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Key value for chemical safety assessment

Effects on fertility

Additional information

No key study addressing effects on fertility is available for hydroxycitronellal.

However, information from the most relevant reproductive toxicity study , performed with another terpene aldehyde with similar structural features as hydroxycitronellal, i.e. citral (CAS 5392-40-5), was taken for assessment of this endpoint via read across. The respective unsaturated aldehyde differs due to the presence of double bonds and lack of an additional hydroxyl residue but contain a terpenoid structure of comparable chain length such as hydroxycitronellal. Physicochemical parameters relevant for oral uptake show comparability in molecular weight and water solubility between hydroxycitronellal and citral (molecular weight of 172.3 and 152.2 ; log Pow at 1.68 and 2.76; water solubility of 35 and 0.420 g/l respectively). Although very low, a higher vapour pressure of citral vs hydroxycitronellal (4.6 vs 0.54 Pa respectively) indicates that citral data represent a worst case concerning adverse effects by vapour inhalation when compared to hydroxycitronellal. Furthermore, due to the additional hydroxyl residue, hydroxycitronellal is likely to be faster and more efficienty conjugated and eliminated than citral. Therefore citral is considered to represent a worst case also in this respect.

A reproduction toxicity screening test in rats was performed according to OECD Guideline 421 and GLP (Yoshimura, 2002). Male and female Sprague Dawley rats were exposed to citral by gavage at dosages of 0, 40, 200, and 1000 mg/kg bw/d in corn oil as vehicle. Male rats were treated for 14 days before mating, throughout the mating period, and up to day 46. Females were dosed from 14 days before mating, throughout the gestation period up to lactation day 3.

In the dose group, receiving 1000 mg/kg bw/day, parental toxicity was found in terms of decreased body weights (significant for body weight changes), temporarily decreased food consumption and histological changes in the forestomach, indicating a irritative potential of the test substance in the GI tract. No test substance related effects were detected in terms of reproductive performance, parental organ weights or histopathology of the reproductive organs. Test substance related developmental toxicity was found at 1000 mg/kg bw/d in terms of reduced pup body weights on postnatal days 0 to 4, whereas no other adverse effects were observed. The NOAELs for developmental toxicity and parental toxicity is set at 200 mg/kg bw/day.The NOAEL for reproductive toxicity in rats is set at 1000 mg/kg bw/day.

Several repeated dose toxicity studies with citral provide supportive information concerning fertility. In subchronic and chronic studies of Fischer 344 rats or B6C3F1 mice, exposed to diets containing a microencapsulated preparation with citral for 14 weeks, histopathological assessment on adrenal gland, clitoral gland, mammary gland, ovary, parathyroid gland, pituitary gland, preputial gland, prostate gland, testis with epididymis and seminal vesicles, thyroid gland and uterus was performed ( see Chapter “repeated dose toxicity” and “carcinogenicity”; NTP, 2003). No adverse effects on these organs were noted that were attributable to a substance-specific effect.

Administration of citral (210 mg citral/kg bw/d)to female rats for 2 years resulted in significantly decreased incidences of clitoral gland adenoma or carcinoma and of mammary gland fibroadenoma. NTP (2003) discussed these to be putatively related to an antiestrogenic effect of citral. Furthermore, data from literature indicate an induction benign and atypic prostrate hyperplasia (BPH and APH) in adolescent male rats after topical administration of citral. The postulated modes of action were putative interactions with testosterone levels or estrogen-like effects of citral.

 

A putative estrogenic activity of citral has been controversly discussed in literature on the basis of predominatly vitro data . However, Citral was found to be inactive in a rat uterotrophic assay (no increase of uterus weights as an indicator of estrogen-like activity) after oral exposure of 300 or 1000 mg/kg bw/d for 3 days (BASF 1999; 07R0155/98090). In line, the reproduction toxicity screening test in rats described above (acc. to OECD 421, GLP) revealed no test substance related effects on reproductive ability, organ weights or histopathology of the reproductive organs, on delivery or on maternal behavior .

 

Overall, the key study of the structural analog to hydroxycitronellal does not give indications for adverse effects on reproduction, therefore no rationale for a reproductive toxicity study (e.g. a two-generation study) with hydroxycitronellal is given based on the current data available. 

Effects on developmental toxicity

Additional information

No key study addressing effects on developmental toxicity is available for hydroxycitronellal.

Two in vitro developmental toxicity studies with hydroxycitronellal were reported in literature. Hen eggs were injected suprablastodermically with hydroxycitronellal in olive oil and malformations and emyryotoxicity in terms of mortality was observed (Abramovici, 1983; Forschmidt, 1979). However, these results were derived in an in vitro test without formal validation are of uncertain human relevance. Therefore these studies cannot be taken into account for assessment.

However, information from developmental toxicity studies , performed with another terpene aldehyde with similar structural features as hydroxycitronellal, i.e. citral (CAS 5392-40-5), was taken for assessment of this endpoint via read across. The respective unsaturated aldehyde differs due to the presence of double bonds and lack of an additional hydroxyl residue but contain a terpenoid structure of comparable chain length such as hydroxycitronellal. Physicochemical parameters relevant for oral uptake show comparability in molecular weight and water solubility between hydroxycitronellal and citral (molecular weight of 172.3 and 152.2 ; log Pow at 1.68 and 2.76; water solubility of 35 and 0.420 g/l respectively). Although very low, a higher vapour pressure of citral vs hydroxycitronellal (4.6 vs 0.54 Pa respectively) indicates that citral data represent a worst case concerning adverse effects by vapour inhalation when compared to hydroxycitronellal. Furthermore, due to the additional hydroxyl residue, hydroxycitronellal is likely to be faster and more efficienty conjugated and eliminated than citral. Therefore citral is considered to represent a worst case also in this respect.

In a developmental toxicity study, comparable to OECD Guideline 414, citral was orally administered via gavage to Wistar rats (0, 60, 125, 250, 500, 1000 mg/kg bw/day) from day 6 to day 15 of pregnancy (Nogueira 1995). A decrease in the corrected body weight gain (- uterus weigths) revealed maternal toxicity at 500 and 1000 mg/kg bw/d. Furthermore, significant reduction in body weight gains during gestation days 6 -11 at 60 and 125 mg/kg bw/d are considered to represent maternal toxicity since embryo weights are insignificant during this gestational phase. Thus, citral was found to be maternally toxic over the dose range tested, and severity of effects correlated with the dose applied.

A slight but statistically significant increase in the ratio of resorptions per implantations was observed in the 60 and 125 mg/kg bw/d dose group, being indicative for post implantation losses. Doses higher than 125 mg/kg led to a dose-dependent reduction of the ratio of pregnant per mated female indicating pre- or peri-implantation losses. Citral seemed to have induced whole-litter rather than intra-litter individual losses. The dose dependent differences in the effects observed, indicated that citral-induced gestational losses occurred earlier as the dose increased. Further developmental effects were observed from 125 mg/kg bw/day onwards, i.e. fetal growth retardation, increased incidences of minor skeletal abnormalities and increases in fetal spleen weights.The overlapping with overt maternal toxicity substantiate, that substance-induced developmental effects were secondary to maternal adverse effects.

In conclusion, developmental effects were observed starting at a dose of 125 mg/kg bw/d. Additionally, citral increased the ratio of resorptions per implantations at 60 and 125 mg/kg bw/d, and impaired implantation in doses higher than 125 mg/kg bw/d. Maternal toxicity, i.e. decreased body weight parameters were observed in all dose groups. Consequently the LOAEL for maternal toxicity and developmental toxicity is set at 60 mg/kg bw/d and no NOAEL is established from this study. The adverse effects on implantations and resorptions could not be confirmed in a guideline reproduction screening study (see below).

In a reproduction toxicity screening test in rats performed according to OECD Guideline 421, male and female Sprague Dawley rats were exposed to citral by gavage at dosages of 0, 40, 200, and 1000 mg/kg bw/d in corn oil as vehicle (Yoshimura et al., 2002).

In the dose group, receiving 1000 mg/kg bw/day, parental toxicity was found in terms of decreased body weights (significant for body weight changes), temporarily decreased food consumption and histological changes in the forestomach, indicating a irritative potential of the test substance in the GI tract. No test substance related effects were detected in terms of reproductive performance, parental organ weights or histopathology of the reproductive organs.Test substance related developmental toxicity was found at 1000 mg/kg bw/d in terms of reduced pup body weights on postnatal days 0 to 4, whereasn o other adverse effects were observed. The NOAELs for developmental toxicity and parental toxicity is set at 200 mg/kg bw/day.The NOAEL for reproductive toxicity in rats is set at 1000 mg/kg bw/day.

 

In a developmental toxicity study comparable to OECD Guideline 414, Sprague-Dawley rats were exposed to citral by inhalation (0, 10, 34, 68 ppm or 63, 215, 430 mg/m3) for 6 hours per day on gestation days 6 -15 (Gaworski et al. 1992). Maternal toxicity was observed at 68 ppm by maternal body weight loss during exposure period and by clinical signs, such as ocular opacity, breathing difficulties, nasal discharge and salivation. The clinical signs were considered to be secondary to the stress produced by severe respiratory tract irritation, and recovery occurred after completion of the exposure period.The number of corpora lutea, implantations, resorptions, foetal viability, litter size, and sex ratio were not adversely affected at any dose level. Although, there was a slight increase in preimplantantion loss in the test substance exposed groups, no biological relevance can be attributed to this finding since no siginficant reduction in litter size was observed. A slight non significant reduction in mean fetal body weights and a slight increase in the incidence of hypoplastic bones was observed in the 68 ppm dose group, being considered as secondary to the maternal toxic effects observed. No exposure-related malformations were observed. A NOAEC for maternal toxicity is set at 34 ppm (215 mg/m3) and a NOAEC for developmental toxicity is set at 68 ppm (430 mg/m3), i.e. the highest concentration tested.

 

In summary, signs of developmental toxicity have been observed after oral or inhalative exposure with citral in the presence of maternally toxic doses. No teratogenic effects, leading to specific malformations were found. Consequently, the observed effects on developmental toxicity are considered to be secondary to maternal toxicity.

 

In a weight of evidence, the available data do not provide sufficient evidence warranting the classification of hydroxycitronellal to be a developmental toxicant.

Justification for classification or non-classification

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