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Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction: Data waiving (study scientifically not necessary): According to REACH Annex VIII, column 2, the study does not need to be conducted becuase pre-natal developmental toxicity study is available.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
According to REACH Annex VIII, column 2, the study does not need to be conducted becuase pre-natal developmental toxicity study is available.
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 study available
Additional information

Toxicity to reproduction: Data waiving (study scientifically not necessary): According to REACH Annex VIII, column 2, the study does not need to be conducted becuase pre-natal developmental toxicity study is available.

Effects on developmental toxicity

Description of key information

Pre-natal developmental toxicity: Key study. Read-across approach. Test method OECD 414, GLP study. Based on the read-across approach, the NOEL for maternal and developmental toxicity of the test item was determined to be 785.84 mg/kg bw/day in rats.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 April 1991 - 28 May 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. certificate)
Limit test:
yes
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hoe: WISKf (SPF71)
- Age at study initiation: 65-70 days
- Weight at study initiation: 191 ± 6 g
- Housing: individually in plastic cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24 ° C
- Humidity (%): 49-53%
- Air changes (per hr): 16-20/h
- Photoperiod (hrs dark / hrs light): 12 light / 12 hours dark (450 Lux)
Route of administration:
oral: gavage
Vehicle:
other: sesame oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The substance was prepared fresh daily.

VEHICLE
- Concentration in vehicle: 200 g/L
- Amount of vehicle (if gavage): 5 mL/kg bw

OTHER:
- The stability and homogeneity of the solution was ensured for a period of 4 hours
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: Females were mated overnight with fertile males.
- M/F ratio per cage: 1 male/1 female
- Proof of pregnancy: Sperm in vaginal smear referred to as day 1 of pregnancy
Duration of treatment / exposure:
Gestation days 7-16
Frequency of treatment:
Once daily
Duration of test:
21 days
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
20 mated females: test group
21 mated females: control group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: A preliminary range-finding test was performed with 3 pair of rats per dose, in a trial. Animals were exposed to 270, 500 and 1000 mg/kg bw/day between day 7-16 of gestation. On day 21, animals were sacrificed. No effects were observed at the highest dose related to maternal toxicity, embryotoxicity and teratogenicity.
Maternal examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/100 g body weight/day: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: Once a week and a day after the last application

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: macroscopic examination and organ weighing of heart, liver, kidneys and spleen
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
- Other: diameter of fetal resorption and placental weight
Fetal examinations:
- External examinations: Yes: all per litter
- Body weight: Yes: all per litter
- External/visceral examinations: Yes: all per litter (external/visceral, abdominal cavity, liver, kidney)
- Skeletal examinations: Yes: all per litter (skeleton, skull, thoracic vert. centra, sacral vert. arch/centra, caudal vert. centra, extra vertebrae/extra rib, sternebra, rib, extra rib, pectoral girdle, forepan, forepan-phalanx, pelvic girdle, hindpaw, hindpaw-phalanx)
- Head examinations: Yes: all per litter
- Other:
Body cross-sections for Wilson, photography: Yes: half per litter
Dead fetus in uterus were fixed, stained and examined microscopically.
Remaining fetus, were fixed in Bouin solution and examined under stereomicroscope.
Statistics:
Comparisons between body weights and organ weights in the test and control group were performed with a classical analysis of variance (MANOVA); to evaluate the relative feed intake, a analysis of variance according to Puri & Sen (1985). Corpora lutea and implantations were performed with the Mantel-Haenszel x2 test (Mantel & Haenszel, 1959), as well as live and dead fetuses and resorptions. Other parameters according to an analysis of variance. The body cross-sectional study of fetuses and skeletal findings were studied with the Fisher Exact test.
Clinical signs:
no effects observed
Description (incidence and severity):
No adverse effects were observed. At Day 11 of gestation one female showed hair loss in the forelimbs and at Day 19 in the belly, flanks and hind limbs.
Dermal irritation (if dermal study):
not examined
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effects were observed. The body weight of the treated animals was similar to control animals.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No adverse effects were observed. At the end of the study the food consumption was slightly higher in the treated group comparing with the control group.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Two females of the treatment group showed moderate enlargement of the right kidney. No other changes were observed.
The heart, kidney, liver and spleen weight did not differ from those of the control group.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Two females of the treatment group showed moderate enlargement of the right kidney. No other changes were observed.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Number of abortions:
no effects observed
Description (incidence and severity):
The treated groups had a number of live fetuses similar to the control group.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
All females gave birth to live fetuses except 1 dam in the 1000 mg/kg bw group. This dam had no fetus, and only 5 empty implantations were observed. The corporea lutea were quite small and could not be accurately determined. The treated groups had corporea lutea, number of implantations and number of live fetuses similar to the control group.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Other effects:
no effects observed
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Remarks on result:
other: No effect observed at the highest dose tested
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal developmental toxicity
Remarks on result:
other: No effect observed at the highest dose tested
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Fetus were normally developed. Body weight and body lengths were similar from those in the control group. In the 1000 mg/kg bw treatment group, the number of live fetuses weighing less than 3 g was lower than in the control group.
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
Description (incidence and severity):
Early intrauterine deaths were observed in both groups. The total number of deaths in the treated group was low and did not differ from the control group. Only one dead fetus was observed in the control groups.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex ratio was balanced in both groups, predominating males.
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
No fetal malformations were observed. The body section and cross-section observations showed 5 fetuses with hematoma in the liver overlap. Although it was statistically significant, it was in accordance with historical control values. In three fetuses at 1000 mg/kg bw group, blood was found in the abdominal cavity. Nine fetus in the control group showed enlarged renal pelvis.
Skeletal malformations:
no effects observed
Description (incidence and severity):
The skeletons were about the same stage of development in both treatment and control groups, corresponding to the 21 day of pregnancy. The number of fetuses with weak ossification of head bones, sternebrae and metacarpal 5 was significantly higher than in the control group. However, it was in line with historical control values. One fetus showed week ossidification of metatarsal 5, phalanx III, ischium and the pubis. Besides these findings, thoracic vertebra with a short or normal length, corrugated/thickened rib, short of fragmented cervical rib and displaces sternebrae were observed in both treatment and control groups. All the effects were within the historical control values.
Visceral malformations:
no effects observed
Description (incidence and severity):
Placental weight in live fetuses (including) macroscopic findings, were similar in both treatment and control groups.
The dead fetus of the control group was retarded in development, which is in accordance with weaker ossification. An examination of the internal organs was not possible because of the small size.
Other effects:
no effects observed
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: Fetuses toxicity
Remarks on result:
other: No effect observed at the highest dose tested
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
The NOEL for maternal and developmental toxicity after an oral exposure of isobornyl acetate was determined to be 1000 mg/kg bw/day in rats under test conditions.
Executive summary:

A pre-natal developmental toxicity test was performed with isobornyl acetate according to OECD Guideline 414. 20 female Wistar rats were exposed by gavage to 0 (control) and 1000 mg/kg bw/day test item between Days 7 and 16 of gestation, in a limit test. On Day 21 of gestation, the animals were killed and both dams and fetus were examined. The investigations showed that the repeated oral exposure to the test item during the sensitive period of organogenesis, do not cause an impairment of the general health of dams, not disturbing the intrauterine development of fetus. The morphological examination of fetuses revealed no evidence for teratogenic effects of the substance. Therefore, the NOEL of isobornyl acetate for maternal and fetal developmental toxicity was determined to be 1000 mg/kg bw/day in rats.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
The analogue substance isobornyl acetate undergoes rapid hydrolysis to acetic acid and isoborneol which shares the same functional groups with the substance D-alpha fenchol and also has comparable values for the relevant molecular properties.
See attached the reporting format.
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOEL
Effect level:
785.84 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Remarks on result:
other: read-across from an analogue for which NOEL = 1000 mg/kg bw/day
Key result
Dose descriptor:
NOEL
Effect level:
785.84 mg/kg bw/day
Basis for effect level:
other: Maternal developmental toxicity
Remarks on result:
other: read-across from an analogue for which NOEL = 1000 mg/kg bw/day
Key result
Abnormalities:
no effects observed
Key result
Dose descriptor:
NOEL
Effect level:
785.84 mg/kg bw/day
Basis for effect level:
other: fetuses toxicity
Remarks on result:
other: read-across from an analogue for which NOEL = 1000 mg/kg bw/day
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Conclusions:
Based on the read-across approach from experimental data on the analogue isobornyl acetate, the NOEL for maternal and developmental toxicity of the test item was determined to be 785.84 mg/kg bw/day in rats.
Executive summary:

A pre-natal developmental toxicity test was performed with the analogue substance isobornyl acetate according to OECD Guideline 414. 20 female Wistar rats were exposed by gavage to 0 (control) and 1000 mg/kg bw/day test item between Days 7 and 16 of gestation, in a limit test. On Day 21 of gestation, the animals were killed and both dams and fetus were examined. The investigations showed that the repeated oral exposure to the analogue substance during the sensitive period of organogenesis, do not cause an impairment of the general health of dams, not disturbing the intrauterine development of fetus. The morphological examination of fetuses revealed no evidence for teratogenic effects of the substance. Therefore, the NOEL of isobornyl acetate for maternal and fetal developmental toxicity was determined to be 1000 mg/kg bw/day in rats. Based on these results, the read-across approach was applied and the NOEL of the test item was determined to be 785.84 mg/kg bw/day for maternal and developmental toxicity in rats.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
785.84 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The key study has a Klimisch score = 1
Additional information

Pre-natal developmental toxicity: Key study. Read-across approach. A pre-natal developmental toxicity test was performed with the analogue substance isobornyl acetate according to OECD Guideline 414. 20 female Wistar rats were exposed by gavage to 0 (control) and 1000 mg/kg bw/day test item between Days 7 and 16 of gestation, in a limit test. On Day 21 of gestation, the animals were killed and both dams and fetus were examined. The investigations showed that the repeated oral exposure to the analogue substance during the sensitive period of organogenesis, do not cause an impairment of the general health of dams, not disturbing the intrauterine development of fetus. The morphological examination of fetuses revealed no evidence for teratogenic effects of the substance. Therefore, the NOEL of isobornyl acetate for maternal and fetal developmental toxicity was determined to be 1000 mg/kg bw/day in rats. Based on these results, the read-across approach was applied and the NOEL of the test item was determined to be 785.84 mg/kg bw/day for maternal and developmental toxicity in rats.

Justification for classification or non-classification

Based on the available information, the substance is not classified for toxicity to reproduction in accordance with CLP Regulation (EC) no 1272/2008.