5H-Cyclopenta[h]quinazoline, 6,6a,7,8,9,9a-hexahydro-7,7,8,9,9-pentamethyl-

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In the reproduction/developmental toxicity screening study according to OECD TG 421 the following results were found:

The systemic NOAEL was determined to be 600 ppm corresponding to 37 mg/kg bw/day based on decreased bodyweight (gain) and food consumption.

The fertility NOAEL is >=1000 ppm corresponding to >=62 mg/kg bw/day based on based on the absence of adverse effects.

The developmental NOAEL is 600 ppm corresponding to 37 mg/kg bw/day based on increased post-implantation loss and decreased pup viability at 1000 ppm in the presence of decreased body weight (gain) and food consumption in dams and considered to be related to the observed developmental toxic effects.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The one reproscreening toxicity study available is of sufficient quality for the present dossier.

Additional information

Reproductive/Reproscreen study

In a reproduction/developmental toxicity screening study (OECD TG 421, GLP) the test substance was administered via diet to Wistar Han™:RccHan™:WIST strain rats for approximately seven weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dietary concentrations of 300, 600 and 1000 ppm equivalent to a mean achieved dosage of 17.9, 37.0 and 61.7 mg/kg bw/day for males, respectively and 20.9, 40.4 and 64.6 mg/kg bw/day for females during the pre-pairing phase, respectively. Dose groups contained 12 males and 12 females. A control group was treated with basal laboratory diet. All parameters included in the OECD TG 421 have been recorded.

Parental results: No adverse effects considered to be associated with treatment were observed for mortality, clinical signs and water consumption. Males treated with 1000 ppm showed a reduction in body weight gain during the second week of treatment. Recovery was evident thereafter however overall body weight gain for males at 1000 ppm was lower than controls. Females treated with 1000 and 600 ppm also showed a reduction in body weight gain during the final two weeks of gestation and during lactation. Cumulative body weight gain and food consumption during gestation was statistically significantly lower in females treated with 1000 ppm than controls. This was considered adverse. Two males treated with 1000 ppm had mottled livers at necropsy of which one correlated with hypertrophy of hepatocytes in the periportal area which was considered adverse. The NOAEL parental is set at the mid dose, 600 ppm / 37.0 mg/kg bw/day based on effects on food consumption and bodyweight (gain) as well as liver effects in males.

Fertility results:Male fertility organs, the testes and epididymes were investigated and no relevant effects were seen. Also no relevant effects were observed for the female fertility organs and uterus. There were no effects on mating, corpora lutea, pre-implantation loss or gestation length. Therefore for fertility the NOAEL is set at the highest dose >=1000 ppm/61.7 mg/kg bw/day.

Developmental results:No adverse effects were observed for offspring clinical signs and body weight gain.Increased post implantation loss was observed the 600 ppm and 1000 ppm dose levels. At the mid dose post implantation loss seem to be increased at 10.8% (not significantly) compared to the control (3.4%) but is clearly within the historical control value (mean 11%, range 0 – 40%, SD 15). The post implantation loss was statistically significantly increased at the high dose (16.3%). Therefore the high dose 1000 ppm/61.7 mg/kg/day is considered to have an adverse effect on post-implantation loss.

The number of live offspring at the 1000 ppm dose level at day 1 was decreased with 23% and at day 4 with 30%. These high dose effects are considered adverse. At the mid dose the effects are minimal (10%) and not statistically significant and therefore not considered adverse.No treatment-related effects on sex ratio were observed and no macroscopic abnormalities were detected for interim death or terminal kill offspring.Overall, the developmental NOAEL is set at the mid dose: 600 ppm equivalent to 37.0 mg/kg bw/day.

Overall conclusion on reproductive toxicity:The parental NOAEL for systemic toxicity is 600 ppm corresponding to 37 mg/kg bw/day based on decreased bodyweight (gain) and food consumption.

The fertility NOAEL is >=1000 ppm corresponding to >=61.7 mg/kg bw/day based on the absence of adverse effects up to and including the highest dose level tested.

The developmental NOAEL is 600 ppm corresponding to 37 mg/kg bw/day based on increased post-implantation loss and decreased pup viabilityin the presence of decreased body weight (gain) and food consumption in dams and considered to be related to the obsserved developmental toxic effects.

Effects on developmental toxicity

Description of key information

See Fertility section

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

37 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The one reproscreening toxicity study available is of sufficient quality for the present dossier.

Additional information

The developmental toxicity information is presented in the fertility section

Justification for classification or non-classification

Based on the results of the reproduction/developmental toxicity screening study the substance does not have to be classified for reproductive toxicity (fertility and developmental toxicity) according to EU CLP (EC 1272/2008 and its amendments).