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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
75 mg/kg bw/day
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

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test is performed in rats, in which male and female rats are exposed to 0 (vehicle), 10, 75 and 150 mg/kg bw/day via gavage (OECD 422).

JEFFAMINE RFD 270 caused clinical signs of toxicity from day 8 to 44 of the test item administration; in addition, a marked total mortality of 50% in males and 50% in females occurred in the high dose group (150 mg/kg bw/day) during the study. These effects were dose related and therefore, attributed to treatment with the test item.

Decreases on body weight, body weight gain and food consumption were observed in males and females in the high dose group and in the high dose satellite male and female groups (150 mg/kg bw/day). Furthermore, even during the recovery period, a complete recovery in the bodyweights was not observed in the satellite animals. Accordingly, changes observed in body weight, body weight gain and food consumption of males and females at 150 mg/kg bw/day were considered to be treatment-related with toxicological significance.

Other than the cage side observations noted, there were no test article effects on reaction to stimuli and motor activity assessment in the functional observational battery study.

Markedly higher mean aspartate aminotransferase levels were observed in male and female rats exposed to 75 and 150 mg/kg bw/day. These findings were supported by other macroscopic and microscopic pathology findings and were considered to be treatment related. No other alterations were found in the hemogram, leukogram and clotting parameters. However, these chemistry effects in the mid and high dose males and females, while not statistically significant, were observed in treated satellite males and females. Furthermore, these findings are considered to be treatment related at the high dose level males and females and satellite males and females. Moreover, male rats at the high dose level and the satellite male groups had decreased cholesterol levels which fell outside of the Bioagri historical control value range. This finding was considered to be a treatment related effect.

The mean number of days of pairing before mating and the length of the gestation period were comparable between the control group and treated groups and within the physiological range of this species and strain, according Bioagri’s historical data base. For the control group, 2/12 females were not pregnant, compared to 0/12, 0/12 and 6/12 at 10, 75 and 150 mg/kg/day groups, respectively. The mating and fertility indices were similar in all groups, except in females at 150 mg/kg/day were they were lower than control (75% and 81.8%, respectively); though, the gestation index was not affected. No biologically or statistically significant changes were observed when the percentages of pre and post implantation loss were compared to the control group. However, the live birth index (-33.1%), viability index on day 4 (-15.4%), corpora lutea number (-26.1%), implantation number (-21.8%), number of total pups at day 0 (-21.8%) and postnatal day 4 (-47.5%) were lower in dams exposed to 150 mg/kg/day compared to the control group. Although all these findings were without statistical significance, they should be considered test item related, because were markedly higher and occurred at the high dose level.

In pups from dams at the high dose level, markedly higher mortality occured at postnatal days 0 and 4. Furthermore, decreases in body weight were noted with related macroscopic findings such as body trauma, cyanosis and cannibalized pups. These effects were associated with maternal toxicity observed at this highest dose and should be attributed to treatment with the test item.

Accordingly, in the experimental conditions of this study, the No Observed Adverse Effect Level of the test item JEFFAMINE RFD 270 in Wistar rats was 10 mg/kg/day for male systemic toxicity and maternal systemic toxicity, and 75 mg/kg/day for embryo-fetal toxicity.

 


Short description of key information:
Betancourt Martell A (2014) performed a combined repeated dose toxicity study with reproduction/developmental toxicity screening test in rats according to OECD guideline 422 (GLP). A NOAEL of 10 mg/kg/day was derived for male systemic toxicity and maternal systemic toxicity and a NOAEL of 75 mg/kg bw/day was derived for embryo-fetal toxicity.

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

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

Justification for classification or non-classification

The results of the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test

showed adverse effects in the embryo/foetus associated with strong evidence of maternal toxicity, that may influence development via non-specific secondary mechanisms. As the adverse effects on fertility and reproductive performance were only seen at levels causing marked systemic toxicity, it is considered that the pup findings are secondary to maternal toxicity and the substance should not be classified for reproductive toxicity according to the DSD and CLP Regulation.