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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
21 April 1992 – 05 August 1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Test method according to OECD guideline 414 and GLP, but only two dose levels were tested.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report date:
1992

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
(Only two dose levels were tested)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Camphene
EC Number:
201-234-8
EC Name:
Camphene
Cas Number:
79-92-5
Molecular formula:
C10H16
IUPAC Name:
2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane
Test material form:
solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Lippische Versuchstierzucht, HAGEMANN GmbH, D-4923 Extertal 1, Stock: Tif: RAI f (SPF)
- Age at study initiation: ca. 54 days old
- Weight at study initiation: 180 - 190 g
- Housing: The dams were kept singly in MAKROLON cages type III.
- Diet (e.g. ad libitum): ALTROMIN 1314 (supplied by: ALTROMIN GmbH, P.O.Box 285, D-4937 Lage/Lippe) served as food, ad libitum.
- Water (e.g. ad libitum): Tap water, ad libitum.
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 ºC
- Humidity (%): 50 ± 15 %
- Photoperiod: 12 hrs dark / 12 hrs light (150 lux at 1.50 m room height)

IN-LIFE DATES: 28 April 1992 – 05 August 1992

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: sesame oil, DAB 10
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test substance-vehicle mixtures were freshly prepared each day immediately before dosing.
The stability and homogeneity of the solution was ensured for a period of 4 hours

VEHICLE
- Concentration in vehicle: 50 mg/ml and 200 mg/ml
- Amount of vehicle (if gavage): 5 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
For the determination of the concentration in the substance-vehicle preparations, 2 samples of 10 mL (each one for the concentrations 50.0 mg/Camphene/mL suspension and 200.0 mg Camphene/mL suspension) were analyzed at the start and at the end of treatment.
The determination of the concentrations was performed by GC using a FID detector.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: Females randomly chosen were mated overnight with fertile ('proved') 4 - 12 months old male rats of the same breed. They were repeatedly employed, at the earliest three days after successful copulation.
- M/F ratio per cage: 1 male/1 female
- Proof of pregnancy: Sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
From the 6th to 15th day of pregnancy
Frequency of treatment:
Daily
Duration of test:
20 days (from day 0 to day 20 of pregnancy)
Doses / concentrationsopen allclose all
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
20 pregnant female rats per group (plus 15 reserve animals)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
During a range-finding study using 3 pregnant rats from the same strain as selected for the present study, a camphene dose-Ievel of 1000 mg/kg b.w., by gavage, was administered from day 6 to 15 of pregnancy. 1000 mg/kg b.w. is the highest requested dose according to the OECD method 414 (limit test for embryotoxicity).
Except for a slight transient reaction after the first dosing, 1000 mg/kg b.w. was well-tolerated by the dams. 1000 mg/kg b.w. did not influence the prenatal development. Based on these results, 250 mg and 1000 mg camphene/kg b.w./day, by gavage, treatment from the 6th to 15th day of prenancy were selected by the sponsor as doses for the main experiment.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked in table were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily checks (once in the morning and once as late on the day as practicable) were performed on behaviour, external appearance, mortality and faeces.

BODY WEIGHT: Yes
- Time schedule for examinations: daily (always at the same time in the morning)

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption was determined daily by weighing the residue.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Intake of drinking-water was observed daily

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: On the 20th day of gestation the surviving rats were laparotomised under ether narcosis. The ovaries and uteri were removed and examined. To check for possible drug effects a dissection was carried out which included macroscopic examination of internal organs. A full macroscopic inspection was carried out in the prematurely deceased dams as soon as possible after their exitus.

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes. The uterus weight was determined (with and without fetuses), weight of the ovaries was determined.
- Number of corpora lutea: Yes.
- Number of implantations: Yes. Implantations and location of fetuses in the uterus were determined.
- Number of early resorptions: Yes.
- Number of late resorptions: Yes.
- Other:
Sex and viability of fetuses were determined. Animals are said to be viable when they are found alive (spontaneous breathing, spontaneous movement).
Weights and length of fetuses and weight of the placentae were determined (fetuses were considered as runts if their weight was less than 70% of the mean litter weight).
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]. According to the method of Wilson.
- Skeletal examinations: Yes: [half per litter]. According to the method of Dawson.
Statistics:
The comparison of malformation and variation rates was carried out using R. A. FISHER's exact test (p ≤ 0.05). All other data were evaluated in the following way:
Homogeneity of variances was tested by the Bartlett chi-square test, and, if the variances were homogeneous, a one-way analysis of variance was applied. When the results indicated a significant difference among groups the DUNNETT test (p ≤ 0.01) was used to compare the experimental groups with the control group.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Six of the 20 dams treated with 1000 mg/kg bw/day showed reduced motor activity and salivation after first dosing, one of them salivation after second dosing. One more dam showed salivation on the second dosing. The reactions occurred within 5 - 20 min after administration and lasted for 20 - 60 min, 1-2 hrs or 2-6 hrs.
No clinical signs were observed in the remaining high-dosed and the low-dosed dams.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Two dams treated with 1000 mg/kg bw/day died prematurely probably due to regurgitation and aspiration of part of the administered test compound. Because deaths were no substance-related these dams were replaced to have 20 pregnant females in this dose group for study examinations.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight and body weight gain remained within the normal range of the controls.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Transient impairment of the food consumption by the highest tested dose (1000 mg/kg bw/day) was observed on the 7th, 8th and 9th gestation day by 6%, 22% and 10%, respectively.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Treatment did not influence drinking-water consumption.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Six of the 20 dams treated with 1000 mg/kg bw/day showed reduced motor activity and salivation after first dosing, one of them salivation after second dosing. One more dam showed salivation on the second dosing. The reactions occurred within 5 - 20 min after administration and lasted for 20 - 60 min, 1-2 hrs or 2-6 hrs.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The uterus weights of the treated groups were not influenced by the exposure to the test compound.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No substance-related pathological changes were detected at autopsy.
Macroscopic inspection during dissection of the two deceased rats revealed emphysematous and spongy lungs, these findings indicating regurgitation and aspiration of part of the administered test compound.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
No abortions were registered either in treated groups or in the control group.
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
There were no substance-related and/or statistically significant differences between the treated groups and the control group for the pre-implantation loss.
However, the high dose caused a slight but not significant (at p < = 0.01) increase of the post-implantation loss (substance-treated group: 11.5%, control group: 5.2%).
Total litter losses by resorption:
effects observed, non-treatment-related
Description (incidence and severity):
The mean value of total losses by resorptions per litter were calculated to be 0.8 in the control group, 1.0 in the low dose group and 1.3 in the high dose group (statistically not significant at p < = 0.01).
Early or late resorptions:
effects observed, non-treatment-related
Description (incidence and severity):
1000 mg camphene/kg b.w./day caused a slight but not significant (at p < = 0.01) increase of the resorption rate (substance-treated group: 11.5%, control group: 5.2%).
Dead fetuses:
no effects observed
Description (incidence and severity):
No dead fetuses occurred in the substance treated and control dams.
The treated groups had a number of viable fetuses per pregnant rat similar to the control group.
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
There were no substance-related and/or statistically significant differences between the treated groups and the control group in conception rate, in the mean number of corpora lutea and implantation site.
The conception rate varied between 84% and 96%.
Other effects:
no effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
NOEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
clinical signs

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
The mean fetal weights and mean placental weights were not influenced by the test substance exposure. All values were within the range of biological variation.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
There were no substance-related and/or statistically significant differences between the treated groups and the control group in the number of viable fetuses.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex distribution of the fetuses in the treated groups was comparable with the control fetuses. The differences observed in comparison to the control are without any biological relevance.
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
External examination of the fetuses revealed malformations (shifted and fused dorsal, lumbar and coccygeal vertebrae, bilateral crossed legs, stump tail, omphalocele) in one fetus out of 243 fetuses in the high dose group and only one variation (haemorrhage in the left anterior chamber of the eye) in one fetus out of 248 fetuses in the low dose group. One out of 258 control foetuses showed one malformation (stump tail). These changes belong to the spontaneous range as to their type and the number of affected foetuses.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No malformations were observed during skeletal examinations.
The variations elicited were related to the ribs (accessory 14th ribs, wavy ribs) and the sternum (sternebra bipartite or misaligned) and were found in all groups, including the control, to about the same extent.
In all groups signs of retardations (incomplete or missing ossification of hyoid, skull, vertebral bodies and/or sternebra were found without any clear differences of biological relevance between the groups, included the control).
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The examination of the organ of the foetuses revealed no malformations in the treated groups.
Variations were detected in all groups. The very common findings (uni- or bilateral dilated renal pelvis, haemorrhages of the liver, 4th cerebral ventricle enlarged) in the rat strain used in the study occurred without any dose-response relationship.
The type and number of variations found in the treated groups were similar to those found in the control group.
Other effects:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Fetuses toxicity
Remarks on result:
other: No adverse effect observed at the highest dose tested

Fetal abnormalities

Key result
Abnormalities:
effects observed, non-treatment-related
Localisation:
other: (shifted and fused dorsal, lumbar and coccygeal vertebrae, bilateral crossed legs, stump tail, omphalocele)
Description (incidence and severity):
One malformed fetus at 1000 mg/kg bw/day belongs to the spontaneous range as to type and number of affected fetuses (control: one fetus with stump tail).

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Under the test conditions, the NOEL for the dams and for the fetal organism was 250 mg camphene/kg bw/day. Camphene did not possess teratogenic properties.
Executive summary:

A pre-natal developmental toxicity test was performed with camphene according to OECD Guideline 414. 20 pregnant Sprague-Dawley rats were orally exposed by gavage during the 'critical' phase of organogenesis (daily from the 6th to 15th day of pregnancy). Tested concentrations were 0, 250 and 1000 mg/kg bw/day, using sesame oil as vehicle. Their development during the gestation period was observed. On day 20 of pregnancy the animals were laparotomised and examined macroscopically for implantation sites, resorptions in the uterus and for condition of the fetuses.

 No substance-related mortality was observed in the dams. Six of the 20 dams treated with 1000 mg/kg bw/day showed reduced motor activity and salivation. No other clinical signs were observed in the remaining high-dosed and the low-dosed dams. Body weights remained within the normal range and body weight gain showed no influence of the test compound. Transient impairment of the food consumption by the highest tested dose was observed. Treatment did not influence drinking-water consumption. No substance-related pathological changes were detected at autopsy.

The highest tested dose caused a slight but not significant (at p<= 0.01) increase of the resorption rate and, consequently, of the post-implantation loss. No further influence on the prenatal development was detected. All other fetal parameters were within the normal range of the control group. External macroscopic inspection, examination of soft tissue (WILSON's method) and skeletal examination (staining of the skeleton according to DAWSON's method) revealed no substance-related variations and/or retardations. One malformed fetus at 1000 mg/kg bw/day (shifted and fused dorsal, lumbar and coccygeal vertebrae, bilateral crossed legs, stump tail, omphalocele) belongs to the spontaneous range as to type and number of affected fetuses (control: one fetus with stump tail). No dead fetuses occurred in the substance treated and control dams.

Under these test conditions, the NOEL for the dams and for the fetal organism was 250 mg camphene/kg bw/day. Camphene did not possess teratogenic properties.