Fatty acids, dehydrated castor-oil

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

11 Mai - 24 Jun 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1983

Report date:

1983

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

test substance was administered solely in the period of GD 6-15

GLP compliance:

not specified

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Heptanoic acid

EC Number:

203-838-7

EC Name:

Heptanoic acid

Cas Number:

111-14-8

IUPAC Name:

heptanoic acid

Details on test material:

- Name of test material (as cited in study report): heptanoic acid (C-181)
- Physical state: clear colourless liquid
- Analytical purity: no data (a purity of 100% was assumend for purposes of dosage calculations)
- Storage condition of test material: well-ventialed at room temperature

Test animals

Species:

rat

Strain:

other: Crl:COBS, CD® (SD) BR

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Kingston, New York, USA
- Age at study initiation: approx. 14 weeks (mating age)
- Housing: individually in elevated wire-mesh cages
- Diet: Purina Rodent Laboratory Chow ®, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 9 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): approx. 24
- Humidity (%): 57 ± 4.8
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 11 Mai 1982 To: 24 Jun 1982

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared weekly by mixing appropriate amounts of the test item with corn oil on a magnetic stirrer (g/v) and transferred to amber bottles. The prepared dilutions were well shaken before use and animals were dosed while solutions were mixed on a magnetic stirrer.

Dosing volumes were based on individual body weights from the most weighing interval. Day 15 dosing was based on the body weight of Day 12.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 1/2
- Length of cohabitation: up to 3 weeks
- After 10 days, females were rotated
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

Day 6 - 15 of gestation

Frequency of treatment:

daily, 7 days/week

Duration of test:

20 days (GD 0-20)

Doses / concentrations

Remarks:

Doses / Concentrations:
1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

22 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The applied dose showed no maternal toxicity in a previous dose-range finding study (Serota et al., 1982).

Examinations

Maternal examinations:

CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
- Parameters checked: e.g. alopecia, bloody crust, wheezing, labored respiration, urine stains, rough haircoat, stains on fur, salivation, corneal defect, wasting feed, water spillage, hunched, dyspnea, red discharge from vagina, soft feces

BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 6, 9, 12, 15 and 20 of gestation

FOOD CONSUMPTION : Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food: Yes
- Time schedule for examinations: Days 6 - 8, 9 - 11, 12 - 14, 15 - 17 and 18 - 20 of gestation

WATER CONSUMPTION: Yes
- Time schedule for examinations: Days 6 - 8, 9 - 11, 12 - 14, 15 - 17 and 18 - 20 of gestation

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus, oavary, cecum, lung, kidney, stomach, liver, pancreas, adrenals, brain, pituitary, thymus, spleen, eyes, lymph nodes (mesenteric, cervical, mandibular)

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 resorptions: Yes (early and late resorptions)
- Other: Nongravid uterine weights (with ovaries attached): Yes

Fetal examinations:

- External examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [two-third per litter]
- Other: Visceral examinations: Yes [one-third per litter]; body weight and crown-rump distance [all per litter]

Statistics:

Mean values and standard deviations were calculated from the examined parameters.
Survival was analysed by the National Cancer Institute Package (Tomas, Breslow and Gart, 1977). The mean maternal body weight changes (days 0 - 6, 6 - 15, 15 - 20 and 0 - 20), mean maternal food and water consumptions), percent males per litter, mean fetal body weights and lengths, fetal viability, percent resorptions, implantation efficiency, gravid and non-gravid uterine weights and the incidence of visceral and skeletal anomalies and variants were analysed by Box´s test for homogeneity of variances. This test was followed by one-way classification analysis of variance (ANOVA) if the variances proved to be homogeneous. If the variances proved to be heterogeneous, a rank transformation of data was performed, which was followed by Box´s test and ANOVA. If ANOVA of untransformed or transformed data was significant, a Dunnett´s T-Test was used for control vs treatment group mean comnparisons. Pregnancy rates were analysed by a test of multiple proproportions using one degree of freedom Chi-square test with Yate´s continuity correction (Fleiss 1981). All pairwise comparisons were evaluated at the 0.5% probability (one-tailed) level.

Indices:

Mean incidence of resorptions (%): group mean of [(resorptions per litter/implantations per litter) x 100]
Mean incidence of fetal mortality (%): group mean of [(dead fetuses per litter/implantations per litter) x 100]
Mean incidence of fetal viability (%): group mean of [(live fetuses per litter/implantations per litter) x 100]
Mean incidence of visceral anomalies(%): group mean of [(number fo fetuses with anomalies per litter/number of fetuses examined viscerally per litter) x 100]
Mean incidence of visceral variants (%): group mean of [(number fo fetuses with variants per litter/number of fetuses examined viscerally per litter) x 100]
Mean incidence of skeletal anomalies (%): group mean of [(number fo fetuses with anomalies per litter/number of fetuses examined skeletally per litter) x 100]
Mean incidence of skeletal variants (%): group mean of [(number fo fetuses with variants per litter/number of fetuses examined skeletally per litter) x 100]

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
, MORTALITY AND CLINICAL OBSERVATIONS
One animal in the treatment group was found dead on day 8 of gestation. However, the survival rate of treated animals (95.5%) were comparable to control (100%).
No increased incidence of clinical observations was noted. Wheezing was observed in three treated rats during GD 6-15 and in two treated rats after treatment (GD 16-20). One treated rat had a rough haircout. In the control group, alopecia (neck), corneal defect, wasting feed and water spillage was each observed in one animal.


BODY WEIGHT CHANGE, FOOD AND WATER CONSUMPTION
No effects on body weights, food and water consumption were noted. The mean body weight change (Day 0-20 of gestation) was 104.2 ± 12.5 g for the treated females compared to 106.9 ± 14.7 g for the control group. The treated rats had a total food consumption intake (Day 9 -20 of gestation) of 243.0 ± 31.3 g (controls: 249.9 ± 43.7).

GROSS PATHOLOGY
The effects noted in gross pathology examinations are present in control and test animals in low frequencies and are therefore not considered as adverse. In detail, control and test animals revealed anomalies of the kidneys (pelvises dilated, firm nodules on surface, depressed area in cortex) and red focal areas in the lung. Further, one test animal each showed yellow areas on the liver surface, reddened/enlarged cervical lymph nodes and a thin and pale nonglandular mucosa and smooth glandular mucosa. One control animal had clear raised areas on the surface of eyes.

OTHER
The pregnancy rate was 100% in the 1000 mg/kg bw/day dose group and in control animals.
No alterations in the number of corpora lutea, implantations and mean implantation efficiencies (number of implantations per number of corpura lutea) and resorptions were observed .
Gravid and nongravid uterine weights were comparable between the control and dose group (table 1).

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

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:
No alterations in the number of live and dead fetuses were observed. Fetal viability, size and sex remained unchanged.
Anomalies determined in gross pathology, visceral and skeleton examinations were present in both, control and test animals and are therefore not considered as treatment-related effects (for details, see table 2).

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

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: Ovarian, Uterine and Litter Data

Parameter	Control	1000 mg/kg bw/day
Mean uterine weights Gravid	69.48 ± 13.953	67.63 ± 11.91
Mean uterine weights Nongravid	6.52 ± 1.424^a	7.04 ± 1.982^a
Corpura lutea (mean number)	15.9	14.7
Implantations (number)	13.5	12.8
Mean implantation efficiency (indeces)	85.7^a	88^a
Resorptions (number)	1.2	0.6
Mean incidence of resorptions (%)	9.2^a	4.3^a
Dead fetuses (number)	0.0	0.0
Mean incidence of fetal mortality (%)	0.0^a	0.0^a
Live fetuses (number)	12.4 ± 2.56	12.2 ±1.91
Mean incidence of fetal viability (%)	90.8^a	95.7^a

Incidences were calculated on a per litter basis.

Data are shown as means.

a: Data analysed following rank transformation

 

Table 2: Examination of the fetuses

Parameter	Control	1000 mg/kg bw/day
Live fetuses
Males
Mean body weight (g)	3.58 ± 0.201^b	3.46 ± 0.264^b
Mean crown-rump distance (cm)	3.8 ± 0.15^b	3.8 ± 0.19^b
Females
Mean body weight (g)	3.39 ± 0.186^b	3.32 ± 0.248^b
Mean crown-rump distance (cm)	3.7 ± 0.14^b	3.7 ± 0.18^b
Males per litter (Mean %)	54.0 ± 18.31	47.4 ± 13.62
Gross pathology findings:
Number of fetuses examined	191	175
Number of fetuses appearing normal	169	166
Skull	0	0
Palate	0	0
Cleft palate	0	0
Heart	0	0
Kidney	0	0
Ureter	0	0
Dilated	16	7
Hydroureter	0	1
Undulated	2	1
Umbilical hernia	1	0
Situs inversus	1	0
Hindleg	0	0
Small	1	0
Exencephaly	0	0
Tail missing	0	0
Mean incidence values for visceral findings
Number of litters	22	22
Number with anomalies	0^a	0.05 ± 0.213^a
Incidence of anomalies (%)^c	0^a	1 ± 5.3^a
Number with variants	0.1 ± 0.29^a	0.1 ± 0.29^a
Incidence of variants (%)^d	3 ± 9.7^a	3 ± 11.7^a
Mean incidence values for skeletal findings
Number of litters	22	22
Number with anomalies	0^a	0^a
Incidence of anomalies (%)^e	0^a	0^a
Number with variants	3 ± 2.3^a	3 ± 2.2^a
Incidence of variants (%)^f	39 ± 25.2^a	31 ± 24.6^a
Visceral Findings
Number of fetuses examined/number of litters	81/22	80/22
Number of fetuses with anomalies/number of litters with anomalies	0/0	1/1
Number of anomalies	0	1
Hydroureter	0	1
Number of fetuses with variants/number of litters with anomalies	2/2	2/2
Number of variants	2	3
Dilated renal pelves	2	1
Dilated ureters	0	2
Fetus small	0	0
Small tongue	0	0
Skeletal Findings
Number of fetuses examined/number of litters	191/22	175/22
Number of fetuses with anomalies/number oflitters with anomalies	0/0	0/0
Number of anomalies	0	0
Number of fetuses with variants/number of litters with variants	73/19	57/18
Number of variants	110	89
Skull:
Intraparietal-incomplete ossification/nonossified	21	20
Supraoccipital-incomplete ossification/nonossified	14	11
Hyoid	25	22
Supraoccipital - nonfused	0	2
Supraoccipital - lopsided	0	0
Supraoccipital - small	0	0
Small	0	0
Nasal bones appear short	0	0
Rib cage:
Parletals – irregular edges	2	4
Ribs – angulated	2	1
Ribs – 13^thpair small	1	0
Ribs – first pair small	0	0
Ribs – forked	0	0
Vertebrae:
Centra – incomplete ossification / nonossified	32	19
Centra – nonfused	10	5
Centra small	0	0
Centra – missing	0	0
Sternabrae – bipartite	1	0
Hemivertebrae	0	0
Vertebrae – less than 3 ossified	0	0
No of vertebrae below 3^rdsacral	0	0
Sacral vertebrae – nonossified	0	0
Halaligned centra ans arches / caudals	0	0
Caudals – less than 3 ossified	0	1
Caudals – incomplete ossification	0	0
Arches – nonossified	0	0
Pelvis:
Pelvic girdle – incomplete ossification	1	2
Pelvic girdle – small	0	0
Pubis – incomplete ossification/nonossified	1	1
Pubis – small	0	0
Ischium – incomplete ossification / nonossified	0	0

Data are shown as mean ± standard deviations.

^a: Incidences were calculated on a per litter basis.

^b: Data analysed following rank transformation

^c: Mean Incidence of Visceral Anomalies (%) – Group mean of ((number of fetuses with anomalies per litter/number of fetuses examined viscerally per litter)x100)

^d: Mean Incidence of Visceral Variance (%) – Group mean of ((number of fetuses with variants per litter/number of fetuses examined viscerally per litter)x100)

^e: Mean Incidence of Skeletal Anomalies (%) – Group mean of ((number of fetuses with anomalies per litter/number of fetuses examined skeletally per litter)x100)

^f: Mean Incidence of Skeletall Variance (%) – Group mean of ((number of fetuses with variants per litter/number of fetuses examined skeletally per litter)x100)