(methylimino)bis(trimethylene)] bis(oleamide).