Registration Dossier
Registration Dossier
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 279-815-0 | CAS number: 81782-77-6
Toxicological information
Toxicity to reproduction
Currently viewing:
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- other: screening
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 21 June 2010 to 13 August 2010
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- A valid study is available for the analogue substance (2E)−3,7−dimethylocta−2,6−dien−1−ol. It is a GLP compliant study conducted in compliance with agreed protocols, with no or minor deviations from standard testing guidelines The read-across is considered to be suitable based on the structural and “mechanistic action” similarities between the target substance (4-methyl-3-decen-5-ol) and source substance ((2E)−3,7−dimethylocta−2,6−dien−1−ol) and their similar physico-chemical properties.
- Justification for type of information:
- 1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that the target substance and 1 source substances have the same expected mode of action and similar physicochemical properties relevant for the read-across endpoints.
The justification of the proposed read-across to geraniol is discussed in the attached RAAF document.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance (undecavertol) is a mono-constituent substance (EC 279-815-0, CAS 81782-77-6). The typical concentration of the single constituent is 98.0%.
The source substance geraniol (EC 203-377-1, CAS 106-24-1) is a mono-constituent substance. The typical concentration of the mono-constituents is 97.0%.
The target substance and the source substance do not contain any impurities present at ≥ 1%. The purity of the test items within the respective REACH registration dossiers for undecavertol and for geraniol indicates purity > 97.0% with no impurities > 1%.
3. ANALOGUE APPROACH JUSTIFICATION
The structures of the target and source substance are provided in Table 1 (RAAF document). The target substance and the source substance have been characterised in this table using the categories and databases present in the OECD [Q]SAR Toolbox. From the profiling provided (Table 1 - (RAAF document)), it can be seen that the 2 substances share structural similarities and also mechanistic actions which are both general and endpoint specific. This supports the hypothesis that the target and source substances have similar properties as a result of structural similarity and the same expected mode of action.
The OECD toolbox predicts all substances to be of low toxicity according to Cramer classes and both substances show no alerts according to DART Scheme v1.0.
Undecavertol and geraniol are structurally similar substances. The primary route of metabolism for undecavertol is aliphatic c-oxidation followed by either o-glucoronidation or beta oxidation. Geraniol is metabolised via epxoidation foolwed by aliphatic c-oxidation. This is supported by the most probable route of metabolism prediction of TIMES v.2.27.17 (rat in vivo model) as illustrated in the RAAF document..
4. DATA MATRIX
Please see the RAAF document.
Cross-reference
Reference
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- other: screening
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 21 June 2010 to 13 August 2010
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- A valid study is available for the analogue substance (2E)−3,7−dimethylocta−2,6−dien−1−ol. It is a GLP compliant study conducted in compliance with agreed protocols, with no or minor deviations from standard testing guidelines The read-across is considered to be suitable based on the structural and “mechanistic action” similarities between the target substance (4-methyl-3-decen-5-ol) and source substance ((2E)−3,7−dimethylocta−2,6−dien−1−ol) and their similar physico-chemical properties.
- Justification for type of information:
- 1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that the target substance and 1 source substances have the same expected mode of action and similar physicochemical properties relevant for the read-across endpoints.
The justification of the proposed read-across to geraniol is discussed in the attached RAAF document.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance (undecavertol) is a mono-constituent substance (EC 279-815-0, CAS 81782-77-6). The typical concentration of the single constituent is 98.0%.
The source substance geraniol (EC 203-377-1, CAS 106-24-1) is a mono-constituent substance. The typical concentration of the mono-constituents is 97.0%.
The target substance and the source substance do not contain any impurities present at ≥ 1%. The purity of the test items within the respective REACH registration dossiers for undecavertol and for geraniol indicates purity > 97.0% with no impurities > 1%.
3. ANALOGUE APPROACH JUSTIFICATION
The structures of the target and source substance are provided in Table 1 (RAAF document). The target substance and the source substance have been characterised in this table using the categories and databases present in the OECD [Q]SAR Toolbox. From the profiling provided (Table 1 - (RAAF document)), it can be seen that the 2 substances share structural similarities and also mechanistic actions which are both general and endpoint specific. This supports the hypothesis that the target and source substances have similar properties as a result of structural similarity and the same expected mode of action.
The OECD toolbox predicts all substances to be of low toxicity according to Cramer classes and both substances show no alerts according to DART Scheme v1.0.
Undecavertol and geraniol are structurally similar substances. The primary route of metabolism for undecavertol is aliphatic c-oxidation followed by either o-glucoronidation or beta oxidation. Geraniol is metabolised via epxoidation foolwed by aliphatic c-oxidation. This is supported by the most probable route of metabolism prediction of TIMES v.2.27.17 (rat in vivo model) as illustrated in the RAAF document..
4. DATA MATRIX
Please see the RAAF document. - Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: EPA OPPTS 870.3550 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crl:WI(Han)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: Charles River Laboratories, Research Models and Services, Germany GmbH- Age at study initiation: approximately 11-12 weeks (at start of administration)- Weight at study initiation: 290.8 - 6322.3 g (males); 189.8 - 219.5 g (females)- Housing: Individually in Makrolon type M III cages (Becker & Co., Castrop-Rauxel, Germany) except during mating when one male and one female were housed together in Makrolon type M III cages. Pregnant females and their litters were housed together until the end of lactation. Pregnant females were provided with nesting material (cellulose wadding) towards the end of gestation. - Use of restrainers for preventing ingestion (if dermal): no- Diet:ground Kliba maintenance diet mouse/rat "GLP" meal (Provimi Kliba SA, Kaiseraugst, Switzerland) ad libitum- Water: ad libitum- Acclimation period: 7 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 20 - 24 °C- Humidity (%): 30 - 70 %- Air changes (per hr): 15 air changes per hour- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light
- Route of administration:
- dermal
- Vehicle:
- corn oil
- Details on exposure:
- TEST SITE- Area of exposure: Dorsal- Type of wrap if used: A semiocclusive dressing (4 layers of absorbent gauze and stretch bandage)- Time intervals for shavings or clipplings: The dorsal skin was clipped at least once a week depending on hair growth.REMOVAL OF TEST SUBSTANCE- Washing: After removal of the dressing, the application area was washed with lukewarm water.- Time after start of exposure: Performed dailyTEST MATERIAL- Amount(s) applied (volume or weight with unit): 4 mL/kg. The calculation of the volume administered was generally based on the most recent individual body weights.- Constant volume or concentration used: noVEHICLE- Amount(s) applied (volume or weight with unit): 4 mL/kgUSE OF RESTRAINERS FOR PREVENTING INGESTION: no
- Details on mating procedure:
- - M/F ratio per cage: one male and one female of the same treatment group - Length of cohabitation: animals were mated overnight (from 16:00 to 07:00 - 09:00 the following morning)- Further matings after two unsuccessful attempts: yes, animals were mated for a maximum of two weeks.- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical verification of test concentrations was performed on samples of all concentrations at the start and towards the end of the adminstration period. Concentration analysis was performed by HPLC with UV detection. The HPLC conditions were as follows:- Column: Gemini C18 5 µ 110A, 150 x 3 mm- Eluent: 50 % acetonitrile + 0.5 M sulphuric acid (5 mL/L); 50 % highly deionised water + 0.5 M sulphuric acid (5 mL/L)- Flow rate: 0.6 mL/min- Injection volume: 2, 5 µL- Column temperature: ambient- Detection: 205 nm- Limit of quantification: 12.8 mg/L
- Duration of treatment / exposure:
- The duration of treatment covered the premating period of 2 weeks and mating period (maximum of 2 weeks) in both sexes, approximately 1 week post-mating in males, and the entire gestation period until gestation day 19 in females (although the females were not treated during the end of gestation and during lactation).
- Frequency of treatment:
- Daily (6 hours exposure per day, 7 days per week)
- Remarks:
- Doses / Concentrations:0, 50, 150, 450 mg/kg bw/dayBasis:nominal conc.(Due to progressive dermal findings, the 450 mg/kg bw/day dose level was reduced to 300 mg/kg bw/day from study day 10 onwards)
- No. of animals per sex per dose:
- 10 males and 10 females per dose level
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: In a previous study rats received dermal applications of test material at the dose levels 0, 300, 500, 750 and 1000 mg/kg bw/day for 14 days. Corn oil served as vehicle. In this study the test material caused scales and erythema at dose levels of 500 mg/kg bw/day and above but no findings at a dose level of 300 mg/kg bw/day. Therefore 450 mg/kg bw/day was selected as the high dose and 150 and 50 mg/kg bw/day were selected as intermediate and low doses, respectively.- Rationale for animal assignment: Animals were distributed according to weight among the individual test groups, separated by sex. The weight variation of the animals used did not exceed 20 % of the mean weight of each sex.
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes - Time schedule: mortality was checked twice daily (once on weekends) and clinical observations were performed at least once dailyBODY WEIGHT: Yes - Time schedule for examinations: Weekly with the following exceptionsFemales were weighed on the day of positive evidence of sperm (GD 0), and on GD 7, 14 and 20 during mating.Females showing no positive sign of sperm in the vaginal smear were weighed once a week during mating as were malesFemales with litter were weighed on the day of parturition (PND 0) and on PND 4.Females without litter were weighed once a weekFemaels between PND 4 and sacrifice were weighed once a week.FOOD CONSUMPTION: Yes- Time schedule for examinations: weekly (food consumption was not determined in the females without positive evidence of sperm during mating and gestation periods and in the females without litter during lactation period) Food consumption was not determined in the second premating week for male animals and during the mating period (both sexes)Food consumption of the females with evidence of sperm was determined for GD 0-7, 7-14 and 14-20.Food consumption for females which gave birth to a litter was determined for PND 1-4.WATER CONSUMPTION: NoOTHER: The parturition and lactation behaviour of the dams was generally evaluated once daily. The day of parturition was considered to be the 24 hour period from about 15:00 of one day until about 15:00 of the following day.
- Litter observations:
- PARAMETERS EXAMINEDThe following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, gross-morphological changes. On post-natal day 1 live pups were weighed
- Postmortem examinations (parental animals):
- SACRIFICE: Parental animals were sacrificed by decapitation under isoflurane anaesthesia. The exanguinated animals were necropsied and assessed by gross pathology.- Male animals: All surviving animals 1 week post-mating- Maternal animals: All surviving animals on gestation day 19Animals which died intercurrently or were sacrificed in a moribund state were necropsied as soon as possible after their death and assessed by gross pathology.ORGAN WEIGHTSThe weights of the following were determined: carcass, epididymides, testes, ovariesORGAN/TISSUE FIXATIONThe following were fixed in 4 % neutral buffered formaldehyde solution or in modified Davidson's solution: all gross lesions, adrenal glands, epididymides, ovaries, pituitary gland, prostate gland, seminal vesicles, coagulation glands, skin (treated), skin (untreated), testes, uterus, oviducts, vagina.The ovaries, testes and epididymides of animals that died or were sacrificed intercurrently were fixed in 4 % buffered formaldehyde solution.HISTOPATHOLOGYAfter organs were fixed, histotechnical processing and examination by light microscopy were performed on gross lesions and treated skin of animals of all test groups and on the epididymides, ovaries, untreated skin and testes in the control and high dose group animals.DETERMINATION OF IMPLANT SITESAfter sacrifice of the female animals the uterus and ovaries were removed and the implantation sites were counted. To determine the number of implantation sites in apparently non-pregnant animals, the uteri from those females were stained in 10 % ammonium sulphide solution for about 5 minutes. the uteri were then rinsed with water. The implantation sites were recorded for the calculation of the post implantation loss.
- Postmortem examinations (offspring):
- On post-natal day 4, the pups were sacrificed under isoflurane anaesthesia with CO2. After sacrifice, the pups were examined externally and eviscerated, and their organs were assessed macroscopically.Pups that died or were sacrificed in a moribund state were eviscerated and examined for possible defects and/or the cause of death.All pups without any notable findings were discarded after their macroscopic evaluation.
- Statistics:
- Dunnett’s-test (two-sided) for the hypothesis of equal means was performed on the following parameters: food consumption; body weight; body weight change; number of mating days; duration of gestation; number of pups delivered per litter; implantation sites and post implantation loss. Pairwise comparison of each dose group with the control group was performed with Fisher’s Exact test on the following parameters: mating indices; fertility indices; gestation index; females with liveborn and stillborn pups; live birth index, stillborn, dead, cannibalised, sacrificed and moribund pups; viability index and number of litters with affected pups at necropsy. Pairwise comparison of each dose group was analysed with the Wilcoxon-test on the parameters: portions of affected pups per litter with necropsy observations.
- Reproductive indices:
- MALE REPRODUCTION DATAThe pairing partners, the number of mating days until vaginal sperm was detected in female animals, and the gestational status of the females were recorded for the F0 breeding pairs. For the males, mating and fertility indices were calculated according to the following:Male mating index (%) = (number of males with confirmed mating* / number of males placed with females) x 100* defined by a female with vaginal sperm or with implants in uteroMale fertility index (%) = (number of males proving their fertility* / number of males placed with females) x 100* defined by a female with implants in uteroFEMALE REPRODUCTION AND DELIVERY DATAThe pairing partners, the number of mating days until vaginal sperm could be detected and gestational status were recorded. For the females, mating, fertility and gestation indices were calculated according to the following:Female mating index (%) = (number of females mated* / number of females placed with males) x 100* defined as the number of females with vaginal sperm of with implants in uteroFemale fertility index (%) = (number of females pregnant* / number of females mated**) x 100* defined as the number of females with implants in utero** defined as the number of females with vaginal sperm or with implants in uteroGestation index (%) = (number of females with live pups on the day of birth / number of females pregnant*) x 100* defined as the number of females with implants in uteroThe live birth index was calculated according to the following:Live birth index (%) = (number if liveborn pups at birth / total number of pups born) x 100Post implantation loss was calculated for each individual pregnant animal according to the following:Post implantation loss (%) = [(number of implantations - number of pups delivered) / number of implantations] x 100
- Offspring viability indices:
- The viability index was calculated according to the following:Viability index (%) = (number of live pups on day 4 after birth / number of liveborn pups on the day of birth) x 100The sex ratio was calculated at post natal day 0 and post natal day 4 according to the following:Sex ratio = (number of live male or female pups on day 0/4 / number of live male and female pups on day 0/4) x 100
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- See "Details on results (parental animals)" for information
- Dermal irritation (if dermal study):
- effects observed, treatment-related
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not examined
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- (reproductive performance)
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Only local signs observed up to the highest dose, no effects on reproductive performance were recorded.
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- (systemic toxicity)
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Only local signs observed, no evidence of systemic toxicity observed.
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
- Other effects:
- not specified
- Behaviour (functional findings):
- not specified
- Developmental immunotoxicity:
- not specified
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- Reproductive effects observed:
- not specified
- Conclusions:
- Under the conditions of the study, the No Observed Adverse Effect Level NOAEL) for reproductive performance and fertility in male and female Wistar rats was 300 mg/kg bw/day. The dermal administration of the test material revealed only local signs of toxicity in male and female rats at all dose levels. This finding was related to the irritating potential of the test material. The NOAEL for general, systemic toxicity of the test material was 300 mg/kg bw/day.
- Executive summary:
The reproductive and developmental toxicity of the test material was investigated in a GLP study which was conducted in accordance with standardised guidelines OECD 421 and EPA OPPTS 870.3550. During the study test material was administered via dermal administration to groups of 10 male and 10 female Wistar rats at dose levels of 0 (vehicle control; test group 0), 50 (test group 1), 150 (test group 2) and 450 mg/kg (test group 3) in order to observe the possible effects of the test material on the integrity and performance of the reproductive system in both sexes. Due to severe dermal findings, the dose level for test group 3 was decreased to 300 mg/kg bw/day from study day 10 onwards. Only signs of local dermal toxicity were observed for males and females at all dose levels. No changes in food consumption or body weight were seen at any dose level. Fertility indices for male and female animals were not impaired by test material administration. Furthermore, there were no treatment related or histological findings in ovaries, testes or epididymides associated with dermal administration of the test material. The local minimal inflammatory reactions in the skin of treated males (test groups 1 to 3) and females (test group 3 only) were regarded as related to treatment and adverse. Under the conditions of the study, the No Observed Adverse Effect Level (NOAEL) for reproductive performance and fertility in male and female Wistar rats was 300 mg/kg bw/day. The dermal administration of the test material revealed only local signs of toxicity in male and female rats at all dose levels. This finding was related to the irritating potential of the test material. The NOAEL for general, systemic toxicity of the test material was 300 mg/kg bw/day.
Important considerations for the use of read-across for reproductive/developmental toxicity screening are: i) 4-methyldec-3-en-5-ol (the target chemical) has similar physico-chemical properties as 4(2E)−3,7−dimethylocta−2,6−dien−1−ol (the source substance), ii) there are structural similarities between the two chemicals and iii) the OECD QSAR Toolbox assigns an identical toxicity profiles to both chemicals.
The information reported in this summary is included to demonstrate comparability between the source (4(2E)−3,7−dimethylocta−2,6−dien−1−ol) and target (4-methyldec-3-en-5-ol) substance.
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)Female no. 127 (dosed at 150 mg/kg bw/day) was sacrificed moribund on study day 11 because of a severe thoracic injury. No test material-related mortalities occurred in any test group.For male animals, several dermal findings were noted in test group 3 (450 and 300 mg/kg bw/day). On study day 10, 5 male rats showed focal and multifocal red spots on treated skin on several days. Based on experience from a previous study, with regard to the progress in severity of dermal findings after application of the test material preparations, the dose level in test group 3 was reduced from 450 to 300 mg/kg bw/day. Starting on study day 11, 9 male rats showed focal scales on treated skin on several days. One rat showed focal erosion on treated skin on several days beginning on study day 14. Starting on study day 15, 5 rats showed slight erythema on treated skin on several days. Similar findings but less pronounced were observed in male animals of test group 2 (150 mg/kg bw/day). No treatment- related findings were observed in male animals of test group 1 (50 mg/kg bw/day).For female animals, different dermal findings were seen on several days. In test group 3, 7 females showed slight and moderate erythema on several days of the study, starting on study day 3. In addition, some animals of test group 3 showed multifocal, focal and diffuse scales on treated skin starting on study day 5. Similar findings but less pronounced were observed in female animals of test group 2, i.e. focal red spots, slight erythema and focal scales on treaed skin on several days of the study. In test group 1, slight erythema as well as focal and diffuse scales on treated skin were observed in individual animals at different time points.Female no. 137 of test group 3, which did not deliver pups, showed a vaginal haemorrhage 27 days after mating.In female animal 127 of test group 2, a severe thoracal injury was observed during pre-mating. It was a self inflicted injury which was caused by the animal's attempt to get rid of the gauze. The injury became more severe by time and the animal had to be sacrificed in a moribund state on study week 1.BODY WEIGHT (PARENTAL ANIMALS)The mean body weight and body weight change of male and female animals showed no significant deviations to the control group in all test groups.FOOD CONSUMPTION (PARENTAL ANIMALS)No changes in food consumption of toxicological significance were seen for male and female animals of all test groups.REPRODUCTION DATA: (MALE PARENTAL ANIMALS)For all parental males, which were placed with parental females to generate F1 pups, mating was confirmed. Thus, the male mating index was 100 % in all test groups. Fertility was proven for most of the parental males within the scheduled mating interval to produce the F1 litter. Thus, the male fertility index ranged between 89 % (test group 2) and 90 % (test groups 0, 1 and 3). These reflected the normal range of biological variation inherent in the strain of rats used for this study.REPRODUCTION DATA: (FEMALE PARENTAL ANIMALS)The female mating index after the mating period for F1 litter was 100 % for all groups.The mean duration until sperm was detected gestation day 0) amounted to 3.2, 2.6, 2.7 and 4.6 days in test group 0 - 3, respectively. Differences between the test groups were assessed as being spontaneous in nature and without any biological relevance.One female in each test group were found to be sperm-positive but did not become pregnant and had no implantation sites in utero. One female of test group 1 and two females of test group 3, were sperm positive, showed implantation sites at necropsy, but delivered no pups. these females were sperm positive after only one mating day. Furthermore, one female of test group 1 was not sperm positive but delivered pups.The female fertility index varied between 89 % (test group 2) and 90 % (test groups 0, 1 and 3).The mean duration of gestation was 22.1 days in test group 0, 22.0 in test groups 1 and 2 and 22.4 days in test group 3.The gestation index varied between 78 % for test group 3, 89 % for test group 1 and 100 % for test groups 0 and 2. the decreased gestation index in test group 3 was assumed as being unrelated to treatment with the test material.The mean number of implantation sites was 13.0, 10.9, 11.8 and 10.6 implants/dam in test group 0 - 3, respectively.Post-implanation loss was increased in test group 3 (28.2 %), however, this was caused by two animals which had only 1 and 3 implantation sites and complete implantation losses. the loss of these implants led to absorption rates of 100 % in each case, which artificially exaggerates the test group average for this parameter. the same was true for test group 1 (14.5 %) was related to 1 female with complete litter loss. Taken together, the increased post-implantation loss values in test groups 1 and 3 were assessed as being a matter of calculating mean values and incidental rather than related to treatment.The mean number of F1 delivered pups per dam was 12.2, 11.4, 10.6 and 12.0 pups/day, in test groups 0 - 3, respectively. the live birth indices ranged between 98 % in test group 3, 99 % in test groups 0 and 1 and 100 % in test group 2.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 rat strain. The rate of pups that died during lactation was 0 % in the control and all treatment groups.Thus, the dermal administration of the test material did not affect reproduction and delivery of the parental females in test groups 1 - 3.The mean number of delivered pups per dam and the rate of liveborn and stillborn pups were evenly distributed among test groups 0, 1, 2 and 3. The respective values reflect the normal range of biological variation inherent in the strain used in this study.ORGAN WEIGHTS (PARENTAL ANIMALS)None of the absolute of relative weight parameters in test groups 1 - 3 showed relevant differences when compared to the control group and were considered to be within the normal range.GROSS PATHOLOGY (PARENTAL ANIMALS)A red-brown lesion was noted on the thorax of female no. 127 of test group 2 which was sacrificed moribund. All gross lesions observed in test animals occurred singularly. They were considered to be spontaneous lesions in origin and not related to treatment.HISTOPATHOLOGY (PARENTAL ANIMALS)The lesion noted on the thorax of female no. 127 correlated to an erosion on the skin. Lymphocytic infiltrates were observed in treated skin sections which were distributed band-like between epidermis and dermis. All other findings noted were single observations which were considered to be incidental and spontaneous in origin and without any relation to treatment.
VIABILITY (OFFSPRING)No significant findings for pups that died during lactation were observed. The viability index varied between 99 % for test groups 1 and 3 and 100 % for test groups 0 and 2.No test material-related changes were obtained.Male pup no. 8, delivered by dam no 118 of test group 1, was sacrificed moribund on post natal day 0 as it showed malformation of the skull, anophthalmia and cleft lip.The sex distribution and sex ratios of live F1 pups on the day of birth and post natal day 4 did not show biologically relevant differences between the control and test groups 1 to 3.CLINICAL SIGNS (OFFSPRING)Dam no 118 (test group 1) gave birth to male pup no 8 with a deformation of its snout. On first sight a cleft lip and anophthalmia were seen. The staining of the pups skull showed that several bones (basisphenoid, palatine, incisive, nasal - including cartilage and maxilla) were deformed and/or displaced. Therefore, F1 pups did not show adverse clinical signs up to schedules sacrifice on post natal day 4.BODY WEIGHT (OFFSPRING)The mean body weight of female pups was increased by 10 % on post natal day 4 in test group 3. Pup body weight change in groups 1 to 3 were comparable to the concurrent control values. GROSS PATHOLOGY (OFFSPRING)No test substance related findings were observed.
Homogeneity and concentration control analyses
The test material was completely miscible with Corn Oil Ph. Eur, and thus, a solution. Therefore, the test material preparation was considered to be homogenous and no further homogeneity analysis was performed.
The concentration control analyses at the beginning and towards the end of the application period revealed values in the expected range of the target concentrations. The means of the nominal concentrations were in a range of 96.5 - 104.3 % of the nominal concentrations.
Table 1: Clinical Observations (Males)
Group |
Week of study |
Total |
|||||
No. of animals examined |
0 |
1 |
2 |
3 |
4 |
||
0 |
10 |
10 |
10 |
10 |
10 |
||
1 |
10 |
10 |
10 |
10 |
10 |
||
2 |
10 |
10 |
10 |
10 |
10 |
||
3 |
10 |
10 |
10 |
10 |
10 |
||
Normal, nothing abnormal declared |
0 |
10 |
10 |
10 |
10 |
10 |
10 |
1 |
10 |
10 |
10 |
10 |
10 |
10 |
|
2 |
10 |
10 |
9 |
10 |
10 |
10 |
|
3 |
10 |
10 |
6 |
6 |
8 |
10 |
|
Dead, scheduled sacrifice |
0 |
0 |
0 |
0 |
0 |
0 |
10 |
1 |
0 |
0 |
0 |
0 |
0 |
10 |
|
2 |
0 |
0 |
0 |
0 |
0 |
10 |
|
3 |
0 |
0 |
0 |
0 |
0 |
10 |
|
Animal body |
|||||||
Treated skin, erythema, slight |
0 |
0 |
0 |
0 |
0 |
10 |
10 |
1 |
0 |
0 |
0 |
0 |
10 |
10 |
|
2 |
0 |
0 |
1 |
3 |
3 |
3 |
|
3 |
0 |
0 |
4 |
5 |
4 |
5 |
|
Treated skin, scales, focal |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
1 |
2 |
2 |
2 |
2 |
|
3 |
0 |
6 |
7 |
9 |
6 |
9 |
|
Treated skin, erosion, focal |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
0 |
0 |
0 |
0 |
0 |
|
3 |
0 |
0 |
1 |
1 |
0 |
1 |
|
Treated skin, red spots, focal |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
4 |
5 |
5 |
3 |
5 |
|
3 |
0 |
0 |
3 |
3 |
2 |
4 |
|
Treated skin, red spots, multifocal |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
0 |
0 |
0 |
0 |
0 |
|
3 |
0 |
1 |
1 |
1 |
0 |
1 |
|
Table 2: Clinical Observations (Females)
Group |
Week of study |
Total |
||||||||
No. of animals examined |
0 |
1 |
2 |
3 |
4 |
5 |
6 |
7 |
||
0 |
10 |
10 |
10 |
1 |
- |
3 |
9 |
10 |
||
1 |
10 |
10 |
10 |
1 |
1 |
4 |
10 |
10 |
||
2 |
10 |
10 |
9 |
- |
- |
2 |
9 |
9 |
||
3 |
10 |
10 |
10 |
3 |
1 |
4 |
7 |
10 |
||
Normal, nothing abnormal declared |
0 |
10 |
10 |
7 |
1 |
- |
3 |
9 |
10 |
10 |
1 |
10 |
10 |
8 |
1 |
1 |
4 |
10 |
10 |
10 |
|
2 |
10 |
10 |
6 |
- |
- |
2 |
9 |
9 |
10 |
|
3 |
10 |
5 |
3 |
3 |
0 |
4 |
7 |
10 |
10 |
|
Dead, sacrificed moribund |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
1 |
0 |
- |
- |
0 |
0 |
0 |
1 |
|
3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
Scheduled sacrifice |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
10 |
10 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
10 |
10 |
|
2 |
0 |
0 |
0 |
- |
- |
0 |
0 |
9 |
9 |
|
3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
10 |
10 |
|
Animal body |
||||||||||
Treated skin, erythema, slight |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
2 |
2 |
1 |
0 |
0 |
0 |
0 |
0 |
2 |
|
2 |
0 |
1 |
0 |
- |
- |
0 |
0 |
0 |
1 |
|
3 |
5 |
5 |
2 |
1 |
1 |
0 |
0 |
0 |
5 |
|
Treated skin, erythema, moderate |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
0 |
0 |
- |
- |
0 |
0 |
0 |
0 |
|
3 |
1 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
|
Treated skin, scales, focal |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
1 |
2 |
1 |
- |
- |
0 |
0 |
0 |
2 |
|
3 |
4 |
4 |
2 |
0 |
0 |
0 |
0 |
0 |
4 |
|
Treated skin, scales, multifocal |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
0 |
0 |
- |
- |
0 |
0 |
0 |
0 |
|
3 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
|
Treated skin, scales, diffuse |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
0 |
0 |
- |
- |
0 |
0 |
0 |
0 |
|
3 |
1 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
|
Injury, thoracal |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
1 |
0 |
- |
- |
0 |
0 |
0 |
1 |
|
3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
Miscellaneous |
||||||||||
Sperm in vaginal smear (day 0 pc) |
0 |
0 |
0 |
9 |
1 |
- |
0 |
0 |
0 |
10 |
1 |
0 |
0 |
9 |
0 |
0 |
0 |
0 |
0 |
9 |
|
2 |
0 |
0 |
9 |
- |
- |
0 |
0 |
0 |
9 |
|
3 |
0 |
0 |
7 |
3 |
0 |
0 |
0 |
0 |
10 |
|
Vaginal haemorrhage |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
0 |
0 |
- |
- |
0 |
0 |
0 |
0 |
|
3 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
1 |
|
ANALOGUE APPROACH JUSTIFICATION:
- See attached “Justification for read-across” document for full details.
- In summary, important considerations for the use of read-across for reproductive/developmental toxicity screening are: i) 4-methyldec-3-en-5-ol (the target chemical) has similar physico-chemical properties as 4(2E)−3,7−dimethylocta−2,6−dien−1−ol (the source substance), ii) there are structural similarities between the two chemicals and iii) the OECD QSAR Toolbox assigns an identical toxicity profiles to both chemicals.
The information reported in this summary is included to demonstrate comparability between the source (4(2E)−3,7−dimethylocta−2,6−dien−1−ol) and target (4-methyldec-3-en-5-ol) substance.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 010
- Report date:
- 2010
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: EPA OPPTS 870.3550 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 2-TRANS-3,7-DIMETHYL-2,6-OCTADIEN-1-OL
- Cas Number:
- 106-24-1
- IUPAC Name:
- 2-TRANS-3,7-DIMETHYL-2,6-OCTADIEN-1-OL
- Reference substance name:
- Geraniol
- EC Number:
- 203-377-1
- EC Name:
- Geraniol
- Cas Number:
- 106-24-1
- Molecular formula:
- C10H18O
- IUPAC Name:
- (E)-3,7-dimethylocta-2,6-dien-1-ol
- Test material form:
- other: liquid, not further specified
- Details on test material:
- - Molecular formula (if other than submission substance): C10H18O- Molecular weight (if other than submission substance): 154.25- Smiles notation (if other than submission substance): C(C)(C)=CCCC(C)=CCO- Structural formula attached as image file (if other than submission substance): see Fig. 1- Appearance: yellowish / clear liquid- Storage condition of test material: room temperature
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- other: Crl:WI(Han)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS- Source: Charles River Laboratories, Research Models and Services, Germany GmbH- Age at study initiation: approximately 11-12 weeks (at start of administration)- Weight at study initiation: 290.8 - 6322.3 g (males); 189.8 - 219.5 g (females)- Housing: Individually in Makrolon type M III cages (Becker & Co., Castrop-Rauxel, Germany) except during mating when one male and one female were housed together in Makrolon type M III cages. Pregnant females and their litters were housed together until the end of lactation. Pregnant females were provided with nesting material (cellulose wadding) towards the end of gestation. - Use of restrainers for preventing ingestion (if dermal): no- Diet:ground Kliba maintenance diet mouse/rat "GLP" meal (Provimi Kliba SA, Kaiseraugst, Switzerland) ad libitum- Water: ad libitum- Acclimation period: 7 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 20 - 24 °C- Humidity (%): 30 - 70 %- Air changes (per hr): 15 air changes per hour- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light
Administration / exposure
- Route of administration:
- dermal
- Vehicle:
- corn oil
- Details on exposure:
- TEST SITE- Area of exposure: Dorsal- Type of wrap if used: A semiocclusive dressing (4 layers of absorbent gauze and stretch bandage)- Time intervals for shavings or clipplings: The dorsal skin was clipped at least once a week depending on hair growth.REMOVAL OF TEST SUBSTANCE- Washing: After removal of the dressing, the application area was washed with lukewarm water.- Time after start of exposure: Performed dailyTEST MATERIAL- Amount(s) applied (volume or weight with unit): 4 mL/kg. The calculation of the volume administered was generally based on the most recent individual body weights.- Constant volume or concentration used: noVEHICLE- Amount(s) applied (volume or weight with unit): 4 mL/kgUSE OF RESTRAINERS FOR PREVENTING INGESTION: no
- Details on mating procedure:
- - M/F ratio per cage: one male and one female of the same treatment group - Length of cohabitation: animals were mated overnight (from 16:00 to 07:00 - 09:00 the following morning)- Further matings after two unsuccessful attempts: yes, animals were mated for a maximum of two weeks.- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical verification of test concentrations was performed on samples of all concentrations at the start and towards the end of the adminstration period. Concentration analysis was performed by HPLC with UV detection. The HPLC conditions were as follows:- Column: Gemini C18 5 µ 110A, 150 x 3 mm- Eluent: 50 % acetonitrile + 0.5 M sulphuric acid (5 mL/L); 50 % highly deionised water + 0.5 M sulphuric acid (5 mL/L)- Flow rate: 0.6 mL/min- Injection volume: 2, 5 µL- Column temperature: ambient- Detection: 205 nm- Limit of quantification: 12.8 mg/L
- Duration of treatment / exposure:
- The duration of treatment covered the premating period of 2 weeks and mating period (maximum of 2 weeks) in both sexes, approximately 1 week post-mating in males, and the entire gestation period until gestation day 19 in females (although the females were not treated during the end of gestation and during lactation).
- Frequency of treatment:
- Daily (6 hours exposure per day, 7 days per week)
Doses / concentrations
- Remarks:
- Doses / Concentrations:0, 50, 150, 450 mg/kg bw/dayBasis:nominal conc.(Due to progressive dermal findings, the 450 mg/kg bw/day dose level was reduced to 300 mg/kg bw/day from study day 10 onwards)
- No. of animals per sex per dose:
- 10 males and 10 females per dose level
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: In a previous study rats received dermal applications of test material at the dose levels 0, 300, 500, 750 and 1000 mg/kg bw/day for 14 days. Corn oil served as vehicle. In this study the test material caused scales and erythema at dose levels of 500 mg/kg bw/day and above but no findings at a dose level of 300 mg/kg bw/day. Therefore 450 mg/kg bw/day was selected as the high dose and 150 and 50 mg/kg bw/day were selected as intermediate and low doses, respectively.- Rationale for animal assignment: Animals were distributed according to weight among the individual test groups, separated by sex. The weight variation of the animals used did not exceed 20 % of the mean weight of each sex.
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes - Time schedule: mortality was checked twice daily (once on weekends) and clinical observations were performed at least once dailyBODY WEIGHT: Yes - Time schedule for examinations: Weekly with the following exceptionsFemales were weighed on the day of positive evidence of sperm (GD 0), and on GD 7, 14 and 20 during mating.Females showing no positive sign of sperm in the vaginal smear were weighed once a week during mating as were malesFemales with litter were weighed on the day of parturition (PND 0) and on PND 4.Females without litter were weighed once a weekFemaels between PND 4 and sacrifice were weighed once a week.FOOD CONSUMPTION: Yes- Time schedule for examinations: weekly (food consumption was not determined in the females without positive evidence of sperm during mating and gestation periods and in the females without litter during lactation period) Food consumption was not determined in the second premating week for male animals and during the mating period (both sexes)Food consumption of the females with evidence of sperm was determined for GD 0-7, 7-14 and 14-20.Food consumption for females which gave birth to a litter was determined for PND 1-4.WATER CONSUMPTION: NoOTHER: The parturition and lactation behaviour of the dams was generally evaluated once daily. The day of parturition was considered to be the 24 hour period from about 15:00 of one day until about 15:00 of the following day.
- Litter observations:
- PARAMETERS EXAMINEDThe following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, gross-morphological changes. On post-natal day 1 live pups were weighed
- Postmortem examinations (parental animals):
- SACRIFICE: Parental animals were sacrificed by decapitation under isoflurane anaesthesia. The exanguinated animals were necropsied and assessed by gross pathology.- Male animals: All surviving animals 1 week post-mating- Maternal animals: All surviving animals on gestation day 19Animals which died intercurrently or were sacrificed in a moribund state were necropsied as soon as possible after their death and assessed by gross pathology.ORGAN WEIGHTSThe weights of the following were determined: carcass, epididymides, testes, ovariesORGAN/TISSUE FIXATIONThe following were fixed in 4 % neutral buffered formaldehyde solution or in modified Davidson's solution: all gross lesions, adrenal glands, epididymides, ovaries, pituitary gland, prostate gland, seminal vesicles, coagulation glands, skin (treated), skin (untreated), testes, uterus, oviducts, vagina.The ovaries, testes and epididymides of animals that died or were sacrificed intercurrently were fixed in 4 % buffered formaldehyde solution.HISTOPATHOLOGYAfter organs were fixed, histotechnical processing and examination by light microscopy were performed on gross lesions and treated skin of animals of all test groups and on the epididymides, ovaries, untreated skin and testes in the control and high dose group animals.DETERMINATION OF IMPLANT SITESAfter sacrifice of the female animals the uterus and ovaries were removed and the implantation sites were counted. To determine the number of implantation sites in apparently non-pregnant animals, the uteri from those females were stained in 10 % ammonium sulphide solution for about 5 minutes. the uteri were then rinsed with water. The implantation sites were recorded for the calculation of the post implantation loss.
- Postmortem examinations (offspring):
- On post-natal day 4, the pups were sacrificed under isoflurane anaesthesia with CO2. After sacrifice, the pups were examined externally and eviscerated, and their organs were assessed macroscopically.Pups that died or were sacrificed in a moribund state were eviscerated and examined for possible defects and/or the cause of death.All pups without any notable findings were discarded after their macroscopic evaluation.
- Statistics:
- Dunnett’s-test (two-sided) for the hypothesis of equal means was performed on the following parameters: food consumption; body weight; body weight change; number of mating days; duration of gestation; number of pups delivered per litter; implantation sites and post implantation loss. Pairwise comparison of each dose group with the control group was performed with Fisher’s Exact test on the following parameters: mating indices; fertility indices; gestation index; females with liveborn and stillborn pups; live birth index, stillborn, dead, cannibalised, sacrificed and moribund pups; viability index and number of litters with affected pups at necropsy. Pairwise comparison of each dose group was analysed with the Wilcoxon-test on the parameters: portions of affected pups per litter with necropsy observations.
- Reproductive indices:
- MALE REPRODUCTION DATAThe pairing partners, the number of mating days until vaginal sperm was detected in female animals, and the gestational status of the females were recorded for the F0 breeding pairs. For the males, mating and fertility indices were calculated according to the following:Male mating index (%) = (number of males with confirmed mating* / number of males placed with females) x 100* defined by a female with vaginal sperm or with implants in uteroMale fertility index (%) = (number of males proving their fertility* / number of males placed with females) x 100* defined by a female with implants in uteroFEMALE REPRODUCTION AND DELIVERY DATAThe pairing partners, the number of mating days until vaginal sperm could be detected and gestational status were recorded. For the females, mating, fertility and gestation indices were calculated according to the following:Female mating index (%) = (number of females mated* / number of females placed with males) x 100* defined as the number of females with vaginal sperm of with implants in uteroFemale fertility index (%) = (number of females pregnant* / number of females mated**) x 100* defined as the number of females with implants in utero** defined as the number of females with vaginal sperm or with implants in uteroGestation index (%) = (number of females with live pups on the day of birth / number of females pregnant*) x 100* defined as the number of females with implants in uteroThe live birth index was calculated according to the following:Live birth index (%) = (number if liveborn pups at birth / total number of pups born) x 100Post implantation loss was calculated for each individual pregnant animal according to the following:Post implantation loss (%) = [(number of implantations - number of pups delivered) / number of implantations] x 100
- Offspring viability indices:
- The viability index was calculated according to the following:Viability index (%) = (number of live pups on day 4 after birth / number of liveborn pups on the day of birth) x 100The sex ratio was calculated at post natal day 0 and post natal day 4 according to the following:Sex ratio = (number of live male or female pups on day 0/4 / number of live male and female pups on day 0/4) x 100
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- See "Details on results (parental animals)" for information
- Dermal irritation (if dermal study):
- effects observed, treatment-related
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not examined
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Details on results (P0)
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)Female no. 127 (dosed at 150 mg/kg bw/day) was sacrificed moribund on study day 11 because of a severe thoracic injury. No test material-related mortalities occurred in any test group.For male animals, several dermal findings were noted in test group 3 (450 and 300 mg/kg bw/day). On study day 10, 5 male rats showed focal and multifocal red spots on treated skin on several days. Based on experience from a previous study, with regard to the progress in severity of dermal findings after application of the test material preparations, the dose level in test group 3 was reduced from 450 to 300 mg/kg bw/day. Starting on study day 11, 9 male rats showed focal scales on treated skin on several days. One rat showed focal erosion on treated skin on several days beginning on study day 14. Starting on study day 15, 5 rats showed slight erythema on treated skin on several days. Similar findings but less pronounced were observed in male animals of test group 2 (150 mg/kg bw/day). No treatment- related findings were observed in male animals of test group 1 (50 mg/kg bw/day).For female animals, different dermal findings were seen on several days. In test group 3, 7 females showed slight and moderate erythema on several days of the study, starting on study day 3. In addition, some animals of test group 3 showed multifocal, focal and diffuse scales on treated skin starting on study day 5. Similar findings but less pronounced were observed in female animals of test group 2, i.e. focal red spots, slight erythema and focal scales on treaed skin on several days of the study. In test group 1, slight erythema as well as focal and diffuse scales on treated skin were observed in individual animals at different time points.Female no. 137 of test group 3, which did not deliver pups, showed a vaginal haemorrhage 27 days after mating.In female animal 127 of test group 2, a severe thoracal injury was observed during pre-mating. It was a self inflicted injury which was caused by the animal's attempt to get rid of the gauze. The injury became more severe by time and the animal had to be sacrificed in a moribund state on study week 1.BODY WEIGHT (PARENTAL ANIMALS)The mean body weight and body weight change of male and female animals showed no significant deviations to the control group in all test groups.FOOD CONSUMPTION (PARENTAL ANIMALS)No changes in food consumption of toxicological significance were seen for male and female animals of all test groups.REPRODUCTION DATA: (MALE PARENTAL ANIMALS)For all parental males, which were placed with parental females to generate F1 pups, mating was confirmed. Thus, the male mating index was 100 % in all test groups. Fertility was proven for most of the parental males within the scheduled mating interval to produce the F1 litter. Thus, the male fertility index ranged between 89 % (test group 2) and 90 % (test groups 0, 1 and 3). These reflected the normal range of biological variation inherent in the strain of rats used for this study.REPRODUCTION DATA: (FEMALE PARENTAL ANIMALS)The female mating index after the mating period for F1 litter was 100 % for all groups.The mean duration until sperm was detected gestation day 0) amounted to 3.2, 2.6, 2.7 and 4.6 days in test group 0 - 3, respectively. Differences between the test groups were assessed as being spontaneous in nature and without any biological relevance.One female in each test group were found to be sperm-positive but did not become pregnant and had no implantation sites in utero. One female of test group 1 and two females of test group 3, were sperm positive, showed implantation sites at necropsy, but delivered no pups. these females were sperm positive after only one mating day. Furthermore, one female of test group 1 was not sperm positive but delivered pups.The female fertility index varied between 89 % (test group 2) and 90 % (test groups 0, 1 and 3).The mean duration of gestation was 22.1 days in test group 0, 22.0 in test groups 1 and 2 and 22.4 days in test group 3.The gestation index varied between 78 % for test group 3, 89 % for test group 1 and 100 % for test groups 0 and 2. the decreased gestation index in test group 3 was assumed as being unrelated to treatment with the test material.The mean number of implantation sites was 13.0, 10.9, 11.8 and 10.6 implants/dam in test group 0 - 3, respectively.Post-implanation loss was increased in test group 3 (28.2 %), however, this was caused by two animals which had only 1 and 3 implantation sites and complete implantation losses. the loss of these implants led to absorption rates of 100 % in each case, which artificially exaggerates the test group average for this parameter. the same was true for test group 1 (14.5 %) was related to 1 female with complete litter loss. Taken together, the increased post-implantation loss values in test groups 1 and 3 were assessed as being a matter of calculating mean values and incidental rather than related to treatment.The mean number of F1 delivered pups per dam was 12.2, 11.4, 10.6 and 12.0 pups/day, in test groups 0 - 3, respectively. the live birth indices ranged between 98 % in test group 3, 99 % in test groups 0 and 1 and 100 % in test group 2.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 rat strain. The rate of pups that died during lactation was 0 % in the control and all treatment groups.Thus, the dermal administration of the test material did not affect reproduction and delivery of the parental females in test groups 1 - 3.The mean number of delivered pups per dam and the rate of liveborn and stillborn pups were evenly distributed among test groups 0, 1, 2 and 3. The respective values reflect the normal range of biological variation inherent in the strain used in this study.ORGAN WEIGHTS (PARENTAL ANIMALS)None of the absolute of relative weight parameters in test groups 1 - 3 showed relevant differences when compared to the control group and were considered to be within the normal range.GROSS PATHOLOGY (PARENTAL ANIMALS)A red-brown lesion was noted on the thorax of female no. 127 of test group 2 which was sacrificed moribund. All gross lesions observed in test animals occurred singularly. They were considered to be spontaneous lesions in origin and not related to treatment.HISTOPATHOLOGY (PARENTAL ANIMALS)The lesion noted on the thorax of female no. 127 correlated to an erosion on the skin. Lymphocytic infiltrates were observed in treated skin sections which were distributed band-like between epidermis and dermis. All other findings noted were single observations which were considered to be incidental and spontaneous in origin and without any relation to treatment.
Effect levels (P0)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- (reproductive performance)
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Only local signs observed up to the highest dose, no effects on reproductive performance were recorded.
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- (systemic toxicity)
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Only local signs observed, no evidence of systemic toxicity observed.
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
- Other effects:
- not specified
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not specified
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not specified
Details on results (F1)
VIABILITY (OFFSPRING)No significant findings for pups that died during lactation were observed. The viability index varied between 99 % for test groups 1 and 3 and 100 % for test groups 0 and 2.No test material-related changes were obtained.Male pup no. 8, delivered by dam no 118 of test group 1, was sacrificed moribund on post natal day 0 as it showed malformation of the skull, anophthalmia and cleft lip.The sex distribution and sex ratios of live F1 pups on the day of birth and post natal day 4 did not show biologically relevant differences between the control and test groups 1 to 3.CLINICAL SIGNS (OFFSPRING)Dam no 118 (test group 1) gave birth to male pup no 8 with a deformation of its snout. On first sight a cleft lip and anophthalmia were seen. The staining of the pups skull showed that several bones (basisphenoid, palatine, incisive, nasal - including cartilage and maxilla) were deformed and/or displaced. Therefore, F1 pups did not show adverse clinical signs up to schedules sacrifice on post natal day 4.BODY WEIGHT (OFFSPRING)The mean body weight of female pups was increased by 10 % on post natal day 4 in test group 3. Pup body weight change in groups 1 to 3 were comparable to the concurrent control values. GROSS PATHOLOGY (OFFSPRING)No test substance related findings were observed.
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Homogeneity and concentration control analyses
The test material was completely miscible with Corn Oil Ph. Eur, and thus, a solution. Therefore, the test material preparation was considered to be homogenous and no further homogeneity analysis was performed.
The concentration control analyses at the beginning and towards the end of the application period revealed values in the expected range of the target concentrations. The means of the nominal concentrations were in a range of 96.5 - 104.3 % of the nominal concentrations.
Table 1: Clinical Observations (Males)
Group |
Week of study |
Total |
|||||
No. of animals examined |
0 |
1 |
2 |
3 |
4 |
||
0 |
10 |
10 |
10 |
10 |
10 |
||
1 |
10 |
10 |
10 |
10 |
10 |
||
2 |
10 |
10 |
10 |
10 |
10 |
||
3 |
10 |
10 |
10 |
10 |
10 |
||
Normal, nothing abnormal declared |
0 |
10 |
10 |
10 |
10 |
10 |
10 |
1 |
10 |
10 |
10 |
10 |
10 |
10 |
|
2 |
10 |
10 |
9 |
10 |
10 |
10 |
|
3 |
10 |
10 |
6 |
6 |
8 |
10 |
|
Dead, scheduled sacrifice |
0 |
0 |
0 |
0 |
0 |
0 |
10 |
1 |
0 |
0 |
0 |
0 |
0 |
10 |
|
2 |
0 |
0 |
0 |
0 |
0 |
10 |
|
3 |
0 |
0 |
0 |
0 |
0 |
10 |
|
Animal body |
|||||||
Treated skin, erythema, slight |
0 |
0 |
0 |
0 |
0 |
10 |
10 |
1 |
0 |
0 |
0 |
0 |
10 |
10 |
|
2 |
0 |
0 |
1 |
3 |
3 |
3 |
|
3 |
0 |
0 |
4 |
5 |
4 |
5 |
|
Treated skin, scales, focal |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
1 |
2 |
2 |
2 |
2 |
|
3 |
0 |
6 |
7 |
9 |
6 |
9 |
|
Treated skin, erosion, focal |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
0 |
0 |
0 |
0 |
0 |
|
3 |
0 |
0 |
1 |
1 |
0 |
1 |
|
Treated skin, red spots, focal |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
4 |
5 |
5 |
3 |
5 |
|
3 |
0 |
0 |
3 |
3 |
2 |
4 |
|
Treated skin, red spots, multifocal |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
0 |
0 |
0 |
0 |
0 |
|
3 |
0 |
1 |
1 |
1 |
0 |
1 |
|
Table 2: Clinical Observations (Females)
Group |
Week of study |
Total |
||||||||
No. of animals examined |
0 |
1 |
2 |
3 |
4 |
5 |
6 |
7 |
||
0 |
10 |
10 |
10 |
1 |
- |
3 |
9 |
10 |
||
1 |
10 |
10 |
10 |
1 |
1 |
4 |
10 |
10 |
||
2 |
10 |
10 |
9 |
- |
- |
2 |
9 |
9 |
||
3 |
10 |
10 |
10 |
3 |
1 |
4 |
7 |
10 |
||
Normal, nothing abnormal declared |
0 |
10 |
10 |
7 |
1 |
- |
3 |
9 |
10 |
10 |
1 |
10 |
10 |
8 |
1 |
1 |
4 |
10 |
10 |
10 |
|
2 |
10 |
10 |
6 |
- |
- |
2 |
9 |
9 |
10 |
|
3 |
10 |
5 |
3 |
3 |
0 |
4 |
7 |
10 |
10 |
|
Dead, sacrificed moribund |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
1 |
0 |
- |
- |
0 |
0 |
0 |
1 |
|
3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
Scheduled sacrifice |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
10 |
10 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
10 |
10 |
|
2 |
0 |
0 |
0 |
- |
- |
0 |
0 |
9 |
9 |
|
3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
10 |
10 |
|
Animal body |
||||||||||
Treated skin, erythema, slight |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
2 |
2 |
1 |
0 |
0 |
0 |
0 |
0 |
2 |
|
2 |
0 |
1 |
0 |
- |
- |
0 |
0 |
0 |
1 |
|
3 |
5 |
5 |
2 |
1 |
1 |
0 |
0 |
0 |
5 |
|
Treated skin, erythema, moderate |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
0 |
0 |
- |
- |
0 |
0 |
0 |
0 |
|
3 |
1 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
|
Treated skin, scales, focal |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
1 |
2 |
1 |
- |
- |
0 |
0 |
0 |
2 |
|
3 |
4 |
4 |
2 |
0 |
0 |
0 |
0 |
0 |
4 |
|
Treated skin, scales, multifocal |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
0 |
0 |
- |
- |
0 |
0 |
0 |
0 |
|
3 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
|
Treated skin, scales, diffuse |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
0 |
0 |
- |
- |
0 |
0 |
0 |
0 |
|
3 |
1 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
|
Injury, thoracal |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
1 |
0 |
- |
- |
0 |
0 |
0 |
1 |
|
3 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
Miscellaneous |
||||||||||
Sperm in vaginal smear (day 0 pc) |
0 |
0 |
0 |
9 |
1 |
- |
0 |
0 |
0 |
10 |
1 |
0 |
0 |
9 |
0 |
0 |
0 |
0 |
0 |
9 |
|
2 |
0 |
0 |
9 |
- |
- |
0 |
0 |
0 |
9 |
|
3 |
0 |
0 |
7 |
3 |
0 |
0 |
0 |
0 |
10 |
|
Vaginal haemorrhage |
0 |
0 |
0 |
0 |
0 |
- |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
2 |
0 |
0 |
0 |
- |
- |
0 |
0 |
0 |
0 |
|
3 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
1 |
|
ANALOGUE APPROACH JUSTIFICATION:
- See attached “Justification for read-across” document for full details.
- In summary, important considerations for the use of read-across for reproductive/developmental toxicity screening are: i) 4-methyldec-3-en-5-ol (the target chemical) has similar physico-chemical properties as 4(2E)−3,7−dimethylocta−2,6−dien−1−ol (the source substance), ii) there are structural similarities between the two chemicals and iii) the OECD QSAR Toolbox assigns an identical toxicity profiles to both chemicals.
The information reported in this summary is included to demonstrate comparability between the source (4(2E)−3,7−dimethylocta−2,6−dien−1−ol) and target (4-methyldec-3-en-5-ol) substance.
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of the study, the No Observed Adverse Effect Level NOAEL) for reproductive performance and fertility in male and female Wistar rats was 300 mg/kg bw/day. The dermal administration of the test material revealed only local signs of toxicity in male and female rats at all dose levels. This finding was related to the irritating potential of the test material. The NOAEL for general, systemic toxicity of the test material was 300 mg/kg bw/day.
- Executive summary:
The reproductive and developmental toxicity of the test material was investigated in a GLP study which was conducted in accordance with standardised guidelines OECD 421 and EPA OPPTS 870.3550. During the study test material was administered via dermal administration to groups of 10 male and 10 female Wistar rats at dose levels of 0 (vehicle control; test group 0), 50 (test group 1), 150 (test group 2) and 450 mg/kg (test group 3) in order to observe the possible effects of the test material on the integrity and performance of the reproductive system in both sexes. Due to severe dermal findings, the dose level for test group 3 was decreased to 300 mg/kg bw/day from study day 10 onwards. Only signs of local dermal toxicity were observed for males and females at all dose levels. No changes in food consumption or body weight were seen at any dose level. Fertility indices for male and female animals were not impaired by test material administration. Furthermore, there were no treatment related or histological findings in ovaries, testes or epididymides associated with dermal administration of the test material. The local minimal inflammatory reactions in the skin of treated males (test groups 1 to 3) and females (test group 3 only) were regarded as related to treatment and adverse. Under the conditions of the study, the No Observed Adverse Effect Level (NOAEL) for reproductive performance and fertility in male and female Wistar rats was 300 mg/kg bw/day. The dermal administration of the test material revealed only local signs of toxicity in male and female rats at all dose levels. This finding was related to the irritating potential of the test material. The NOAEL for general, systemic toxicity of the test material was 300 mg/kg bw/day.
Important considerations for the use of read-across for reproductive/developmental toxicity screening are: i) 4-methyldec-3-en-5-ol (the target chemical) has similar physico-chemical properties as 4(2E)−3,7−dimethylocta−2,6−dien−1−ol (the source substance), ii) there are structural similarities between the two chemicals and iii) the OECD QSAR Toolbox assigns an identical toxicity profiles to both chemicals.
The information reported in this summary is included to demonstrate comparability between the source (4(2E)−3,7−dimethylocta−2,6−dien−1−ol) and target (4-methyldec-3-en-5-ol) substance.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
