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

Endpoint summary

Description of key information

A NOAEL for systemic 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).

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

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

Conclusions:

A NOAEL for systemic 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).

Endpoint conclusion

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 422 Guideline with GLP

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

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 after repeated exposure 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.

A total of 3 females (two of the main groups and one of the recovery groups) died or were sacrificed for humane reasons during the treatment period. Based on the post mortem and histopathological findings (clear and/or white fluid or creamy content in the thoracic cavity, adherence to heart, aorta and lungs with or without evident thymus), the cause of death of these animals was attributed to a mis-dosing.

In addition, one female receiving 1000 mg/kg/day was sacrificed for humane reasons on

Day 22 post coitum for difficulty in parturition, this isolated case was considered incidental.

No mortality occurred in males.

 

No significant clinical signs were observed throughout the study in all treated animals of both sexes. Neurotoxicity assessment was unaffected by treatment. No differences in body weights and body weights gain were recorded in animals of both sexes compared to the control group, throughout the study, both for main and recovery groups.

 

No effects on food consumption were observed in either males or females throughout the study, both for main and recovery groups.

 

At haematological investigation performed in the animals of the main groups at the end of

treatment, leucocytosis was recorded in high dose males. This finding was considered to be not adverse. The other statistically significant differences recorded between control and treated animals were not dose-related, therefore they were considered unrelated to treatment.

The statistically significant difference of activated partial thromboplastin time observed between controls and mid-dose males was not dose-related, therefore it was considered to be incidental. Recovery groups animals Lymphocytes data were comparable with controls.

The other statistically significant changes recorded were not observed during the treatment period, therefore they were considered incidental.

 

The differences recorded in some clinical chemistry parameters in main group animals were not dose-related and/or of minimal severity, therefore they were considered not to be adverse or of no toxicological relevance. No differences between control and treated animals of recovery groups were recorded. The other statistically significant differences recorded only in females were not observed during the treatment period, therefore they were considered incidental.

 

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.

 

No changes were observed in terminal body weight or organ weights (absolute and relative) of treated animals of main group, when compared to the controls. No changes were observed in terminal body weight or absolute organ weights of recovery animals, when compared to the controls. Changes in relative kidneys or adrenals observed in treated males and females respectively were considered not treatment-related, since the effects were not observed in main group animals.

 

No differences were noted at post mortem examination in treated animals sacrificed at the end of treatment and recovery periods, that could be considered treatment-related.

 

Animals that completed the treatment or recovery period and killed at termination did not show relevant macroscopic changes that could be considered treatment-related. The sporadic changes such as small prostate observed respectively in two high dose males and one low dose male or single dark depressed area in one high dose male were considered spontaneous and incidental, having a comparable incidence in control and treated groups and/or are characteristically seen in untreated Sprague Dawley SD rats of the same age.

 

Conclusion:

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

Justification for classification or non-classification

Repeated dose 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,N’[(methylimino)bis(trimethylene)]bis(stearamide).

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

Evaluating information from the sub-acute toxicity study a classification with STOT-RE according to GHS Regulation EC No 1272/2008 for N, N’-[(methylimino)bis(trimethylene)] bis(oleamide) is not warrant.