Registration Dossier
Registration Dossier
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EC number: 279-815-0 | CAS number: 81782-77-6
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Link to relevant study records
- 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.
Reference
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.
Effect on fertility: via oral route
- Endpoint conclusion:
- no study available
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 300 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The available study was performed to GLP and was conducted in accordance with standardised guidelines with a high level of reporting. As the study was conducted on the read-across substance, 3,7-dimethylocta-2,6-dien-1-ol, it has been assigned a reliability score of 2.
Additional information
The reproductive and developmental toxicity of the test material, 3,7-dimethylocta-2,6-dien-1-ol an analogue of 4-methyl-3-decen-5-ol, 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.
Short description of key information:
Key study NOAEL (reproductive toxicity) 300 mg/kg bw/day; NOAEL (systemic toxicity) 300 mg/kg bw/day, OECD 421, EPA OPPTS 870.3550, Buesen et al. 2010
Justification for selection of Effect on fertility via dermal route:
Only one study is available.
Effects on developmental toxicity
Description of key information
Key study: NOAEL (developmental toxicity) 300 mg/kg bw/day; NOAEL (maternal toxicity) 300 mg/kg bw/day, OECD 421, EPA OPPTS 870.3550, Buesen et al. 2010
Link to relevant study records
- Endpoint:
- developmental toxicity
- 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:
- other: 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)
- 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: 286.8 - 322.3 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:
- other: 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
- 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
- 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
- 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)
- Duration of test:
- Up to gestation day 19 for parental animals (with a two week pre-mating period and a two week (maximum) mating period), and postnatal day 4 for offspring
- No. of animals per sex per dose:
- 10 females per dose level
- Control animals:
- yes
- 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.
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes - Time schedule: mortality was checked twice daily 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 during the mating periodFood 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.SACRIFICE: Parental animals were sacrificed by decapitation under isoflurane anesthesia. The exanguinated animals were necropsied and assessed by gross pathology.- Sacrifice 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 and ovariesORGAN/TISSUE FIXATIONThe following were fixed in 4 % neutral buffered formaldehyde solution or in modified Davidson's solution: all gross lesions, adrenal glands, ovaries, pituitary gland, coagulation glands, skin (treated), skin (untreated), uterus, oviducts, vagina.The ovaries 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 ovaries and untreated skin in the control and high dose group animals.
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: YesExaminations included:- Number of implantations: Yes
- Fetal examinations:
- 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.On post-natal day 4, the pups were sacrificed under isoflurane anesthesia 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. Pair-wise 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, stilibrin, 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.
- 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
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not examined
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- not specified
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed - Changes in number of pregnant:
- no effects observed
- Other effects:
- not specified
- Details on maternal toxic effects:
- Maternal toxic effects:no effects. Remark: Only local signs of irritation were reportedDetails on maternal toxic effects: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 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 tre6aed 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 WEIGHTThe mean body weight and body weight change of animals showed no significant deviations to the control group in all test groups.FOOD CONSUMPTION No changes in food consumption of toxicological significance were seen for male and female animals of all test groups.ORGAN WEIGHTSNone 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 PATHOLOGYA 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 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.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed - Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- no effects observed
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effectsDetails on embryotoxic / teratogenic effects: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.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects observed
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- Under the conditions of the study the No Observed Adverse Effect Level (NOAEL) for maternal toxicity was determined to be 300 mg/kg bw/day. The NOAEL for developmental toxicity was determined to be 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 epipdiymides 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 maternal toxicity was determined to be 300 mg/kg bw/day. The NOAEL for developmental toxicity was determined to be 300 mg/kg bw/day.
Important considerations for the use of read-across for acute toxicity are: i) 4-methyl-3-decen-5-ol (the target substance) has similar physico-chemical properties to (2E)-3,7-dimethylocta-2,6 -dien-1-ol (the source substance), ii) there are structural similarities between the two substances and iii) the OECD QSAR Toolbox assigns an identical toxicity profile to both chemicals. The source substance is therefore considered suitable for classification and labelling and risk assessment purposes using a read-across approach (see 'Justification for read-across' in Section 13 for further details).
Reference
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.
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.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 300 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- The available study was performed to GLP and was conducted in accordance with standardised guidelines with a high level of reporting. As the study was conducted on the read-across substance, 3,7-dimethylocta-2,6-dien-1-ol, it has been assigned a reliability score of 2.
Additional information
The reproductive and developmental toxicity of the test material, 3,7-dimethylocta-2,6-dien-1-ol an analogue of 4-methyl-3-decen-5-ol, was investigated in a GLP study which was conducted in accordance with standardised guidelines OECD 421 and EPA OPPTS 870.3550. During the study the 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 maternal toxicity was determined to be 300 mg/kg bw/day. The NOAEL for developmental toxicity was determined to be 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.
Justification for selection of Effect on developmental toxicity: via dermal route:
Only one study is available.
Justification for classification or non-classification
According to the criteria outlined in Regulation 1272/2008 and Directive 67/548/EEC, the substance is considered to be unclassified for reproductive toxicity.
Additional information
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