A mixture of: cis-tetrahydro-2-isobutyl-4-methylpyran-4-ol; trans-tetrahydro-2-isobutyl-4-methylpyran-4-ol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

OECD 443, oral, BASF SE, 2018:

- NOAEL (general systemic toxicity) = 4000 ppm (about 359 mg/kg bw/d)

- NOAEL (fertility and reproductive performance) = 12500 ppm (about 1113 mg/kg bw/d)

OECD 421, dermal, BASF SE, 2015:

- NOAEL (general systemic toxicity, fertility and reproductive performance) = 1000 mg/kg bw/d

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

GLP guideline study

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP guideline study

Additional information

Pyranol was administered to groups of 25 male and 25 female healthy young Wistar rats (F0 parental generation) as a homogeneous addition to the food in different concentrations (0, 1000, 4000 and 12500 ppm) during an Extended One-Generation Reproduction Toxicity Study according to OECD 443 and GLP (BASF SE, 2018). These concentrations were reduced to 50% (500, 2000 and 6250 ppm) during lactation.This dietary adjustment, derived from historical body weight and food consumption data, maintained the dams at the desired target doses of Pyranol during this period of increased food intake. The overall mean doses of Pyranol throughout all study phases and across all cohorts were approx. 90 mg/kg body weight/day (mg/kg bw/d) in the 1000 ppm group, approx. 359 mg/kg bw/d in the 4000 ppm group and approx. 1113 mg/kg bw/d in the 12500 ppm group.

There were no test substance-relatedmortalitiesor adverseclinical observationsnoted in any of the groups. In particular, regularly conducted detailed clinical observations revealed no effects. The high-dose of the test substance (12500 ppm) produced some signs of adverse systemic effects in the F0 parental rats and F1 offspring. In the 12500 ppm F0 femalesfood consumptionwas consistently reduced during lactation. In contrast to this food consumption in the 1000 ppm and 4000 ppm F0 females as well as in the F0 males and F1 adolescents (Cohort 1A and 1B) of all dose groups remained unchanged. Body weights and body weight change of all test substance-treated male and female F0 rats were essentially comparable to the concurrent control values throughout the entire study. The final body weights of the high-dose F0 males and females (12500 ppm) were marginally (approximately 3-5%) below control, but as the difference was not statistically significant and very small it could not be attributed to the treatment without doubt.

In contrast body weights and, particularly, body weight change of the F1 high-dose (12500 ppm) Cohort 1A and Cohort 1B males and females were consistently below the concurrent control throughout the in-life period. The body weight difference gained statistical significance usually towards the end of their study and final weights were about 5-7% below control. The F1 high-dose adolescents of both cohorts generally gained 7-10% less body weight than the control throughout in-life. Pup body weight developmentof the high-dose offspring (12500 ppm) was affected by the treatment towards the end of lactation, as these offspring weighed about 5-7% less than control at weaning (PND 21) and their weights were below the historical control range.Accordingly, there was no test compound-related influence on high-dose F1 pup body weight change until PND 14. In the last week of lactation (PND 14 – 21), however, themean body weight change of these pups was statistically significantly below the concurrent control values (about 9% for both sexes) which crucially contributed to the overall lower weight gain (about 6% for both sexes) of this test group throughout lactation. During the last week of lactation the offspring already consume considerable amounts of medicated diet and the post-weaning body weight gain of the high-dose adolescents in the F1A and B cohorts continued to be lower compared to the control. Thus, it can be assumed that the lower pre-weaning body weights/body weight gain in the high-dose group were caused by direct exposure of the offspring to the test compound through the diet rather than representing developmental toxicity.In addition, the pup body weight effects had no influence on postnatal pup survival or well-being, neither during early lactation nor later, as clinical and/or gross necropsy examinations of the high-dose F1 pups revealed no adverse findings. A statistically significant delay in vaginal opening of about one day beyond the concurrent control was observed in the female F1 offspring of the high-dose group (12500 ppm). The delay is also slightly (less than a day) beyond the historical control range of the test facility. There was a small but consistent effect on post-weaning body weight development in the affected females notable, and no corresponding increase in body weight was observed in the older animals at the time of puberty. On the other hand, there was no effect on estrous cyclicity or the integrity of sexual organs in these females, including differential ovarian follicle count, during later life. Thus, there is evidence that the rather small difference to the control indicates that the later onset of puberty is most likely a consequence of systemic toxicity and subsequent general developmental delay, and not a specific effect on the timing of puberty. A statistically significant delay in preputial separation of about 1.5 days beyond the concurrent control was observed in the female F1 offspring of the high-dose group (12500 ppm). As, however, all values for days and weights for all treatment groups including the high-dose group were well within the historical control range, any observed statistical change was considered incidental and not treatment-related. In addition, no effect on the integrity of sexual organs (including accessory sexual glands) was noted in all treated males.

Thus, under the conditions of the present extended one-generation reproduction toxicity study the NOAEL (no observed adverse effect level) for general, systemic toxicity is 4000 ppm (about 359 mg/kg bw/d), based on decreased food consumption and body weight/body weight gain at 12500 ppm, in the F0 parental females as well as adolescent and adult F1 offspring. The NOAEL for fertility and reproductive performance for the parental rats is 12500 ppm (about 1113 mg/kg bw/d), the highest tested dose. The NOAEL for developmental toxicity in the F1 progeny is 12500 ppm (about 1113 mg/kg bw/d), the highest tested dose. Lower pup body weights/body weight gain in the high-dose pups shortly before weaning as well as a small delay of puberty in females were caused by systemic toxicity of the test substance after direct exposure through the diet and do not represent developmental toxicity.

In order to address the potential for reproduction toxicity of Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol (Pyranol, CAS 63500-71-0) a screening test for reproduction/developmental toxicity in rats according to OECD 421 and GLP was conducted (BASF SE, 2015). Since skin contact in production and use is likely, the physicochemical properties suggest a significant rate of absorption through the skin and in vitro tests indicate significant dermal absorption (detailed information see IUCLID Chapter 7.8.1 Study proposal), the dermal route is the most relevant route of exposure. Therefore, ten male and ten female Wistar rats per dose received Pyranol at doses of 100, 300 and 1000 mg/kg/d by semiocclusive dermal application. The control group received the vehicle corn oil alone. The application period was a minimum of four weeks for males and a minimum of six weeks for the females starting at least 14 day before mating. After the mating period, the male animals were sacrificed while the females were allowed to litter and rear their pups until day 4 post partum. Thereafter, the pups (F1-generation) and the F0-females were sacrificed. No test substance-related effects were observed concerning body weight and food consumption. Vaginal discharge was detected in single animals of the control as well as the treated groups during mating phase. One female of the control group showed piloerection during gestation phase. These findings were assessed as being incidental in nature since they occurred in individual animals only and did not show a dose-response relationship. No effects on parental organ weights and gross- and histopathological findings as well as offspring examinations were observed. Thus, under the conditions of this reproduction/developmental toxicity screening study the NOAEL for general systemic toxicity as well as reproductive performance and fertility in male and female Wistar rats was 1000 mg/kg bw/d.

 

Furthermore, a screening study was performed to obtain initial information on the effect of Pyranol on male sexual organs after repeated oral administration to Wistar rats (BASF SE, 2010). Pyranol was administered by gavage (olive oil as vehicle) over a period of 14 days at 1000 mg/kg bw/day to 5 male young Wistar rats. Food consumption and body weight were recorded regularly throughout the study period. The state of health of the animals was checked each day. All animals were assessed by gross pathology, special attention being given to the reproductive organs. Weight was determined for anesthetized animals, testes, epididymis, cauda epididymidis, prostate and seminal vesicles including coagulation glands. Furthermore, cauda epididymidis sperm motility, sperm morphology, spermatid concentration in the testis and concentration in the cauda epididymidis were determined. Left testis, left epididymis, seminal vesicles, coagulation glands, prostate and all gross lesions were examined histologically. Salivation was observed after treatment in all animals. Neither sperm evaluation nor gross pathology and histopathology of male sexual organs revealed treatment-related findings in the animals exposed to Pyranol. No treatment-related adverse effects regarding the male reproductive organs were observed in this study.

Conclusion

Based on the results from the oral Extended One-Generation Reproduction Toxicity Study and the dermal screening test for reproduction/developmental toxicity in ratsand the oral screening study on testes toxicity in male rats, no evidence for adverse effects on fertility by Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol (Pyranol) was found up to the dose levels of 1000 mg/kg bw/d for males and females.

Short description of key information:
Toxicity to fertility:
- NOAEL = 1000 mg/kg bw/d (OECD 443, oral, BASF SE, 2018; OECD 421, dermal, BASF SE, 2015)

Effects on developmental toxicity

Description of key information

- NOAEL (developmental toxicity) = 1000 mg/kg bw/d (OECD 414, dermal, BASF SE, 2015)

- NOAEL (developmental toxicity) = 12500 ppm (about 1113 mg/kg bw/d) (OECD 443, oral, BASF SE, 2018)

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

GLP guideline study

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP guideline study

Additional information

In order to address the potential for developmental toxicity of Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol (Pyranol, CAS 63500-71-0) a pre-natal developmental toxicity study in rats according to OECD 414 and GLP was conducted (BASF SE, 2015). Since skin contact in production and use is likely, the physicochemical properties suggest a significant rate of absorption through the skin and in vitro tests indicate significant dermal absorption (detailed information see IUCLID Chapter 7.8.2 Study proposal), the dermal route is the most relevant route of exposure. The test substance Pyranol was tested for its prenatal developmental toxicity in Wistar rats. The test substance was given daily dermally (6 hours/day) as an oily solution to groups of 25 time-mated female Wistar rats at dose levels of 100, 300 and 1000 mg/kg body weight/day (mg/kg bw/d) to the intact shaven dorsal skin using a semi-occlusive dressing on gestation days (GD) 6 through 19. The control group, consisting of 25 females, was dosed with the vehicle (corn oil) in parallel. A standard dose volume of 2 mL/kg body weight was used for each test group. At terminal sacrifice on GD 20, 24-25 females per group had implantation sites. No test substance-related, adverse effects were noted at any dose group. Under the conditions of this prenatal developmental toxicity study, the dermal application of Pyranol to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose level of 1000 mg/kg bw/d did not cause any evidence of maternal toxicity. In conclusion, the NOAEL for maternal toxicity was 1000 mg/kg bw/d, the highest dose tested. The NOAEL for parental developmental toxicity was also 1000 mg/kg bw/d. No toxicologically relevant adverse fetal findings were evident.

Justification for classification or non-classification

The present data on reproductive/developmental toxicity do not fulfill the criteria laid down in 67/548/EEC and 272/2008/EEC, and therefore, a non-classification is warranted.