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Repeated dose toxicity – oral

No valid key study on oral repeated dose toxicity is available for citronellol. However oral repeated dose toxicity data from literature with citronellol in a mixture or with structurally and metabolically related test substances are taken for assessment in a weight of evidence.

 

In a feeding study in rats from secondary literature, a mixture of linalool/citronellol (50% each) were orally administered daily for 90 days, thus giving a daily amount of approx. 50 mg/kg bw/d citronellol (Trubek, 1958). Food intake and body weight gain was reduced in males, however, the authors attributed this effect to be caused by the palatability of the given mixture and considered these effects to be biologically insignificant.

In a limited urine analysis, in haematology, in gross examinations and in liver and kidney weights, no test substance related effects were observed. The NOEL was determined as 51 and 56 mg/kg bw/d citronellol for males and female, respectively.

 

In a subacute feeding study in female chicken from secondary source with limited documentation, no effects were observed at a dose of 200 mg/kg bw/day citronellol when fed for five weeks (Hood, 1978). This study was regarded as irrelevant for the assessment of the given endpoint.

 

In this weight of evidence, data from a study performed with geraniol (3,7-dimethyl-2,6-octadien-1-ol) were also taken into account. Inclusion of geraniol into this assessment is justified by the structural similarity with citronellol (3,7-dimethyloct-6-en-1-ol). These structures are identical except for an additional double bond found in geraniol. The structure of geraniol is considered to represent a worst case when compared to citronellol based on this second double bond as possible additional reactive feature. Furthermore, relevant physicochemical parameters show comparability between geraniol and citronellol (molecular weight of 154.2 and 156.3 ; log Pow at 2.6 and 3.41; vapour pressure of 1 and 8.6 Pa; water solubility of 769 and 307 mg/l respectively).

A mixture of geraniol (3,7-dimethyl-2,6-octadienol) and the isomer (3,7-dimethyl-1,6-octadienol) was fed to five male and five female individually housed Osborne-Mendel rats per dose group (Hagan, 1967). Thereby, a concentrations of 1000 ppm (= ca. 55 mg/kg bw/day) was administered for 189-169 days and a concentration of 10000 ppm (= ca. 550 mg/kg bw/day) was given for 112 days. During the study, the food consumption was monitored and blood was collected at the end of study and was subjected analysis of white cell counts, red cell counts and hemoglobin and hematocrit content. Also, animals were necropsied and histopathology was performed. Since no clinical signs, no effects on body weight as well as no histopathological changes were observed, the NOEL could be estimated as 10000 ppm. Thus the NOAEL would be > 550 mg/kg bw/day.

 

Furthermore, data from the metabolically related acetates of citronellol and geraniol; i.e. citronellyl acetate (CAS 150-84-5) and geranyl acetate (CAS 105-87-3), are taken into account for further assessment. These acetates are expected to hydrolyze to geraniol or citronellol and acetic acid. In animals, hydrolysis of aliphatic esters are catalyzed by classes of enzymes recognized as carboxylesterases or esterase. Citronellyl acetate was reported to be completely hydrolyzed within 2 hours by simulated intestinal fluid containing pancreatin at pH 7.5.

 

Repeated dose toxicity was analyzed in a 13 week oral toxicity study in rats performed by the National Toxicity Program of the US National Institutes of Health (NTP, 1987). In this study, doses of 250, 500, 1000, 2000 and 4000 mg/kg bw/d of food-grade geranyl acetate (71% geranyl acetate (CAS 105-87-3) and 29% citronellyl acetate (CAS 150-84-5)) in corn oil was administered by gavage to ten male and female Fischer 344 rats for 13 weeks. 1/10 female and 2/10 male of the 4000 mg/kg bw/d group died, in addition to one animal accidently killed by gavage error in the 500 mg/kg bw/d group. Besides mortality, the observed substance related toxic effect was a depressed mean body weight of the animals of the 4000 mg/kg bw/d group compared to control (19% for the males, 8% for the females). Three males showed reddened mucosa of the stomach, however no test substance related histopathological changes were observed. Thus, a NOAEL of 2000 mg/kg bw/d of food-grade geranyl acetate has been set, corresponding to 580 mg/kg bw/d citronellyl acetate.

In the same study, also, ten male and female B6C3F1 per dose were gavaged by doses of 125, 250, 500, 1000, 2000 mg/kg bw food-grade geranyl acetate in corn oil for the 13 week study.

Seven males and nine females of the 2000 mg/kg bw group died. Also, three females of the lower dose groups died, but this was accidentally due to an error of gavage. No other clinical signs of toxicity were noted during the study. The males of the 2000 mg/kg bw group exhibit a delay in body weight gain. Liver, kidney and myocardium of males and females of the 2000 mg/kg bw group displayed cytoplasmic vacuolization with lipid inclusions indicative of fatty degeneration. Furthermore, stomach lesions including inflammation and edema were reported in this group. Thus, the NOAEL was set at 1000 mg/kg bw/d food-grade geranyl acetate corresponding to 290 mg/kg bw/d citronellyl acetate.

 

Repeated dose toxicity – inhalative

No valid key study on inhalative repeated dose toxicity is available for citronellol. In a subchronic inhalation study, available in literature only, 12 male and female CD and Sprague-Dawley rats and Syrian hamsters were exposed to 50 mg/m3 of fragrance mixtures including citronellol for 6 to 13 weeks (Fukayama, 1999). In a published russian chronic inhalation study, 25 rats per dose were exposed to 0.03, 0.3, 2.8 mg/m3 for 100 days, resulting in some changes in the nervous system as well as some liver and immunological changes (Kostrodymov, 1981). However, both inhalation studies cannot be taken into account for assessment due to methodological deficits.

 

Concerning putative irritative effects of citronellol to the respiratory tract, subacute repeated dose inhalation studies in rats from fragrance materials, with irritating properties i.e. linalool (CAS 78-70-6), or skin sensitizing properties, i.e. hydroxycitronellal (CAS 107-75-5) are taken for assessment.

Physicochemical parameters show general comparability between the terpene alcohols linalool and citronellol (molecular weight of 154.2 and 156.3; log Pow at 2.9 and 3.41; water solubility of 1560 and 307 mg/l and vapour pressure of 27.3 Pa vs. 8.6 Pa respectively), giving confidence in using linalool inhalation data to cover putative irritative effects of citronellol.

In a repeated dose toxicity study according to OECD TG 412 and GLP, linalool was administered as a 6-hour, nose-only inhalation exposure to Crl:CD(SD) rats (Wil 2012). Exposures were conducted on a 5-day per week basis for a period of 2 weeks (10 total exposures for each animal). The target exposure concentrations were 0.63, 6.3 and 63 mg/m3 (equivalent to 0.1, 1, and 10 ppm, respectively) and the overall mean exposure concentrations were 0.76, 6.6, 56 mg/m3. There were no test substance-related effects on survival, clinical observations, body and organ weights, food consumption, hematology, coagulation, serum chemistry, BALF clinical chemistry, BALF cytology parameters, or BALF cytokine levels, or macroscopic findings in any of the test substance-treated groups. Test substance-related microscopic findings (inflammation and epithelial squamous and transitional hyperplasia) were noted in the nasal cavity of males and females exposed to 0.63, 6.3, and 63 mg/m3 of the test substance. These findings were considered exacerbated background lesions as they were also observed in control group males and females, and were not considered adverse. Therefore, the no-observed-adverse-effect concentration was set at 63 mg/m3 (equivalent to 10 ppm), the highest exposure concentration tested.

The terpenoid aldehyde hydroxycitronellal is comparable in molecular weight (172.26) and log Pow (1.68) however shows a higher water solubility (35000 mg/l) than citronellol. Vapour pressure of citronellol is low but indicated to be somewhat higher than of hydroxycitronellal (0.54 Pa). However, due to its skin sensitizing properties, hydroxycitronellal inhalation data are included into this assessment.

In a repeated dose toxicity study according to OECD TG 412 and GLP, hydroxycitronellal was administered as a 6-hour, nose-only inhalation exposure to Crl:CD(SD) rats (Wil 2013). Exposures were conducted on a 5-day per week basis for a period of 2 weeks (10 total exposures for each animal). The target exposure concentrations were 0.70, 7.0, and 70 mg/m3 (equivalent to 0.1, 1, and 10 ppm, respectively) and the overall mean exposure concentrations were 0.84, 6.4, and 73 mg/m3. Exposure was well tolerated at all exposure levels. Test substance-related effects were limited to non-adverse clinical observations (yellow material on body surfaces) in the 70 mg/m3 group females. Therefore, the no-observed-adverse-effect concentration was considered to be 70 mg/m3 (equivalent to 10 ppm), the highest exposure concentration tested.

Since a putative local respiratory effect of citronellol would depend on a threshold concentration for cytotoxicity, and this threshold concentration would be independent from exposure duration, a subacute inhalation study would be considered sufficient for the derivation of a local threshold inhalation concentration (see ECETOC TR No.110, 2010). Therefore, in order to support the weight of evidence of the data given above, a 5-day inhalation toxicity study in rats with focus on investigations of the respiratory tract with citronellol as test substance is proposed.

Justification for classification or non-classification

The present data on repeated dose toxicity do not fulfill the criteria laid down in 67/548/EEC and regulation (EU) 1272/2008, and therefore, a non-classification is warranted.