Registration Dossier

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
21 June 1988 - 4 December 1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was conducted according to an equivalent of OECD guideline 421 and under GLP conditions.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report Date:
1989

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
males were not dosed
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): B10 (Coriander oil containing 72.9% linalool)
- Physical state: Liquid
- Storage condition of test material: Protected from light in the refrigerator




Test animals

Species:
rat
Strain:
other: Crl:CD (SD)BR
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan
- Age at study initiation: (P) 10 wks
- Weight at study initiation: (P) Females: 187-232 g
- Housing: Individually
- Diet (e.g. ad libitum): Ad libitum, Certified Rodent Chow
- Water (e.g. ad libitum): Ad libitum, filtered local water (chlorine added)
- Acclimation period: one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25
- Humidity (%): 35-65
- Air changes (per hr): min. 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Test article dissolved in corn oil at concentrations of 0, 50, 100 and 200 mg/mL.

DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly

VEHICLE
- Concentration in vehicle: 0, 50, 100 and 200 mg/mL
- Amount of vehicle (if gavage): 5 ml/kg, adjusted daily on the basis of individual body weights
- Lot/batch no. (if required): APR0789B, APR1489A and 80299
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: max. 7 days
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): Individually
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Study summaried in record "Developmental toxicity / teratogenicity_TIF00009_2006_KEY_rat" shows that linalool is stable in corn oil
Duration of treatment / exposure:
7 days prior to cohabitation.
After cohabitation until day 4 of lactation or day 25 of presumed gestation.
Frequency of treatment:
Once daily
Details on study schedule:
Not relevant
Doses / concentrations
Remarks:
Doses / Concentrations:
250, 500, 1000 mg coriander oil/kg bw/day, equivalent to 183, 365, 829 mg linalool/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on toxicity studies that were conducted earlier
Positive control:
Not necessary

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations checked:
Viability

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Two times during acclimation period and daily during dosage period

BODY WEIGHT: Yes
- Time schedule for examinations: Daily during dosage period

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Oestrous cyclicity (parental animals):
Not performed
Sperm parameters (parental animals):
Not relevant, males were not dosed
Litter observations:
STANDARDISATION OF LITTERS
Not relevant, termination of study on day 4 postpartum

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead.
Postmortem examinations (parental animals):
SACRIFICE
- Maternal animals: All surviving animals on day 4 or 5 of lactation. Dams that did not deliver litter on day 25 of presumed gestation, were sacrificed that day.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including gross lesions and placement of implantation sites.

HISTOPATHOLOGY
Tissues of dams (gross lesions, ovaries) were preserved for possible future evaluation.
Postmortem examinations (offspring):
SACRIFICE
No data

GROSS NECROPSY
- Pups that died were subjected to postmortem examinations and examined for the cause of death.
- Gross necropsy consisted of external examination for gross lesions.

HISTOPATHOLOGY / ORGAN WEIGTHS
Tissue of litter (gross lesions) were preserved for possible future evaluation.
Statistics:
Parametric
- Bartlett's test: For homogeneity of variance
- Dunnett's test
- Covariance analysis T-test
Nonparametric
- Kruskal-Wallis
- Dunn's test
- Fisher's Exact Test
Test for proportion data
- Variance test for homogeneity of the binomial distribution
Reproductive indices:
Pregnant rats/rats mated
Offspring viability indices:
Pups surviving 4 days/liveborn pups

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
Excess in salivation was noted at all dose groups being significant for middle and high dosage group. Significant number of rats in the 1000 mg/kg/day group had urine-stained abdominal fur during premating period and 1-2 rats in this group showed ataxia and/or decreased motor activity infrequently during the premating and/or gestation periods. However, excess salivation was not considered to be evidence for strong toxicity and was therefore considered as non-adverse.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Biologically remarkable decreases in body weight gain and feed consumption occurred for the 1000 mg/kg/day dosage group rats during premating (significant after first dosage). During gestation, biologically remarkable increase in weight and feed consumption occurred for each group given the test article. Statistically significant increases in body weight gain occurred for the low and high dosage group rats and statistically significant increases in absolute and relative feed consumption values occurred for each group given the test article. These effects decreased in severity during lactation.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: decreased food consumption, body weight
Dose descriptor:
NOAEL
Remarks:
linalool
Effect level:
365 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: decreased food consumption, body weight

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Details on results (F1)

VIABILITY (OFFSPRING)
Pup mortality was significantly increased for litters of dams given 1000 mg/kg/day corianders oil. When comparing implantation averages to delivered litter size in the 1000 mg/kg/day, the litter size was more decreased as compared to other groups. This indicates more resorptions in the high dosage group.

Effect levels (F1)

open allclose all
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
500 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: decreased litter size; increased pup mortality
Dose descriptor:
NOAEL
Remarks:
linalool
Generation:
F1
Effect level:
365 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: decreased litter size; increased pup mortality

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Not relevant

Applicant's summary and conclusion

Conclusions:
The maternal NOEL for coriander oil (containing 72.9% linalool) was below 250 mg/kg/day, based on clinical signs, such as salivation and altered body weight gains and feed consumption. These changes were not considered to be evidence for strong toxicity, hence the NOAEL was set higher at 500 mg/kg/day. The highest-dosage (1000 mg/kg/day) group had reduced delivered litter sizes, indicating in utero deaths, and siginifcant incidences of pup mortality in the first four days postpartum. No adverse effects regarding mating, fertility or duration of gestation or parturition occurred in any treatment group including the high-dose at 1000 mg/kg/day. Clear adverse effects on reproductive performance and pup development occurred at 1000 mg/kg/day, that also resulted in significant maternal clinical signs, significant inhibition of average maternal weight gain before mating and significant increases in maternal weight gain and feed consumption during gestation. In the absence of significant toxicity to the dams, B10 did not affect the reproductive performance or the developmental parameters of pups. The effects observed on reproduction and development are not, therefore, uniquely reprotoxic or developmentally toxic effects but general toxic effects.

The maternal and developmental NOAELs were established to be 500 mg/kg/day. This corresponds with a NOAEL of 365 mg linalool/kg bw/day. It can be concluded that linalool does not need to be classified as toxic to reproduction based on the criteria outlined in Annex I of 1272/2008/EC and Annex VI of 67/548/EEC.
Executive summary:

A reproductive and developmental toxicity screening test (similar to OECD 421) was performed. Female rats were orally (gavage) administered 0, 250, 500 and 1000 mg/kg/day of coriander oil (containing 72.9% linalool). Males were excluded from the test system. Females were dosed throughout the 7-day premating period, mating, gestation and lactation (post-natal day 4). The rats were observed for clinical signs, weight, feed consumption and were necropsied and examined for gross lesions. Litter (F1) were examined for number, viability, weight, sex ratio and external morphology of the pups. Delivered pups were additionally examined for viability, clinical signs and body weight during a 4-day postparturition period.

Excess in salivation was noted in all groups being significant for middle and high dosage group. A significant number of rats in the 1000 mg/kg/day group had urine-stained abdominal fur during premating period and 1-2 rats in this group showed ataxia and/or decreased motor activity infrequently during the premating and/or gestation periods.

Biologically remarkable decreases in body weight gain and feed consumption occurred for the 1000 mg/kg/day dosage group rats during premating (significant after first dosage). During gestation, biologically remarkable increase in weight and feed consumption occurred for each group given the test article. Statistically significant increases in body weight gain occurred for the low and high dosage group rats and statistically significant increases in absolute and relative feed consumption values occurred for each group given the test article. These effects decreased in severity during lactation.

No adverse effects on mating, fertility or the durations of gestation or parturition occurred for female rats given dosages of linalool as high as 1000 mg/kg/day.

Pup mortality was significantly increased for litters of dams given 1000 mg/kg/day linalool. When comparing implantation averages to delivered litter size in the 1000 mg/kg/day, the litter size was more decreased as compared to other groups. This indicates more resorptions in the high dosage group.

The maternal NOEL for coriander oil was below 250 mg/kg/day, based on clinical signs, such as salivation and altered body weight gains and feed consumption. These changes were not considered to be evidence for strong toxicity, hence the NOAEL was set higher at 500 mg/kg/day. The highest-dosage (1000 mg/kg/day) group had reduced delivered litter sizes, indicating in utero deaths, and siginifcant incidences of pup mortality in the first four days postpartum. No adverse effects regarding mating, fertility or duration of gestation or parturition occurred in any treatment group including the high-dose at 1000 mg/kg/day. Clear adverse effects on reproductive performance and pup development occurred at 1000 mg/kg/day, that also resulted in significant maternal clinical signs, significant inhibition of average maternal weight gain before mating and significant increases in maternal weight gain and feed consumption during gestation. In the absence of significant toxicity to the dams, B10 did not affect the reproductive performance or the developmental parameters of pups. The effects observed on reproduction and development are not, therefore, uniquely reprotoxic or developmentally toxic effects but general toxic effects.

The maternal and developmental NOAELs were established to be 500 mg/kg/day. This corresponds with a NOAEL of 365 mg linalool/kg bw/day. It can be concluded that linalool does not need to be classified as toxic to reproduction based on the criteria outlined in Annex I of 1272/2008/EC and Annex VI of 67/548/EEC.