Reaction mass of 3,7-dimethyl-1-octyl acetate and citronellyl acetate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

This information is used for read-across to Citronellyl Acetate Multi.

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read-across information

Justification for type of information:

The read-across justification is presented in the Endpoint summary Toxicity to reproduction. The accompanying files are also attached there.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Remarks on result:

other: read-across from Geraniol

Key result

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: reduced fetal body weights and a temporary delay of prenatal development of offspring at 1000 mg/kg bw/day were associated with congenerous effects in their mothers and thus not considered as an independent effect

Remarks on result:

other: read-across from Geraniol

Developmental effects observed:

not specified

Conclusions:

The NOAEL for developmental toxicity is 300 mg/kg bw/d, based on read-across from Geraniol 60.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes (incl. QA statement)

Remarks:

BASF SE

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reaction mass of (2E)-3,7-dimethylocta-2,6-dien-1-ol and (2Z)-3,7-dimethylocta-2,6-dien-1-ol

EC Number:

906-125-5

Molecular formula:

Unspecified

IUPAC Name:

Reaction mass of (2E)-3,7-dimethylocta-2,6-dien-1-ol and (2Z)-3,7-dimethylocta-2,6-dien-1-ol

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Strain: Crl:WI(Han)
- Age at study initiation: about 10-12 weeks
- Weight at study initiation: 143.7 - 191.7 g
- Housing: Makroion cages type M III with wooden gnawing blocks and dust-free wooden bedding
- Diet: Ground Kliba maintenance diet mouse/rat "GLP", Provimi Kliba SA, Kaiseraugst, Switzerland; ad libitum
- Water: drinking water ad libitum
- Acclimation period: from GD 0 (day of supply) to the beginning of administration (GD 6)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The specific amount of test substance was weighed, topped up with corn oil in a graduated flask and intensely mixed by shaking until it is dissolved.

Analytical verification of doses or concentrations:

yes

Details on mating procedure:

- Impregnation procedure: purchased timed pregnant
The animals paired by the breeder (time-mated animals) will be supplied at noon on the day of evidence of mating; this day is referred to as GD 0 and the following day as GD 1.

Duration of treatment / exposure:

GD 6-19

Frequency of treatment:

once daily

Duration of test:

on GD 20, all surviving females were sacrificed

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

100 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

300 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day on working days or once a day on Saturday, Sunday or on public holidays (GD 0-20)

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once a day, or more often when clinical signs of toxicity were elicited (GD 0-20)

BODY WEIGHT: Yes
- Time schedule for examinations: GD 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20

FOOD CONSUMPTION: Yes
- Time schedule for examinations: GD 0-1, 1-3, 3-6, 6-8, 8-10, 10-13, 13-15, 15-17, 17-19 and 19-20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: gross pathology

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 early resorptions: Yes
- Number of late resorptions: Yes
- Number of dead fetuses: Yes

Fetal examinations:

- Weight of each fetus: Yes
- Sex: Yes
- Weight of placentas: Yes
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter

Statistics:

- DUNNETT's test: Food consumption, body weight, body weight change, corrected body weight gain (net maternal body weight change), carcass
weight, weight of unopened uterus, number of corpora lutea, number of implantations, number of resorptions, number of live fetuses, proportions
of preimplantation loss, proportions of postimplantation loss, proportions of resorptions, proportion of live fetuses in each litter, litter mean fetal body weight, litter mean placental weight
- FISHER's exact test: Female mortality, females pregnant at terminal sacrifice, number of litters with fetal findings
- WILCOXON test: Proportions of fetuses with malformations, variations and/or unclassified observations in each litter

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Details on maternal toxic effects:
- CLINICAL EXAMINATIONS:
Test group 0 (0 mg/kg bw/d):
• one female not pregnant
Test group 2 (300 mg/kg bw/d):
• three females not pregnant
Test group 3 (1000 mg/kg bw/d):
• one female not pregnant

- MORTALITY:
There were no substance-related or spontaneous mortalities in any females of all test groups.

- CLINICAL SYMPTOMS:
All females of the mid- and high-dose groups (300 and 1000 mg/kg bw/d) and some females (11 out of 25) of the low-dose group (100 mg/kg bw/d) showed transient salivation during the treatment period (i.e. up to 15 minutes after daily gavage dosing; initially observed on GD 7).
No further clinical signs or changes of general behavior, which may be attributed to the test substance, were detected.

- FOOD CONSUMPTION:
The mean food consumption of the high-dose dams (1000 mg/kg bw/d) was statistically significantly decreased on GD 6-10, afterwards it recovered and was slightly increased on GD 15-17 attaining statistical significance (comparable amount of food intake for the entire treatment period of high-dose group and control group animals).

- BODY WEIGHT:
Test group 3 (1000 mg/kg bw/d):
The mean body weights were comparable to the concurrent control group. However, the mean body weight gain (BWC) of this group was statistically significantly decreased on GD 6-8 (53% below control) and GD 10-13 (28% below control). These dams gained overall about 10% less weight than the concurrent control during the treatment period (GD 6-19), attaining statistical significance.
Test group 2 and 1 (300 and 100 mg/kg bw/d):
The mean body weights and the average body weight gain were in general comparable to the controls throughout the entire study period.

- CORRECTED (NET) BODY WEIGHT GAIN:
Mean carcass weights were unaffected by the treatment (test groups 1-3).
Test groups 2 and 3 (300 and 1000 mg/kg bw/d):
The corrected body weight gain was statistically significantly lower (about 13% and 14% below concurrent control).
Test group 1 (100 mg/kg bw/d):
no difference of any biological relevance

- UTERUS WEIGHT:
No test-substance related findings.

- NECROPSY FINDINGS:
No test-substance related findings.

- REPRODUCTION DATA:
conception rate of
• Test group 0 (0 mg/kg bw/d): 96%
• Test group 1 (100 mg/kg bw/d): 100%
• Test group 2 (300 mg/kg bw/d): 88%
• Test group 3 (1000 mg/kg bw/d): 96%
No test-substance related findings in conception rate, in the mean number of corpora lutea and implantation sites or in the value calculated for the postimplantation loss, the number of resorptions and viable fetuses.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Details on embryotoxic / teratogenic effects:
- SEX DISTRIBUTION:
comparable to the control fetuses

- WEIGHT OF PLACENTAE:
comparable to the corresponding control group

- WEIGHT OF FETUSES:
Test group 3 (1000 mg/kg bw/d):
slightly but statistically significantly reduced mean fetal weights (about 9% below control)

- FETAL EXTERNAL MALFORMATIONS:
External malformations were recorded for one control and two high-dose fetuses (0 and 1000 mg/kg bw/d). The total incidence of external malformations in treated animals did not differ significantly from the control group and was comparable to the historical control data.

- FETAL EXTERNAL VARIATIONS:
no external variations were recorded

- FETAL EXTERNAL UNCLASSIFIED OBSERVATIONS:
no unclassified external observations were recorded

- FETAL SOFT TISSUE MALFORMATIONS:
One soft tissue malformation was recorded for two control fetuses and one mid-dose fetus (0 and 300 mg/kg bw/d). The overall incidences of soft tissue malformations were comparable to those found in the historical control data.

- FETAL SOFT TISSUE VARIATIONS:
Three soft tissue variations were detected, i.e. short innominate, dilated renal pelvis and dilated ureter. The incidences of dilated renal pelvis were statistically significantly increased in the mid- and high-dose groups (300 and 1000 mg/kg bw/d). As these incidences were not related to dose, they may well be incidental findings.

- FETAL SOFT TISSUE UNCLASSIFIED OBSERVATIONS:
no unclassified soft tissue observations were recorded

- FETAL SKELETAL MALFORMATIONS:
A number of skeletal malformations was detected in test groups 0, 1 and 3 (0, 100 and 1000 mg/kg bw/d) affecting the skull, sternum and vertebral column (with or without involving the ribs). One fetus of test group 0 and 3, respectively, had associated external findings. All other findings were single cases, most of them can be found in the historical control data. An association to the treatment is not assumed.

- FETAL SKELETAL VARIATIONS:
For all test groups, skeletal variations of different bone structures were observed, with or without effects on corresponding cartilages. The observed skeletal variations were related to several parts of fetal skeleton and, in most cases, appeared without a relation to dosing. The overall incidences of skeletal variations were comparable to the historical control data.

- FETAL SKELETAL UNCLASSIFIED CARTILAGE OBSERVATIONS:
Some isolated cartilage findings without impact on the respective bone structures, which were designated as unclassified cartilage observations, occurred in all test groups. The observed unclassified cartilage findings were related to the skull, the vertebral column, the sternum and ribs and did not show any relation to dosing.

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: reduced fetal body weights and a temporary delay of prenatal development of offspring at 1000 mg/kg bw/day were associated with congenerous effects in their mothers and thus not considered as an independent effect

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The NOAEL for developmental toxicity is 300 mg/kg bw/d.

Executive summary:

For Geraniol 60 a prenatal developmental study was performed according to OECD TG 414 and in compliance with GLP criteria. In this study, doses were 100, 300 or 1000 mg/kg bw/day test item in corn oil.

The mean body weight gain of the mid and high dose rats was 13% and 14% below the control group. No test-substance related findings in the value calculated for the post implantation loss, the number of resorptions and viable fetuses were found. Reduced fetal body weights were found at 1000 mg/kg bw/day. Three soft tissue variations were detected, i.e. short innominate, dilated renal pelvis and dilated ureter. The incidences of dilated renal pelvis were statistically significantly increased in the mid- and high-dose groups (300 and 1000 mg/kg bw/d). As these incidences were not related to dose, they may well be incidental findings. No other test-item related embryotoxic/teratogenic effects were found. Based on the reduced fetal body weights at 1000 mg/kg bw/day, the NOAEL for development was concluded to be 300 mg/kg bw/day.