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

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

- The dietary Reproscreen study (OECD TG 421) with additional systemic toxicity parameters shows a NOAEL for systemic toxicity of 150 ppm (9.1 mg/kg bw). The NOAEL for fertility and developmental toxicity is 500 ppm (equivalent to 31.0 and 34.0 mg/kg bw/day for males and females, respectively). This dose was the maximum dose tested.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

31 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

OECD 421 Toxicity to reproduction:

The substance was administered by continuous dietary admixture to three groups, each of twelve male and twelve female Wistar Han™:RccHan™:WIST strain rats, for up to seven weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dietary concentrations of 50, 150 and 500 ppm (equivalent to a mean achieved dosage of 3.0, 9.1 and 31.0 mg/kg bw/day for males and 3.4, 10.5 and 34.0 mg/kg bw/day for females during pre-pairing). A control group of twelve males and twelve females was fed basal laboratory diet. This study was conducted according to OECD TG 421 and GLP principles. Clinical signs, body weight change, dietary intake and water consumption were monitored during the study. Pairing of animals within each dose group was undertaken on a one male: one female basis within each treatment group on day 15 of the study, with females subsequently being allowed to litter and rear their offspring to day 5 of lactation. During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and assessment of surface righting reflex. Adult males were terminated on day 43, followed by the termination of all females and surviving offspring on day 5 postpartum. All animals were subjected to a gross necropsy examination and histopathological evaluation of reproductive tissues was performed.

Results, mortality and clinical signs showed that there were no unscheduled deaths. There were no clinical signs apparent for animals of either sex treated with 50, 150 or 500 ppm. There were no treatment-related effects detected in body weight development for males treated with 50, 150 or 500 ppm. Females treated with 500 ppm showed a reduction in body weight gain during maturation, the first two weeks of gestation and during lactation. No toxicologically significant effects were detected in females treated with 150 or 50 ppm. There were no treatment-related effects on food consumption or food conversion efficiency for males treated with 50, 150 or 500 ppm. Females treated with 500 ppm showed a slight reduction in food consumption and food conversion efficiency during the first week of treatment. Recovery was evident thereafter. No such effects were detected in females treated with 150 or 50 ppm. There were no treatment-related effects on water consumption.

Fertility: No treatment-related effects were detected in mating performance. Fertility as assessed by pregnancy rate was unaffected by dietary exposure at all dietary levels. Gestation lengths were between 22 and 23½ days and the distribution of gestation lengths for treated females was essentially similar to control.

Developmental toxicity: Of the litters born, litter size at birth and subsequently on days 1 and 4 postpartum were comparable to controls. Sex ratio was comparable to controls. Offspring body weight gain and litter weights on days 1 and 4 postpartum were comparable to control litters. Surface righting was also comparable to controls. The clinical signs and necropsy findings apparent for offspring on the study were typical for the age observed. Neither the incidence nor distribution of these observations indicated any adverse effect of maternal treatment on offspring development at 50, 150 and 500 ppm.

Macroscopy: There were no macroscopic abnormalities detected. Animals of either sex treated with 500 ppm and females treated with 150 ppm showed a statistically significant increase in liver weight both absolute and relative to terminal body weight. Females treated with 500 ppm also showed a statistically significant increase in thyroid/parathyroid weight and reduced pituitary weight both absolute and relative to terminal body weight. No such effects were detected in males treated with 150 ppm or in animals of either sex treated with 50 ppm.

Microscopy: There were no microscopic abnormalities detected for histopathology.

Conclusion: Based on these findings, the oral administration substance to rats at dietary concentrations of 50, 150 and 500 ppm resulted in a reduced body weight gain, reduced initial food consumption, increased thyroid weights and reduced pituitary weights in females treated with 500 ppm and increased liver weights in animals of either sex treated with 500 ppm and in females treated with 150 ppm. The NOAEL is considered to be 150 ppm equivalent to 9.1 and 10.5 mg/kg bw (the 9.1 mg/kg bw is taken forward to the risk assessment). No treatment-related effects were evident in the reproductive parameters measured, and therefore, the NOEL for reproductive toxicity was considered to be 500 ppm 31 and 34 mg/kg bw for fertility and developmental toxicity.

Effects on developmental toxicity

Description of key information

- In the Reproscreen study (OECD TG 421) the NOAEL is set to the maximum dose tested, which is 500 ppm (equivalent to 31.0 and 34.0 mg/kg bw/day for males and females, respectively) for developmental toxicity.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

31 mg/kg bw/day

Species:

rat

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

OECD 421 Developmental toxicity:

The substance was administered by continuous dietary admixture to three groups, each of twelve male and twelve female Wistar Han™:RccHan™:WIST strain rats, for up to seven weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dietary concentrations of 50, 150 and 500 ppm (equivalent to a mean achieved dosage of 3.0, 9.1 and 31.0 mg/kg bw/day for males and 3.4, 10.5 and 34.0 mg/kg bw/day for females during pre-pairing). A control group of twelve males and twelve females was fed basal laboratory diet. This study was conducted according to OECD TG 421 and GLP principles. Clinical signs, body weight change, dietary intake and water consumption were monitored during the study. Pairing of animals within each dose group was undertaken on a one male: one female basis within each treatment group on day 15 of the study, with females subsequently being allowed to litter and rear their offspring to day 5 of lactation. During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size and offspring weights and assessment of surface righting reflex. All animals were subjected to a gross necropsy examination and histopathological evaluation of reproductive tissues was performed.

Results showed that there were no unscheduled deaths. There were no clinical signs apparent for animals of either sex treated with 50, 150 or 500 ppm. Females treated with 500 ppm showed a reduction in body weight gain during maturation, the first two weeks of gestation and during lactation. No toxicologically significant effects were detected in females treated with 150 or 50 ppm.. Females treated with 500 ppm showed a slight reduction in food consumption and food conversion efficiency during the first week of treatment. Recovery was evident thereafter. No such effects were detected in females treated with 150 or 50 ppm. There were no treatment-related effects on water consumption. No treatment-related effects were detected in mating performance. Fertility as assessed by pregnancy rate was unaffected by dietary exposure at all dietary levels. Gestation lengths were between 22 and 23½ days and the distribution of gestation lengths for treated females was essentially similar to control. Of the litters born, litter size at birth and subsequently on days 1 and 4 postpartum were comparable to controls. Sex ratio was comparable to controls. Offspring body weight gain and litter weights on days 1 and 4 postpartum were comparable to control litters. Surface righting was also comparable to controls. The clinical signs and necropsy findings apparent for offspring on the study were typical for the age observed. Neither the incidence nor distribution of these observations indicated any adverse effect of maternal treatment on offspring development at 50, 150 and 500 ppm. There were no macroscopic abnormalities detected. Animals of either sex treated with 500 ppm and females treated with 150 ppm showed a statistically significant increase in liver weight both absolute and relative to terminal body weight. Females treated with 500 ppm also showed a statistically significant increase in thyroid/parathyroid weight and reduced pituitary weight both absolute and relative to terminal body weight. There were no microscopic abnormalities detected for histopathology.

Based on these findings, the oral administration substance to rats at dietary concentrations of 50, 150 and 500 ppm resulted in a reduced body weight gain, reduced initial food consumption, increased thyroid weights and reduced pituitary weights in females treated with 500 ppm and increased liver weights in animals of either sex treated with 500 ppm and in females treated with 150 ppm. No treatment-related effects were evident in the reproductive parameters measured, and therefore, the NOEL for developmental toxicity was considered to be 500 ppm.

 

Justification for classification or non-classification

Based on the results of the available reproductive toxicity studies, 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).