Fatty acids, C16-18 (even numbered), aluminum salts

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated 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: see 'Remark'

Remarks:

Guideline Study, tested with the source substance CAS 124-07-2. In accordance to ECHA guidance document "Practical guide 6: How to report read-across and categories (May 2010)", the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Data source

Reference

Reference Type:

publication

Title:

Developmental Toxicity and Structure-Activity Relationships of Aliphatic Acids, Including Dose-Response Assessment of Valproic Acid in Mice and Rats

Author:

Narotsky, M.G. et al.

Year:

1994

Bibliographic source:

Fundamental and Applied Toxicology 22(2):251-65

Materials and methods

Principles of method if other than guideline:

Octanoic acid was evaluated in the Chernoff/Kavlock developmental toxicity screen in rats.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Octanoic acid

EC Number:

204-677-5

EC Name:

Octanoic acid

Cas Number:

124-07-2

IUPAC Name:

octanoic acid

Details on test material:

- Name of test material (as cited in study report): octanoic acid (OCT)
- Analytical purity: 99.5%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC, USA
- Diet: Purina Lab Chow No. 5001, ad libitum
- Water: tap-water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2 ± 1.1
- Humidity (%): 50 ± 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

VEHICLE
- Amount of vehicle (if gavage): 2 mL/kg bw

Analytical verification of doses or concentrations:

no

Details on mating procedure:

- Proof of pregnancy: vaginal plug or vaginal sperm referred to as day 0 of pregnancy

Duration of treatment / exposure:

Day 6-15 of gestation

Frequency of treatment:

once daily

Duration of test:

28 days (22 days of gestation and 6 days post natal)

Doses / concentrations

Remarks:

Doses / Concentrations:
1125 and 1500 mg/kg bw/day
Basis:
nominal conc.

No. of animals per sex per dose:

16 females (test groups); 20 females (control)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on a preliminary range-finding study. The highest dose was expected to induce moderate maternal toxicity and the lowest dose was set to 75% of the highest dose.

Examinations

Maternal examinations:

CLINICAL OBSERVATIONS: Yes
- Time schedule: throughout the experimental period; beginning on gestational day 20, the dams were observed up to seven times during the normal workday to determine the time of parturition

BODY WEIGHT: Yes
- Time schedule for examinations: on gestation day 6, 8, 10, 13, 16 and 20

Ovaries and uterine content:

Dams were killed on PND 6 and the number of uterine implantation sites was determined.

Fetal examinations:

Pups of each litter were examined and counted on PND 1, 3 and 6. Body weights were determined collectively on PND 1 and 6.

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: pups found dead and externally malformed pups
- Skeletal examinations: Yes: externally malformed pups and 2 surviving pups per litter (one per sex)

Statistics:

Statistical analysis were based on general linear models (GLM), analysis of variance and Student's t test

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Mortality rates of 31 (5/16) and 44% (7/16) were observed in the low- and high-dose group. As the number includes deaths which occured shortly after dosing, mortaility due to paragastric intubation cannot be excluded. However, most deaths were attributed to the respiratory effects of treatment visible as rales and dyspnea which might be induced by gastroesophagal reflux and subsequent aspiration of dosing solution (please refer to Table 1).

Reduced body weight gain was observed in test animals reaching statistical significance in the high-dose group already in the early treatment period (gestation day 6 – 10) and in both dose groups in the late treatment period (gestation day 6 – 20).

Effect levels (maternal animals)

1

Dose descriptor:

LOAEL

Effect level:

1 125 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

>= 1 500 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Gestation length observed in control and treated animals were comparable.
The number of live pups did not differ between control and low-dose animals but was significantly reduced in the high-dose group on PND 6. As dams in this dose group showed severe peripartum respiratory symptoms, the decreased viability of pups might be due to maternal toxicity. Further, the rate of perinatal loss increased for high-dose dams but did not reach statistical significance. Pup weights determined in PND 1 or 6 were comparable among the groups and no malformations including lumbar ribs were noted.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

>= 1 500 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Table 1: Clinical findings and maternal body weight changes in the Chernoff/Kavlock Assay

		control group (20 rats)	1125 mg/kg bw/day (16 rats)	1500 mg/kg bw/day (16 rats)
Clinical signs	death^a no. (%)	0	5 (31%)	7 (44%)
	rales no. (%)	0	15 (95%)	15 (95%)
	dyspnea no. (%)	0	4 (25%)	7 (44%)
	motor depression no. (%)	0	0	0
Body Weight change	GD 6 – 10 (g)	15.6 ± 1.5	4.9 ± 5.7	-24.0 ± 8.7***
	GD 6 – 20 (g)^b	42.8 ± 3.1	15.3 ± 5.2***	-5.7 ± 6.2***

^a: the number includes deaths which occurred shortly after dosing and might be due to paragastric intubation

^b: adjusted to live litter weight on PND 1

***: significantly different from concurrent control with p < 0.001

 

Table 2: Developmental data

	control group (15 rats)	1125 mg/kg bw/day (11 rats)	1500 mg/kg bw/day (9 rats)
No. implants	12.4 ± 1.2	13.4 ± 0.8	11.9 ± 1.1
No. live pups PND 1	10.4 ± 1.2	12.1 ± 0.8	9.5 ± 1.1
No. live pups PND 6	10.3 ± 1.1	11.8 ± 0.7	7.4 ± 1.7*
Perinatal loss^c(%)	20.1 ± 6.7	10.8 ± 2.6	35.8 ± 11.9
Pup weight on PND1	7.4 ± 0.1	7.0 ± 0.2	6.8 ± 0.4
Pup weight on PND6	14.3 ± 0.4	13.8 ± 0.4	13.0 ± 1.2

PND: postnatal day

^c: perinatal loss = implants not surviving until PND6 (analysis of this endpoint included litters that were delivered late)

*: significantly different from concurrent control with p < 0.05