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Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented and conducted similarly to OECD Guideline 414 with deviations: mating conditions (1 male for 3 females); food consumption not followed; bodyweight only recorded at Day 0, 6, 16 and 20 of gestation
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Study on embryo-foetotoxicity of beta-myrcene in the rat
Author:
Delgado, I.F., Carvalho, R.R., Nogueira, A.C., Mattos, A.P., Figueiredo, L.H., Oliveira, S.H., Chahoud, I., Paumgartten, F.J.
Year:
1993
Bibliographic source:
Food Chem Toxicol. 1993 Jan;31(1):31-5

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
mating conditions (1 male for 3 females); food consumption not followed; bodyweight only recorded at Day 0, 6, 16 and 20 of gestation
Principles of method if other than guideline:
Not applicable
GLP compliance:
not specified
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
7-methyl-3-methyleneocta-1,6-diene
EC Number:
204-622-5
EC Name:
7-methyl-3-methyleneocta-1,6-diene
Cas Number:
123-35-3
Molecular formula:
C10H16
IUPAC Name:
7-Methyl-3-methyleneocta-1,6-diene
Details on test material:
- Name of test material (as cited in study report): β-Myrcene
- Source: Sigma Chemical Co., St Louis, MO, USA
- Analytical purity: 90%

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Oswaldo Cruz Foundation Central Animal House breeding stock
- Housing: Housed in plastic cages with wood shavings as bedding
- Diet (e.g. ad libitum): Nuvital diet for laboratory animals, Nuvilab Ltd, Curitiba, Brazil; ad libitum
- Water (e.g. ad libitum): Tap water; ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23 °C
- Photoperiod (hours dark / hours light): 12 hours dark / 12 hours light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Test material was dissolved in corn oil
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Not applicable
Details on mating procedure:
- Impregnation procedure: Cohoused
- If cohoused:
- M/F ratio per cage: 1:3
- Length of cohabitation: 2 h
- Proof of mating: Sperm in vaginal smear referred to as Day 0 of pregnancy
Duration of treatment / exposure:
10 days (Day 6-15 of pregnancy)
Frequency of treatment:
Once daily
Duration of test:
20 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 250, 500 and 1200 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
Treated females: 22-36; pregnant females: 16-29
Control animals:
yes, concurrent no treatment
yes, concurrent vehicle
Details on study design:
Control animals: as no statistically significant difference was found between the untreated and the vehicle treated control animals, in any of the parameters analysed, the data of both groups were pooled and were thereafter designated the control group.

Examinations

Maternal examinations:
BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 6, 16 and 20 of pregnancy
Ovaries and uterine content:
The uterine content was examined after termination: Yes, animals were sacrificed on Day 20 for caesarean examinations
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of living and dead foetuses: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes [all living foetuses]; weighed and examined for externally visible malformations
- Soft tissue examinations: Yes [5-7 litters per group]: evaluated for visceral malformations; heart, lungs, thymus, liver, spleen and kidneys were weighed and microdissected
- Skeletal examinations: Yes [all the remaining litters]
Statistics:
- Statistical analysis was by one way analysis of variance or, alternatively, by the Kruskal-Wallis test whenever the data did not fit a normal distribution
- Statistically significant differences between groups were tested by using a two sided Student's t-test or the Mann-Whitney U-test
- Proportions were analysed by the chi-square test
- Difference was considered to be statistically significant at P < 0.05
Indices:
No data
Historical control data:
No

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
At 250 and 500 mg/kg bw /day: No treatment-related effects

At 1200 mg/kg bw/day:
- Mortality: 1/29 dams died on Day 11 of pregnancy
- Body weights: Statistically significant decrease in weight gain during days 6-11 of pregnancy (17.3 ± 7 g vs. 3.2 ± 13.2 g in control vs. 1200 mg/kg group, respectively)
- Cesarean examination: Number of visible implantation sites was significantly reduced (12.6 ± 2.2 vs. 10.2 ± 2.9 in control vs. 1200 mg/kg group, respectively)

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: other:

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
- Body weight: Treatment-related effects on foetal weight were only very slight, or even insignificant, if the litter is taken as the statistical unit of analysis
- External examinations: Increased frequency of irregularly positioned hind paws was observed in 1200 mg/kg bw/day group
- Visceral examinations: Visceral malformations such as enlarged ureters associated with an enlarged renal pelvis (one control foetus and one in 1200 mg/kg group), shorter ureter (one control foetus and one in 250 mg/kg bw/day group) and accessory (seventh) lobe in the liver (three foetus in 250 mg/kg bw/day group)
- Skeletal examinations: Increased incidence of delayed ossification and minor gross structural anomalies in the foetal skeleton were observed in 1200 mg/kg bw/day group

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1 . Occurrence of delayed ossification in foetuses of rats treated orally with β-myrcene on Days 6-15 of pregnancy

 

β-Myrcene (mg/kg bw)

Treatment

0

250

500

1200

Foetuses examined (no.)

114

106

116

209

Percentage of foetuses with signs of delayed ossificationα in:

Skull bones

4.4

0.9

3.4

9.6*

Caudal vertebrae

7

2.8

6

37.8*

Forelimbs/metacarpus

2.6

0

0.9

9.1*

Hind limbs/metatarsus

5.3

2.8

3.4

29.2*

α Signs of delayed ossification: not ossified (whole bone is not stained), poorly ossified (whole bone is poorly stained), and irregular spongy bones.

* P < 0.05; chi-square test

 

Applicant's summary and conclusion

Conclusions:
The no-observed-adverse-effect level (NOAEL) for maternal toxicity and for embryo-foetotoxicity of β-myrcene administered orally (gavage) was considered to be 500 mg/kg bw/day in Wistar rats.
Executive summary:

A study was conducted to evaluate the embryo-foetotoxic potential of β-myrcene in the Wistar rats similarly to OECD Guideline 414.

β -Myrcene (250, 500 and 1200 mg/kg bw/day) in corn oil was given orally to Wistar rats from Day 6 to 15 of pregnancy. Two control groups, one received vehicle only and another without treatment, were also studied simultaneously. All rats were weighed on Day 0, 6, 16 and 20 of pregnancy. Caesarean sections were performed on Day 20 of pregnancy, and the number of resorptions and implantation sites were recorded. Foetuses were weighed and examined for external, visceral and skeletal malformations.

No adverse effects on the offspring were seen with the lowest dose tested, but at 500 mg/kg bw/day and higher doses, decreased birth weight, increased perinatal mortality and delayed day of appearance of landmarks of postnatal development were observed. Moreover, fertility was impaired in female offspring exposed to the two highest doses of β-myrcene. However it is difficult to know if this effect was related to reprotoxicity or due to the general toxicity observed at these dose-levels .

In conclusion, the no-observed-adverse-effect level (NOAEL) for maternal toxicity and for embryo-foetotoxicity of β -myrcene administered orally (gavage) was considered to be 500 mg/kg bw/day in Wistar rats.

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