Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity - 
NOAEL (male/female) = 125 mg/kg bw/d (gavage, OECD 407, GLP)
NOAEL (male/female) = 1000 mg/kg bw/d (dermal, OECD 411, GLP)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Oral administration

Pyranol was administered orally (gavage) to rats in a repeated dose (28 day) toxicity study according to GLP and equivalent to OECD TG 407 (Toxicol Laboratories 1989, FCH/2/88). Three groups of 10 male and 10 female Crl:CD(SD) BR strain (VAF plus) rats received a suspension of Pyranol in 1% aqueous hydroxypropylmethylcellulose by gavage at dose levels of 25, 125 or 625 mg/kg bw/day whilst the fourth group received 1% aqueous hydroxypropylmethylcellulose alone and acted as control. All animals were dosed once daily for 4 weeks until the day before necropsy.

No deaths occurred during the whole study period. Administration of Pyranol by gavage at a dose level of 625 mg/kg bw/day was associated with minor changes only. These included salivation, changes in coat condition, marginal reductions in red blood cell values (dubious biological significance), moderate increases in plasma triglycerides, the presence of ketones in the urine (males only) and slightly raised liver weight and adrenal weight (females only). The increases in plasma triglycerides, associated with increased liver weight, are considered to be genuine effects. In the absence of any microscopic evidence of hepatotoxicity, these probably reflect physiological adaptation to the metabolism of a xenobiotic. The presence of ketones in the urine of males is significant since ketones are not normally found in rat urine. Possibly, this response arises from breakdown products of the test article. Bodyweight gain and food intake were unaffected by treatment.The remaining changes are considered to be of doubtful significance.

In conclusion the NOAEL of Pyranol for repeated dose toxicity study in SD-rats was defined as 125 mg/kg bw/d.

 

Dermal administration

The described data above indicate that Pyranol is of relatively low toxicity via the oral route. The primary route of exposure when in use is via skin contact as Pyranolis a fragrance material and only present in dermal consumer products (i.e. cosmetics, laundry care products). Exposure of humans via the oral route can therefore practically be excluded and is irrelevant compared to the primary route of exposure which is dermal. Besides, an in vitro study on dermal penetration of 14C-Pyranol through rat skin (according to OECD 428 and GLP, see also IUCLID chapter 7.1.2) showed significant dermal absorption. In order to address the endpoint of sub-chronic toxicity of Pyranol a 90-day repeated dose study in rats, oral route (according to OECD 411) was performed (BASF SE 2014, 82R0639/09R137). Pyranol was administered 5 days per week to male and female Wistar rats dermally at dose levels of 0 (test group 0), 100 (test group 1), 300 (test group 2) and 1000 (test group 3) mg/kg bw/day over a period of 90 days. Each test group consisted of 10 animals per sex.

Some male and female animals showed slight erythema, erosion and scales. These finding are attributed to the irritating properties of the test substance. No other test substance-related effects concerning clinical signs, body weight food consumption, water consumption, haematology, clinical chemistry, urinalysis, neurobehaviour, organ weights and histopathology were observed. Therefore, the NOEAL for repeated dose toxicity of this study was set to 1000 mg/kg bw/day.

 

Inhalation

There are no data available.

 

Conclusion

In a dermal 90 day repeated dose toxicity study (BASF SE, 2015), apart from slight erythema, erosion and scales in some animals no other thest substance related effects were observed. Therefore, the NOAEL was set to 1000 mg/kg bw/day.

In an oral 28 day repeated dose study (Toxicol Laboratories 1989, FCH/2/88), there was no substance-specific organotoxicity detectable after 28 day repeated oral administration of Pyranol to rats. As treatment-related findings in the study, salivation, changes in coat condition, minor changes in haematological and clinical chemistry parameters, increased liver weight (without histological correlation) as well as ketones in the urine (males only) were observed at 625 mg/kg bw/day.

In conclusion, the NOAEL for repeated dose toxicity has been set at 125 mg/kg bw/day.

Justification for classification or non-classification

Based on the available data, Pyranol (Tetrahydro-4-methyl-2-(2-methylpropyl)-2H-pyran-4-ol) is not subjected to classification and labelling for repeated dose or specific target organ toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC.