Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
25 mg/kg bw/day
Study duration:
subchronic
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
Short description of key information:
The following summarises the test data collected for the close analogue, losartan potassium. Maternal NOEL= 25 mg/kg/day. The F1 and F2 NOAEL is considered to be 25 mg/kg/day based on slight decreased pup weights (5.8-7.8%) during Days 14 to 21 of lactation and slight (4.3%) decrease in F1 body weight during 1-9 weeks postweaning. The results of the female rat fertility study suggest that developmental toxicity are indicative of potential fetal toxicity late in pregnancy and/or during the early lactation timeframe. These effects are suitable for classification of losartan free acid, by read-across, as fertility reprotoxicant according to CLP and DSD.

Justification for selection of Effect on fertility via oral route:
Maternal NOEL= 25 mg/kg/day. The F1 and F2 NOAEL is considered to be 25 mg/kg/day based on slight decreased pup weights (5.8-7.8%) during Days 14 to 21 of lactation and slight (4.3%) decrease in F1 body weight during 1-9 weeks postweaning.

Effects on developmental toxicity

Description of key information
LFA is the acid form of the drug losartan which is an angiotensin converting enzyme (ACE) receptor blocker. The following description of information on losartan potassium applies to the similar substance, losartan free acid, by read-across.  
In the Oral Developmental Toxicity Study in Rats, there was no evidence of developmental toxicity based on postimplantation survival, fetal weight and external, visceral or skeletal examinations of fetuses in all treatment groups (control, 50 mg/kg/day, 100 mg/kg/day and 200 mg/kg/day).
In the Oral Developmental Toxicity Study in Rabbits, developmental toxicity occurred in the form of decreased fetal body weight and delays in fetal ossification in the 40 mg/kg/day treatment group. However, maternal toxicity manifested in the 40 mg/kg/day treatment group, and the decreased fetal body weight and delays in fetal ossification are likely coincident with the maternal toxicity.
In the Oral Fertility Study in Female Rats, there were no treatment-related effects on reproductive performance, including mating or fertility in F0 female rats given 25 mg/kg/day. There was no evidence of teratogenicity in any dose group in the F1 or F2 generations. Developmental toxicity was observed in all dose groups (25mg/kg/day, 100 mg/kg/day and 300/200 mg/kg/day) which were dose and time-dependent in nature. The timing and nature of the effects on the F1 generation observed during this study suggest that the toxicity observed may be due to late gestational/lactation exposure.
The results of the female rat fertility study suggest that developmental toxicity are indicative of potential fetal toxicity late in pregnancy and/or during the early lactation timeframe. These results with the close analogue, losartan potassium, lead to classification by read-across of losartan free acid as Reprotox 1B and Effect on or via lactation on the basis that ACE drugs acting directly on the renin-angiotensin system can cause harm to the developing fetus.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
40 mg/kg bw/day
Study duration:
subchronic
Species:
rabbit
Quality of whole database:
These data are used to conservatively estimate developmental toxicity due to exposure to LFA.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information
Justification for selection of Effect on developmental toxicity: via oral route:
Maternal toxicity manifested in the 40 mg/kg/day treatment group, and the decreased fetal body weight and delays in fetal ossification are likely coincident with the maternal toxicity

Justification for classification or non-classification

Based on the results obtained in a female rat fertility study with statistically significant effects observed to the developing foetus and clinical data (not included in REACH dossier) indicating that ACE drugs which directly act on the renin-angiotensin system causing harm to the developing foetus, LFA has been classified as

Reprotox 1B and effect on or via lactation according to Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures ('CLP') and as R61 - May cause harm to the unborn child;

R64 - May cause harm to breastfed babiespecific effect if known > <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>according to Directive 67/548/EEC (‘DSD’).