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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
600 mg/kg bw/day
Effect on fertility: via dermal route
Dose descriptor:
NOAEL
300 mg/kg bw/day
Additional information

According to Cadby et al. (Consumer Exposure to Fragrance Ingredients: Providing Estimates for Safety Evaluation, Regulatory Toxicology and Pharmacology 36, 246 - 252 (2002)) the dermal route is the most relevant of systemic exposure to fragrance materials. "Safety evaluation of fragrance ingredients is based on data from tests, in which material is administered to human or animal subjects by placing it on the surface of the skin. For this reason, it is unnecessary to consider anything further than estimating quantities of these ingredients deposited on the surface of the skin." For this reason and according to REACh-Annexes ("most appropriate route of administration, having regard to the likely route of human exposure") a dermal reproduction / developmental toxicity screening test according to OECD 421 has been performed in wistar rats (BASF SE, 2010).

 

A 10 day range finding study with 3 female rats per dose using doses of 1000, 750, 500 and 300 mg/kg bw/day led to different grades of skin irritation (scales and erythema) in the doses of 500 - 1000 mg/kg bw/d, and no clinical findings of the treated skin in the 300 mg/kg bw/day group. Based on these findings, doses of 0, 50, 150 and 450 mg/kg bw/day were chosen for the reproduction screening study. The test substance was administered to 10 male and 10 female young Wistar rats dissolved in corn oil. Application area was the intact clipped skin of the back (dorsal and dorsolateral areas of the trunk; not less than 10% of the body surface). The first clipping was carried out at least 24 hours before the randomization. The rats were reclipped at least once a week (depending on the hair growth). Dermal application of the test-substance preparations to the clipped intact dorsal skin was carried out with 3-mL syringes and a semiocclusive dressing (4 layers of absorbent gauze and stretch bandage). The test-substance preparation was applied to the dorsal skin with the syringe in each case. After removal of the dressing, the application area was washed with lukewarm water. Application was daily for at least six hours.

During the course of the study the initial high dose (450 mg/kg bw/day) turned out to be intolerable for the rat skin (strong irritation reactions), so that from day 10 onwards the high dose had to be reduced to 300 mg/kg bw/day. About 2 weeks after the beginning of treatment, animals were mated to produce a litter. Mating pairs were from the same dose group. Pregnant females were allowed to give birth and the offspring was brought up until postnatal day (PND) 4. The study was terminated with the sacrifice of the pups on PND 4 and of lactating dams shortly thereafter.

Regarding clinical examinations, only signs of local dermal toxicity were observed for males and females at all dose levels. No changes in food consumption and body weight data were seen at any dose level.

Fertility indices for male and female animals were not impaired by test-substance administration.

Regarding pathology, there were no treatment-related necropsies or histological findings in ovaries, testes or epididymides associated with dermal administration of the test substance. The local minimal inflammatory reactions in the skin of treated males (test groups 1-3) and females (test group 3 only) were regarded as related to treatment and adverse.

Therefore, the NOAEL for fertility for geraniol is shown to be >300 mg/kg bw/day via the dermal route. Systemic exposure to geraniol is limited by the strong local irritation effects.

 

Apart from studies with the test substance geraniol, studies using structurally similar compounds were taken into account to address the endpoint of toxicity to reproduction. Geraniol (trans-3,7-dimethyl-2,6-octadien-1-ol) and nerol (cis-3,7-dimethyl-2,6-octadien-1-ol) are trans/cis-isomers and therefore differ only in their relative orientation of functional groups within the molecule. Furthermore, relevant physicochemical parameters show comparability between geraniol and nerol.

A study according to OECD 421 using the oral route of exposure was performed with the reaction mass of geraniol and nerol (E- and Z-isomer, 60:40 -mixture) (BASF SE, 2010).

The test substance was administered to groups of 10 male and 10 female young Wistar rats dissolved in corn oil, via daily gavage. The dose levels were 0, 100, 300 and 1000 mg/kg body weight/day. About 2 weeks after the beginning of treatment, animals were mated to produce a litter. Mating pairs were from the same dose group. Pregnant females were allowed to give birth and the offspring was brought up until postnatal day (PND) 4. The study was terminated with the sacrifice of the pups on PND 4 and of lactating dams shortly thereafter.

All mid- and high-dose as well as some low-dose animals of both sex showed transient salivation for a few minutes immediately after each treatment. This was likely to be induced by the unpleasant taste of the test substance or by local irritation of the upper digestive tract. It is neither considered to be a sign of systemic toxicity nor as adverse.

Clinical observations indicated distinct toxicity in the exposed parental animals of the high dose group (1000 mg/kg bw/d) but not in the animals of the mid- and low-dose group.

A reduction of food consumption (up to 10% in males and females during treatment weeks 0-1 as well as females (-34%) during lactation), and decreased body weight in males (up to -5%) had been determined during treatment weeks 2-4. A similar pattern as for clinical observations was noted for body weight and body weight change of the parental animals. A distinct decrease was noted in the high-dose animals of both sex even manifested in different time periods of the study. The body weight change in males was reduced from week 0 to 5 (-28% on average in this time period). In females a significant body weight change was observed during lactation leading to a body weight loss (-3%). Consequently, the body weight was decreased in males during treatment weeks 2-5 (-7%) and in females of week 6 (-9%).

The test compound did not adversely affect fertility of the F0 generation parental animals at all dose levels as there were no changes of male/female mating and fertility indices, time until successful copulation, duration of pregnancy and mean number of implantations.

Since the reaction mass of geraniol and nerol consists of ca. 60% geraniol and 40% nerol, it was concluded that a systemic exposure to 600 mg/kg bw/day of geraniol can be regarded as NOAEL concerning effects on fertility.However, the NOAEL for systemic effects is lower.

 

A Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD TG 422) has been performed (DRT, 2013). The test item nerol was administered by dietary admixture (initially mixed with 2% corn oil) to three groups of Han Wistar rats for up to 42 consecutive days (main phase males, toxicity females and recovery animals) or between 41 and 53 days (including three weeks exposure phase, pairing, gestation and early lactation; main phase females) at dietary concentrations of 3000, 6000 and 12000 ppm (equivalent to 191.2, 374 and 720 mg/kg bw/day, respectively). A control group was treated with basal laboratory diet (with 2% corn oil). Two recovery groups, each of five males and five females, were treated with the high dose (12000 ppm) or basal laboratory diet alone for 42 consecutive days and then maintained without treatment for a further 14 days. Pairing of main phase animals and recovery males within each dose group was undertaken on a one male:one female basis within each treatment group on Day 22 of the study, with females subsequently being allowed to litter and rear their offspring to Day 7 of lactation.

No findings, which were considered to be test item-related, were noted during clinical observations, functional observational battery testing or locomotor activity testing in males or females at any dose level.Visual inspection of water bottles did not reveal any significant intergroup differences during the study, whereas food consumption was reduced during the first days of treatment in all treated groups. This reduction in food intake was maintained at the high dose throughout the treatment period in both males and females but particularly for main phase females. This reduction in food consumption was considered to reflect a reluctance to eat the diet admixture due to its low palatability, particularly at the high dose. During the lactation period, the dietary intake of main phase females was reduced (up to 37% decrease compared to controls at 12000 ppm) in all test item treated groups. In main phase females, the overall reduction of food consumption throughout the study was 7, 11 and 23% of control group for 3000, 6000 and 12000 ppm groups, respectively.

In males in the 12000 ppm group, the reduction in bodyweight gain was particularly high during the first week of treatment (-80%) and remained lower than controls throughout the treatment period (-17% between days 8 - 42). During the recovery period, previously treated males at 12000 ppm showed a 50% increase in bodyweight gain compared to controls. During the pre-pairing period, females showed a decrease in bodyweight gain, especially during the first week of the treatment. From day 8 to the end of the study, toxicity group females showed similar mean bodyweight gain when compared to controls at 3000 and 6000 ppm but a 25% decrease in mean bodyweight gain compared to controls at 12000 ppm. During the recovery phase, their mean bodyweight gain was 3 times higher than the concurrent control group. During gestation period, main phase females showed an overall decrease in mean bodyweight gain at 3000, 6000 and 12000 ppm (-11, -6 and -33%, respectively), mainly observed during the last week of gestation. This decrease in bodyweight gains was also observed during lactation period (-50%) in all treated groups compared to controls.

No treatment related findings were observed in organ weights.Treatment with the test item at the dose levels of 12000 ppm caused a statistically significant decrease of total bilirubin, sodium level, globulin and tryglycerid, and increase in creatinin, ALP and albumin in males and decreased potassium level in recovery phase females. No further changes of biochemical blood parameters which were considered to be test item related were found in males or females at any dose level. Three main phase group males treated with 12000 ppm of the test substance revealed an enlarged liver that correlated with slight centrilobular hypertrophy of liver cells which was considered to be test item-related. Microscopic examination of liver sections revealed minimal centrilobular and partially reversible liver cell hypertrophy in all males. Furthermore treatment-related irritant effects were present in forestomach of main phase males and toxicity phase females.

No treatment related effects on mating, fertility and gestation length were observed. Therefore, the NOAEL concerning effects on fertility was set to the highest dose tested of 12000 ppm.

 

 

The Registrant received an ECHA draft decision on a testing proposal evaluation (communication number: TPE-D-0000002210-93-04/D) on geraniol (CAS No. 106-24-1, EC No. 203-377-1), in which the registrant is requested to perform either a two-generation reproductive toxicity study in rats, oral route (test method: EU B.35/OECD 416) or an extended one-generation reproductive toxicity study in rats, oral route (test method: OECD 443) including the extension of Cohort 1B to mate the F1 animals to produce the F2 generation which shall be kept until weaning. The Registrant prefers to perform the extended one-generation reproductive toxicity study in rats, oral route (test method: OECD 443) without extension of Cohort 1B to mate the F1 animals to produce the F2 generation until weaning (see study proposal submission IUCLID Chapter 7.8.1). Mating of F1 animals has not been found to be mandatory in order to fulfill the data requirements of Annex X, 8.7.3 based on a sound scientific evidence available (Piersma et al. (1), Martin et al. (2), Janer et al. (3), Beekhuijzen et al. (4), Rorije et al. (5)). Therefore, the extended one-generation reproductive toxicity study in rats, oral route (test method: OECD 443) with Cohort 1A will be fully sufficient in order to allow for a proper risk assessment including valid classification and labelling, unless the results obtained during the study are ambiguous and do not allow a clear decision towards classification or no classification. Overall, for animal welfare reasons it was proposed to make the second generation optional based on the results observed during the study and to leave this decision to the registrant.  Furthermore, the Registrant received an ECHA decision (communication number: TPE-D-0000002211-91-05/F) on a testing proposal evaluation for the related Reaction mass of 2,6-Octadien-1-ol, 3,7-dimethyl-, (E) and 2,6-Octadien-1-ol, 3,7-dimethyl-, (Z)-, (reaction mass of geraniol (60%) and nerol (40%); EC No. 906-125-5), in which the Registrant is required to carry out either of the following studies to fulfill the endpoint requirement for reproductive toxicity at Annex X, 8.7.3: Two-generation reproductive toxicity study in rats, oral route (test method: EU B.35/OECD 416) or extended one-generation reproductive toxicity study in rats, oral route (test method: OECD 443) including the extension of Cohort 1B to mate the F1 animals to produce the F2 generation which shall be kept until weaning. These studies shall be performed with the named reaction mass (geraniol and the respective stereoisomer nerol). In the comments sent to ECHA on 19th March 2012 and 19th September 2012 the Registrant has communicated an overall testing strategy covering both pure geraniol (CAS No. 106-24-1, EC No. 203-377-1) and the related reaction mass (EC No. 906-125-5). This strategy has been further specified in the member state committee meeting on 23th October 2012. The Registrant has proposed to initially perform a one-generation reproductive toxicity study in rats with pure geraniol (CAS No. 106-24-1, EC No. 203-377-1) without Cohort 1B as explained above. If clear results can be obtained in the respective study with pure geraniol, these are to be taken into consideration for read-across for the reaction mass ((E-) and (Z-) isomers) in terms of classification and labelling and for animal welfare reasons. Possibly the results gained with geraniol can be used to sufficiently cover both endpoints, pre/post-natal development and reproductive toxicity for the reaction mass and spare further animal studies. Therefore, the Registrant disagrees with the study requests of ECHA concerning the test substance reaction mass of 2,6-Octadien-1-ol, 3,7-dimethyl-, (E) and 2,6-Octadien-1-ol, 3,7-dimethyl-, (Z)-, (pre-natal developmental study in rats, oral route (test method: EU B.31/OECD 414) and either of the following studies, i.e. a Two-generation reproductive toxicity study in rats, oral route (test method: EU B.35/OECD 416) or extended one-generation reproductive toxicity study in rats, oral route (test method: OECD 443) including the extension of Cohort 1B to mate the F1 animals to produce the F2 generation which shall be kept until weaning). In order to avoid redundant testing and for animal welfare reasons, a tiered testing strategy based on a one-generation reproductive toxicity test using pure geraniol in combination with the reproductive toxicity data on pure nerol as outlined above is considered appropriate.   References:1. Piersma AH, Rorije E, Beekhuijzen ME, Cooper R, Dix DJ, Heinrich-Hirsch B, Martin MT, Mendez E, Muller A, Paparella M, Ramsingh D, Reaves E, Ridgway P, Schenk E, Stachiw L, Ulbrich B, Hakkert BC. Combined retrospective analysis of 498 rat multi-generation reproductive toxicity studies: on the impact of parameters related to F1 mating and F2 offspring. Reprod Toxicol. 2011 May;31(4):392-401. 2. Martin MT, Mendez E, Corum DG, Judson RS, Kavlock RJ, Rotroff DM, Dix DJ. Profiling the reproductive toxicity of chemicals from multigeneration studies in the toxicity reference database. Toxicol Sci. 2009 Jul;110(1):181-90. 3. Janer G, Hakkert BC, Slob W, Vermeire T, Piersma AH. A retrospective analysis of the two-generation study: what is the added value of the second generation? Reprod Toxicol. 2007 Jul;24(1):97-102. 4. Beekhuijzen M, Zmarowski A, Emmen H, Frieling W. To mate or not to mate: a retrospective analysis of two-generation studies for evaluation of criteria to trigger additional mating in the extended one-generation design. Reprod Toxicol.2009 Sep;28(2):203-8. 5. Rorije E, Muller A, Beekhuijzen ME, Hass U, Heinrich-Hirsch B, Paparella M, Schenk E, Ulbrich B, Hakkert BC, Piersma AH. On the impact of second generation mating and offspring in multi-generation reproductive toxicity studies on classification and labelling of substances in Europe. Regul Toxicol Pharmacol. 2011 Nov;61(2):251-60. 

Short description of key information:
Toxicity to fertility:
- NOAEL: 300 mg/kg bw/day (OECD 421, dermal application)
- NOAEL: 600 mg/kg bw/day (OECD 421, oral administration of reaction mass of geraniol and nerol (60:40); actual ingested dose: 1000 mg/kg bw/day of reaction mass)
- NOAEL: >12000 ppm (corresponding to 720 mg/kg bw/day) (OECD 422, oral application via feed of nerol)

Effects on developmental toxicity

Description of key information
Developmental toxicity/teratogenicity
- NOAEL: 300 mg/kg bw/day (OECD 414, oral, test substance Geraniol Extra)
- NOAEL: 300 mg/kg bw/day (OECD 414, oral, test substance Geraniol 60)
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
300 mg/kg bw/day
Additional information

Developmental toxicity was evaluated in a study performed according to OECD Guideline 414 (BASF SE, 2016). The test substance Geraniol Extra was administered as a solution in corn oil to 25 "time-mated" (mated by breeder) female Wistar rats/group by stomach tube at doses of 30, 100 and 300 mg/kg bw on day 6 through day 19 post coitum (p.c.). On day 20 p.c., all females were sacrificed and assessed by gross pathology including the uterus and the placentae where corpora lutea were counted and number and distribution of implantation sites (differentiated as resorptions, live and dead fetuses) were determined. The fetuses were removed from the uterus, sexed, weighed, and further investigated for any external findings. Thereafter, one half of the fetuses of each litter were examined for soft tissue findings and the remaining fetuses for skeletal findings.

Under the conditions of this prenatal developmental toxicity study, the oral administration of Geraniol Extra to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at doses as high as 300 mg/kg bw/d caused neither evidence of maternal nor developmental toxicity.

In conclusion, the no observed adverse effect level (NOAEL) for maternal and prenatal developmental toxicity is 300 mg/kg bw/d.

 

In a dermal screening study according to OECD 421 (BASF SE, 2010), 10 young male and female Wistar rats per dose (0, 50, 150 and 300 mg/kg bw/day) were treated daily with geraniol dissolved in corn oil for at least six hours on the clipped intact dorsal skin (semiocclusive dressing). About 2 weeks after the beginning of treatment, animals were mated to produce a litter. Mating pairs were from the same dose group. Treatment of the dams was discontinued from GD 20 onwards. Pregnant females were allowed to give birth and the offspring was brought up until postnatal day (PND) 4. The study was terminated with the sacrifice of the pups on PND 4 and of lactating dams shortly thereafter. The live birth indices as well as the rate of stillborn pups was comparable between all test groups and the control and reflected the normal range of biological variation inherent in this strain. None of the pups died during lactation in the control group and in all test groups. F1 pups did not show adverse clinical signs up to scheduled sacrifice. Therefore, also the NOAEL for developmental toxicity / teratogenicity is shown to be >300 mg/kg bw/day via the dermal route.

 

Apart from studies with the test substance geraniol, studies using structurally similar compounds were taken into account to address the endpoint of toxicity to reproduction. Geraniol (trans-3,7-dimethyl-2,6-octadien-1-ol) and nerol (cis-3,7-dimethyl-2,6-octadien-1-ol) are trans/cis-isomers and therefore differ only in their relative orientation of functional groups within the molecule. Furthermore, relevant physicochemical parameters show comparability between geraniol and nerol.

Developmental toxicity was evaluated in a study performed according to OECD Guideline 414 (BASF SE, 2015). The test substance Geraniol 60 was administered as a solution in corn oil to 25 "time-mated" (mated by breeder) female Wistar rats/group by stomach tube at doses of 100, 300 and 1000 mg/kg bw on day 6 through day 19 post coitum (p.c.). On day 20 p.c., all females were sacrificed and assessed by gross pathology including the uterus and the placentae where corpora lutea were counted and number and distribution of implantation sites (differentiated as resorptions, live and dead fetuses) were determined. The fetuses were removed from the uterus, sexed, weighed, and further investigated for any external findings. Thereafter, nearly one half of the fetuses of each litter were examined for soft tissue findings and the remaining fetuses for skeletal findings.

As a result, administration of 1000 mg/kg bw elicited substance-induced effects on the dams including signs of maternal toxicity like reduced body weight gain on GD 6-8 (-53%) and GD 10-13 (-28%) resulting in about 10% less weight gain during treatment period (GD 6-19). The reduced corrected (net) body weight gain was about 14% below the concurrent control value. The dosage of 300 mg/kg bw/day resulted in reduced body weight gain on GD 6-8 (-43%) and reduced corrected (net) body weight gain about 13% below the concurrent control value. At the low dose (100 mg/kg bw/day) no substance-induced effects on dams occurred. The test substance had no influence on gestational parameters. Fetal examinations revealed that there is no effect of the compound on the respective morphological structures up to the highest dose tested (1000 mg/kg bw/d). Incidences of dilated renal pelvis and incomplete ossifications of various skeletal elements represent temporary delays in development which have no permanent effect on morphology and function of the affected organs or structures.

Based on these results, the no observed adverse effect level (NOAEL) for maternal toxicity is 100 mg/kg bw/day. The NOAEL for prenatal developmental toxicity could be fixed at 300 mg/kg bw/day.

The oral screening study according to OECD 421 with the reaction mass of geraniol and nerol (E- and Z-isomer) (BASF SE, 2010) showed effects on pup survival. The dose levels were 0, 100, 300 and 1000 mg/kg body weight/day. About 2 weeks after the beginning of treatment, animals were mated to produce a litter. Mating pairs were from the same dose group. Pregnant females were allowed to give birth and the offspring was brought up until postnatal day (PND) 4. The study was terminated with the sacrifice of the pups on PND 4 and of lactating dams shortly thereafter. Pregnancy was unaffected at the low-dose. However, there is an alert for a dose-dependent adverse effect of the test substance on pre-/postnatal development of the F1 offspring at mid and high-dose level (300 and 1000 mg/kg bw/d). For the high-dose a lower live birth index (89 %) was noted. Pup survival until PND 4 was decreased by 25% and average pup body weight on PND 4 was decreased by 18%. This reduced live birth index was due to losses in only one animal in the group (all others showed no losses). The significantly reduced postnatal offspring weight/weight gain during the first 4 days after birth are likely related to maternal toxicity and ability to care and nurse for the pups as evidenced by clinical observations, empty stomachs in 10% of pups and significantly reduced feed consumption and body weights during the lactation period. Overall, it may be considered that the pup effects seen are secondary to maternal toxicity which effects pup care and nursing. At the mid dose level, the same effects were noted, but at a lesser incidence and no significant effect on weight/weight gain was observed. The mid-dose also had a lower live birth index (94%). The slightly higher (non-significant) number of stillborns may well be contributed to the greater litter size in this group, which leaves the adverse effects on development of offspring in the mid-dose group to be limited to a slightly reduced pup survival (-9%). At least partially, the reduced pup survival may be secondary to a disturbance of maternal care as it became obvious by empty stomachs in pups which have been observed in 5% of mid-dose. In addition, findings in the mid dose appear to be limited to one animal. This animal appears to have maternal toxicity issues as evidenced by clinical observations (pups not properly nursed and insufficient maternal care of the pups), significantly reduced feed consumption and empty stomachs in the pups. These effects are similar to those seen at the top dose and it may therefore be concluded that maternal toxicity in this one animal is also responsible for the effects seen. The findings in this one animal appear to be an outlier in this group and excluding this animal from the data would show no significant findings vs. controls. No such findings were noted at the low-dose. Overall, maternal toxicity as evidence by lack of care of the pups, significantly reduced feed consumption in the dams and empty stomachs in the pups appears to be responsible for the findings seen at the top and mid dose groups. Effects are mainly due to one animal each at either dose group. The observed findings show a questionable correlation between the effects seen on maternal toxicity and effects seen on the offspring. Hence, their relevance based only on this screening study is doubtful and more complete studies at tolerated doses are required. Furthermore, it is unclear whether these effects are due to the corresponding amount of geraniol, which is 600 and 180 mg/kg bw/day in high and mid dose, or the respective amount of nerol, which is 400 and 120 mg/kg bw/day in high and mid dose. Therefore, this study cannot be regarded to assess the potential of geraniol alone and no NOAEL can be derived.

 

A Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD TG 422) has been performed (DRT, 2013). The test item nerol was administered by dietary admixture (initially mixed with 2% corn oil) to three groups of Han Wistar rats for up to 42 consecutive days (main phase males, toxicity females and recovery animals) or between 41 and 53 days (including three weeks exposure phase, pairing, gestation and early lactation; main phase females) at dietary concentrations of 3000, 6000 and 12000 ppm (equivalent to 191.2, 374 and 720 mg/kg bw/day, respectively). A control group was treated with basal laboratory diet (with 2% corn oil). Two recovery groups, each of five males and five females, were treated with the high dose (12000 ppm) or basal laboratory diet alone for 42 consecutive days and then maintained without treatment for a further 14 days. Pairing of main phase animals and recovery males within each dose group was undertaken on a one male:one female basis within each treatment group on Day 22 of the study, with females subsequently being allowed to litter and rear their offspring to Day 7 of lactation.

Test-item related finding observed in parental animals are described in detail in the discussion on fertility effects and in IUCLID Chapter 7.8.1.

No treatment related effects were noted in the length of gestation between control and treated groups. Implantation sites were slightly reduced at 3000 and 12000 ppm, without reaching statistical significance). A significant dose-related increase in post-implantation loss was observed: control 5.6%, 3000 ppm 11.0%, 6000 ppm 13.5% and 12000 ppm 18.0% (mean values of mid and high dose animals outside the historical control data). This change was considered to be test item-related. Other parameters of offspring growth and developmental were not affected by the treatment with the test item. Under the chosen test conditions the NOAEL for developmental toxicity was set to 3000 ppm (corresponding to 191.2 mg/kg bw/day) due to the observed post-implantation losses. However maternal toxicity was even observed at the lowest concentration tested, namely decrease in bodyweight gain at 3000 ppm in females during the last week of gestation (-17%) and during early lactation (-67%, associated with -20% in food consumption). The LOAEL for maternal toxicity was set at 3000 ppm. Overall, maternal toxicity may be associated with the post-implantation losses observed in this study.

 

 

The design of the planned study, i.e. extended one-generation reproductive toxicity study in rats, oral route (test method: OECD 443) without extension of Cohort 1B to mate the F1 animals to produce the F2 generation until weaning (see UICLID Chapter 7.8.1) does allow to address both endpoints, i.e. pre/post-natal developmental toxicity and adverse effects on fertility. Therefore, the data obtained need to be assessed if they meet the criteria for classification concerning adverse effects on fertility and developmental toxicity and if they are adequate to support a robust risk assessment.

In the comments sent to ECHA on 19thMarch 2012 and 19thSeptember 2012 the Registrant has communicated an overall testing strategy covering both pure geraniol (CAS No. 106-24-1, EC No. 203-377-1) and the related reaction mass (EC No. 906-125-5). This strategy has been further specified in the member state committee meeting on 23thOctober 2012. The Registrant has proposed to initially perform a one-generation reproductive toxicity study in rats with pure geraniol (CAS No. 106-24-1, EC No. 203-377-1) without Cohort 1B. If clear results can be obtained in the respective study with pure geraniol, these are to be taken into consideration for read-across for the reaction mass ((E-) and (Z-) isomers) in terms of classification and labelling and for animal welfare reasons. Possibly the results gained with geraniol can be used to sufficiently cover both endpoints, pre/post-natal development and reproductive toxicity for the reaction mass and spare further animal studies. In order to avoid redundant testing and for animal welfare reasons, a tiered testing strategy based on a one-generation reproductive toxicity test using pure geraniol in combination with the reproductive toxicity data on pure nerol as outlined above is considered appropriate. 

Justification for classification or non-classification

Untill further clarification is provided, no classification on fertility or developmental toxicity according to Regulation (EC) No 1272/2008 is proposed.