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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:
supporting study
Study period:
03 January 1992 – 02 April 1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Dose-Range-Finding study. Test method according to OECD guideline 414 and GLP.

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
(Only three animals were used per group)
GLP compliance:
yes (incl. certificate)
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Lippische Versuchstierzucht, HAGEMANN GmbH, D-4923 Extertal 1
- Age at study initiation: ca. 71 days old
- Weight at study initiation: 211 - 245 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: Five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 ºC
- Humidity (%): 50 ± 15 %
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 03.01.1992 To: 23.01.1992

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: sesame oil, DAB 9
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test substance-vehicle mixtures were freshly prepared each day immediately before dosing.
Volume of administration: 5 mL/kg bw
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Fertile ('proved') 4 - 12 months old male rats of the same breed served as partners. They were repeatedly employed, at the earliest three days after successful copulation. The female breeding partners were randomly chosen.
Matings were monogamous.
- 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 / concentrations
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
3 pregnant female rats per group (plus 2 reserve animals)
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
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 was ascertained daily - always at the same time in the morning - and these measurements were also used for calculating the daily amount of test compound to be administered.
Food consumption was determined daily by weighing the residue. Intake of drinking-water was observed daily.
Ovaries and uterine content:
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.
Fetuses were removed and the following examinations performed:
A count was taken of fetuses and placentae.
Sex and viability of fetuses were determined. Animals are said to be viable when they are found alive (spontaneous breathing, spontaneous movement).
Number and size of resorptions were determined.
Corpora lutea in the ovaries, implantations and location of fetuses in the uterus were determined.
The uterus weight was determined (with and without fetuses), weight of the ovaries was determined.
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:
Fetuses were inspected externally for damages, especially for malformations.
Fetuses were dissected and the number and type of possible variations (incl. retardations) or malformations was determined macroscopically.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Two of the three dams treated with 1000 mg Camphene/kg bw showed reduced motor activity and salivation after the first dosing. These reactions occurred within 20 minutes after gavage treatment and lasted for 1-2 hours in dam nº. 5 and for 2-6 hours in dam nº. 6. No corresponding clinical signs were seen at the further observations and examinations, the third dam used remained inconspicuous. Consistency of faeces did not differ between substance-treated and control rats.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
None of the dams died prematurely.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
1000 mg Camphene/kg bw/day had no influence on body weight gain of the dams. All values remained within the range of the controls.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
1000 mg Camphene/kg bw/day had no influence on food consumption of the dams. All values remained within the range of the controls.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
1000 mg Camphene/kg bw/day had no influence on drinking-water consumption of the dams. All values remained within the range of the controls.
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):
Two of the three dams treated with 1000 mg Camphene/kg bw showed reduced motor activity and salivation after the first dosing. These reactions occurred within 20 minutes after gavage treatment and lasted for 1-2 hours in dam nº. 5 and for 2-6 hours in dam nº. 6.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The uterus and ovaries weights of the treated groups were not influenced by the exposure to the test compound.
Gross pathological findings:
no effects observed
Description (incidence and severity):
None of the dams showed macroscopically visible organic changes at necropsy.
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
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Number of implantations showed no abnormalities.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
Resorptions were within the normal range.
Early or late resorptions:
no effects observed
Description (incidence and severity):
Resorptions were within the normal range.
Dead fetuses:
no effects observed
Description (incidence and severity):
Macroscopic inspection during laparotomy revealed that dead foetuses did not occur.
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Number of corpora lutea, implantations and foetuses showed no abnormalities.
Other effects:
no effects observed

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
< 1 000 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Foetal weights and length as well as weight of the placentae did not differ substance-relatedly from the controls.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not specified
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Description (incidence and severity):
Macroscopic inspection during laparotomy revealed no variations/retardations or malformed foetuses. None of the foetuses was a runt.
Skeletal malformations:
no effects observed
Description (incidence and severity):
Macroscopic inspection during laparotomy revealed no variations/retardations or malformed foetuses. None of the foetuses was a runt.
Visceral malformations:
no effects observed
Description (incidence and severity):
Macroscopic inspection during laparotomy revealed no variations/retardations or malformed foetuses. None of the foetuses was a runt.
Other effects:
no effects observed

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Under the present test conditions, Camphene did not influence the prenatal development. Except for a slight transient reaction after the first dosing (reduced motor activity, salivation) the dose-level of 1000 mg/kg bw/day was well-tolerated by the dams.
Executive summary:

Pregnant Sprague-Dawley rats were orally treated with the test substance by gavage during the 'critical' phase of organogenesis (daily from the 6th to 15th day of pregnancy). Tested concentrations were 0 and 1000 mg/kg bw/day, using sesame oil as vehicle. 3 pregnant rats were used in each group. Their development during the gestation period is 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.

Influence on the dam:

None of the dams died prematurely. Two of the three treated dams showed reduced motor activity and salivation after the first dosing. These reactions occurred within 20 minutes after gavage treatment and lasted for 1-2 hours in dam nº. 5 and for 2-6 hours in dam nº. 6. No corresponding clinical signs were seen at the further observations and examinations, the third dam used remained inconspicuous. Consistency of faeces did not differ between substance-treated and control rats. Test substance had no influence on body weight gain, food and drinking-water consumption of the dams. All values remained within the range of the controls. None of the dams showed macroscopically visible organic changes at necropsy.

Influence on the fetus:

Camphene did not influence the prenatal development of rats. Number of corpora lutea, implantations and foetuses showed no abnormalities, the resorptions were within the normal range. Foetal weights and length as well as weight of the placentae did not differ substance-relatedly from the controls. Macroscopic inspection during laparotomy revealed no variations/retardations, malformed or dead foetuses did not occur. None of the foetuses was a runt.

Under the present test conditions, Camphene did not influence the prenatal development at 1000 mg/kg bw/day. Except for a slight transient reaction after the first dosing (reduced motor activity, salivation) this dose-level was well-tolerated by the dams.