Fatty acids, tall-oil, reaction products with formaldehyde and (Z)-N-9-octadecenyl-1,3-propanediamine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Toxicity to reproduction:

A combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test (Peter, 2013) was performed with the Reaction Product of Oleic acid, N1 -(9Z)-9 -octadecen-1 -y-1,3 -propanediamine and paraformaldehyde in rats by oral gavage. The study was performed according to OECD 422 guidelines and in compliance with GLP.

After acclimatization, four groups of ten male and ten female Wistar Han rats were exposed to the test substance at 0 (vehicle), 100, 300 and 1000 mg/kg.

The following observations and examinations were evaluated: mortality/viability, clinical signs (daily), functional observations and locomotor activity (end of treatment), body weight and food consumption (at least weekly intervals), clinical pathology (end of treatment), macroscopy at termination, organ weights and histopathology on a selection of tissues, and reproduction/developmental parameters, consisting of mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights and macroscopy). Formulations were analyzed once during the study to access accuracy, homogeneity and stability.

Reproductive results:

No reproductive toxicity was observed up to the highest dose level tested (1000 mg/kg). The mating, fertility and conception indices, precoital time, and number of corpora lutea and implantation sites were unaffected by treatment.

Developmental results:

At 1000 mg/kg (group 4), the mean sex ratio was slightly skewed towards males (64% male pups in the high dose groups as compared to 52% in the control group). This was mainly caused by the three litters (nos. 71, 73, 78) which had relatively high numbers of males as compared to females (ratio males/females: 11/2, 10/3 and 5/1, respectively). A minimum of eight pregnant females is advised by the OECD 422 test guideline. There were eight pregnant females at 1000 mg/kg, though only seven litters were available for evaluation since one of these females was euthanized during the post-coitum phase.

The change in the mean sex ration in group 4 was only slight, reaching no statistical significance when comparing to the controls. The laboratory's control data (122 screening studies in the period from 2008 until now) includes two studies with a percentage of 63 -64% for male pups. As these two historical studies show the ultimate limit of the historical data range, a possible relationship to treatment could not be excluded for the tendency to a changed sex ratio in the high dose group. It should be noted that in this type of study the sex of the pups is determined externally by the anogenital distance and sex organs are not examined.

No toxicologically relevant effects on gestation index and duration, parturition, maternal care and early postnatal pup development (mortality, clinical signs, body weight and macroscopy) were observed.

In conclusion, no reproductive toxicity was observed for treatment up to 1000 mg/kg. Developmental toxicity was observed at 1000 mg/kg as a possible relationship to treatment could not be excluded for the change in sex ratio.

Based on these results, the following NOAELs were derived:

Reproductive NOAEL: at least 1000 mg/kg

Developmental NOAEL: 300 mg/kg

Annex IX further testing:

2 -GENERATION STUDY:

An OECD 422 test has been performed with Reaction Product of Oleic acid, N1-(9Z)-9-octadecen-1-yl-1,3-propanediamine and paraformaldehyde. No reproductive toxicity was observed after exposure up to the highest dose (NOAEL = 1000 mg/kg bw/day). The developmental NOAEL was defined to be 300 mg/kg bw/day due to a deviation in the mean sex ratio observed at 1000 mg/kg. It should, however, be noted that this change was only slight and didn’t reach statistical significance when compared to controls. This effect was observed in the presence of significant parental (female) toxicity and some mortality at that doses, resulting in a smaller group of females. Furthermore the sex ratio values were within the ultimate limit of the historical data range of the laboratory for this strain. No other developmental endpoint was affected by the treatment. An OECD 414 study is proposed to further investigate the sex ratio change observed in the OECD 422 test. Therefore, no multi-generation test is required for this substance.

Short description of key information:
Toxicity to reproduction:
Peter (2013) performed a combined repeated dose toxicity study with reproduction/developmental toxicity screening test (K1 study) in rats according to OECD guideline 422 (GLP). A NOAEL of at least 1000 mg/kg was observed for reproductive toxicity and a NOAEL of 300 mg/kg was observed for developmental toxicity since a possible treatment related effect on the sex ratio at 1000 mg/kg could not be excluded based on the limited data available from this screening study.

Justification for selection of Effect on fertility via oral route:
Only one study available

Justification for selection of Effect on fertility via inhalation route:
Only one route of exposure is needed for this endpoint.

Justification for selection of Effect on fertility via dermal route:
Only one route of exposure is needed for this endpoint.

Effects on developmental toxicity

Description of key information

Annex IX further testing:
A testing proposal has been added to IUCLID section 7.8.2 as next to other endpoints examined in the OECD 414 study, the registrant further wants to address the sex ratio changes in pups observed in the OECD 422 study with fatty tetrahydropyrimidine.

Justification for classification or non-classification

Based on the available data and the criteria of the DSD and CLP Regulation, the substance should not be classified for reproductive toxicity.