Amines, C16-18-alkyl, acetates

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Prenatal developmental toxicity dose-range finder study according to OECD 414 guideline and GLP but with limited animal number

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

dose-range-finder with limited animal number

Principles of method if other than guideline:

A satellite group was administered the compound also for one week prior to mating

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

C16-18-(even numbered)-alkylamines acetates

EC Number:

800-526-8

Cas Number:

1273322-45-4

Molecular formula:

R-NH2xHOOCCH3 R = alkyl, mainly C16-18-(even numbered)

IUPAC Name:

C16-18-(even numbered)-alkylamines acetates

Constituent 2

Reference substance name:

C16-18-(even numbered)-alkylamine acetates

IUPAC Name:

C16-18-(even numbered)-alkylamine acetates

Test material form:

other: solid wax

Details on test material:

test

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Age at study initiation: 11-12 weeks
- Weight at study initiation:
- Housing: Full barrier in an air-conditioned room; the animals were kept individually in IVC cages, type III H, polysulphone cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Adequate acclimatisation period (at least five days)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 3 °C
- Humidity (%): 55 +- 10%
- Air changes (per hr): 10 x / hour
- Photoperiod (hrs dark / hrs light): Artificial light, sequence being 12 hours light, 12 hours dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: sesame oil

Details on exposure:

VEHICLE
- Justification for use and choice of vehicle (if other than water): Sesame oil is a recommended vehicle for this type of study and was chosen due to solubility reasons

Analytical verification of doses or concentrations:

yes

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 1 : 2 (male to female)
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

From GD 0 to GD 19 (main groups)
One week prior to mating, and from GD 0 to GD 19 (satellite group)

Frequency of treatment:

daily

Duration of test:

20 days

No. of animals per sex per dose:

8 females and 4 males per group

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Existing screening studies
- Rationale for animal assignment (if not random): random
- Other: A satellite group was administered the test item already for one week before mating

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: saily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: Main groups - GD 0, 3, 5, 8, 11, 14, 17 and 20 (females, male animals not weighed); Satellite group - once before treatment, weekly during premating period, GD 0, 3, 5, 8, 11, 14, 17 and 20 (females)

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20

OTHER: Haematology

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
- Other: Position / number of fetuses in each uterine horn

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter

Historical control data:

Available

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Body weight reduction in high dose animals

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

> 75 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

> 75 mg/kg bw/day

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Based on the results of this screening study, the registration substance caused some maternal toxic effects at the highest dose but no developmental toxic and/or teratogenic effects.

Executive summary:

The test item C16 -18 -(even numbered)-alkylamine acetates was administered at 0, 12, 30 and 75 mg/kg body weight to pregnant female rats from gestation day 0 until gestation day 19 (main group) to account for pre-implantations. A satellite group was administered with the test item one week before mating, during mating and during the gestation period until GD 19 at a doose level of 30 mg/kg body weight. For the main group females, at 75 mg/kg body weight, signs of maternal toxicity were observed in lower body weight and food consumption. The evaluation of relevant reproduction and developmental parameters did not indicate any test item-related effect. Pregnancy rates were not affected. Mean number of corpora lutea, implantation sites and incidence of pre- and post-implantation losses were similar within the groups. Mean litter size and mean fetal weight were not affected by the treatment with the test item. During the external examination of fetuses, no severe malformations were observed. Data on visceral and skeletal examinations did not indicate significant abnormalities. For the satellite females, the evaluation was performed only at 30 mg/kg bw. No relevant changes were observed in mean food consumption and mean body weight. Relevant reproduction parameters did not give any indication of an adverse effect of the test item. No severe malformations were observed during the fetal examination. Based on the results of this study, administration of the test item at 75 mg/kg body weight during the gestation period caused maternal toxicity. Administration of the test item at 30 mg/kg body weight before the mating and during the gestation period as well as 75 mg/kg body weight during GD 0 up to GD 19 did not cause adverse effects on maternal organisms and did not indicate an adverse effect on reproduction