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Key value for chemical safety assessment

Effects on fertility

Description of key information

In a three generation study with the read-across source substance 2 (LAS Na) no significant effects on fertility were observed in rats resulting in a NOAEL of 350 mg/kg bw/d for the parental and both offspring generations.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
350 mg/kg bw/day
Study duration:
chronic
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

No experimental data on toxicity to reproduction or effects on fertility is available for the test item. However, experimental data for the read-across source substance 2, LAS Na (CAS68411 -30 -3), is available and a read-across approach is applied. Please refer to read-across justification document attached in IUCLID Section 13. Furthermore, only key studies of the source substances are taken into account. For further supporting information please refer to respective dossier of each source substance.

Na-LAS was fed to 4 groups of weanling rats for two years (three generations). No significant effects were observed at the highest dose tested and the resulting NOAEL for the parental and both offspring generations was 350 mg/kg bw (0.5%).

Effects on developmental toxicity

Description of key information

Developmental toxicity was investigated for the read-across source substance 2 in mouse and rat and for the read-across source substance 3 in mouse, rat and rabbit, respectively.
Lowest NOAELs for developmental toxicity and respective route of exposure were found as follows:

NOAEL oral route 50 mg DEA/kg bw/d in the rat
NOAEC inhalation > 0.2 mg DEA / L in the rat

NOAEL dermal 350 mg DEA/kg/ bw/d in the rabbit

In none of the studies of both source substances developmental effects were observed in the absence of maternal effects. Consequently, NOAELdevelopmental was equal or greater than NOAELmaternal in all cases.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
200 mg/m³
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
350 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Additional information

No experimental data on developmental toxicity or teratogenicity is available for the test item. However, experimental data for two read-across substances are available and a read-across approach is applied. For more detailed information please refer to read-across justification document attached in IUCLID Section 13. Furthermore, only key studies of the source substances are taken into account. For further supporting information please refer to respective dossier of each source substance.

Source substance 2 (CAS 68411 -30 -3)

Pregnant female mice were exposed to LAS via gavage on days 6 -15 of gestation. Increased mortality was observed at the two highest doses (300 and 600 mg/kg bw/day). These doses also exhibited retarded weight gain and adverse signs in the necropsy. Pregnancy was comparable, however, for all groups. At doses without maternal toxicity, no differences were observed in any parameters. Because of the very wide range between the 2 mg/kg and 300 mg/kg doses, the maternal NOAEL of 2 mg/kg bw/day must be considered very conservative. The NOAEL for teratogenicity was 300 mg/kg bw/day.

 

Female rats were given LAS orally in distilled water from gestation days 6 to 15 during pregnancy. Some effects such as decreased weight gain and transient diarrhea occurred at the highest dose. Pregnancy rates were comparable at all doses. Litter parameters were not significantly affected at any dose. No significant differences were observed in visceral anomalies or skeletal variants, with the exception of a marginal retardation of sternebral ossification at the highest dose.

Source substance 3 (CAS 111 -42 -2)

 

The exposure of pregnant female Wistar rats to an aerosol of DEA in a head/nose exposure systems for 6 h/day on day 6 through day 15 post coitum at concentrations of 0; 0.01; 0.05; 0.2 mg/l (0; 10, 50, 200 mg/m³) led to signs of maternal toxicity at the highest concentration (0.2 mg/l) (BASF AG, 1993b, OECD TG 414 study). Maternal toxicity was substantiated by adverse clinical symptoms (vaginal haemorrhages) in 8 of the 21 pregnant rats on day 14 p.c. At this dose level a markedly increased number of fetuses with skeletal variations (mainly cervical rib(s)) were also recorded but substance-related teratogenic effects were not detected in any foetus. Thus, signs of prenatal developmental toxicity did only occur at a maternal toxic concentration. There were no adverse effects on dams or foetuses at the low or mid concentrations (0.01 or 0.05 mg/l). The NOAEC for maternal and prenatal developmental toxicity was 0.05 mg/l (50 mg/m³), the NOAEC for teratogenicity was >0.2 mg/l (200 mg/m³).

 

DEA was administered dermally to pregnant CD rats from gestation day 6 through day 15 at doses of 0, 150, 500 and 1500 mg/kg bw/day (Marty et al, 1999, a protocol equivalent/similar to OECD TG 414). At 500 and 1500 mg/kg bw/day moderate and severe skin irritation was caused, respectively. Maternal body weight gain was decreased in the 1500 mg/kg bw. Absolute and relative kidney weights were increased at 500 and 1500 mg/kg bw/day. Haematological effects including anaemia, abnormal red cell morphology (poikilocytosis, anisocytosis, polychromasia), and decreased platelet count were observed in all treatment groups. The 1500 mg/kg bw/day group also had increased lymphocytes and total leukocytes. In the fetuses, there were no effects of treatment on body weight or on incidence of external, visceral, or skeletal malformations/abnormalities. Increased incidences of six skeletal variations involving the axial skeleton and distal appendages were observed in litters from the 1500 mg/kg bw/day group. The skeletal variations included poor ossification in the parietal bones, cervical centrum #5, and thoracic centrum #10, lack of ossification in all proximal hindlimb phalanges and some forelimb metacarpals, and callused ribs. Consequently, the LOAEL for maternal toxicity was 150 mg/kg bw/day, while the NOAEL for prenatal developmental toxicity was adjusted to 380 mg/kg bw due to dosing discrepancy at the 500 mg/kg bw/day group. The NOAEL for teratogenicity was >1500 mg/kg bw/day. Thus, signs of prenatal developmental toxicity did only occur at clearly maternal toxic dose levels.

 

DEA was administered dermally to pregnant New Zealand White rabbits from gestation day 6 through day 18 at doses of 0, 35, 100 and 350 mg/kg bw/day (Marty et al, 1999, a protocol equivalent/similar to OECD TG 414). Rabbit dams at 350 mg/kg bw/day showed several signs of marked skin irritation, reduced food consumption, and colour changes in the kidneys but no haematological changes. Body weight gain was reduced at 100 mg/kg bw/day. There was no impairment of gestational parameters. No evidence of developmental toxicity was observed at any dose level, especially, there were no apparent effects of treatment on the incidences of external, visceral, or skeletal abnormalities. Consequently, the NOAEL for maternal toxicity was 35 mg/kg bw/day, the NOAEL for prenatal developmental toxicity including teratogenicity was >350 mg/kg bw/day.

 

Treatment of time-mated pregnant rats with DEA dose levels of 0, 50, 125, 200, 250, 300 mg/kg bw/day by oral gavage from gestation day 6-19 (Price, 1999) led to maternal morbidity or mortality occurred at 200 and 250 mg/kg bw/day and all females at 300 mg/kg bw/day had to be terminated early due to excessive toxicity. Maternal water intake was transiently affected during early gestation (125 and 250 mg/kg bw/day) but was comparable to controls for all measurement periods after GD 12. Maternal absolute kidney weight was increased on PND 21 (>= 125 mg/kg bw/day) indicating persistence of DEA-induced toxicity for up to about 3 weeks after cessation of exposure. Reduced maternal body weight and weight change, as well as reduced feed intake, were noted at >= 200 mg/kg bw/day. Exposure to 50 mg/kg bw/day was not associated with any significant maternal toxicity during or after the treatment period. Developmental toxicity was observed specifically in form of an increase in post implantation mortality at >= 200 mg/kg bw/day on PND 0, and early postnatal mortality (PND 0-4) was increased at >= 125 mg/kg bw/day. Pup body weight was reduced at >= 200 mg/kg bw/day, with females more affected than males. When expressed as a percentage of control weight, pup body weight reductions were most pronounced during the early postnatal period. Statistically significant differences were also evident at the end of the lactation period. Consequently, the NOAEL for maternal and developmental toxicity was 50 mg/kg bw/day. Signs of developmental toxicity did only occur at maternal toxic dose levels.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data on two read-across substances are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. None of both source substances indicated potential of toxicity on fertility or developmental toxicity /teratogenicity up to doses where systemic toxicity was observed. As a result the substance is not considered to be classified for toxicity to reproduction under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.