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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions. The parenteral route of application was intravenous and only two dose levels included. The number of corpora lutea was not reported.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
parenteral route of application was intravenous, only two dose levels, number of corpora lutea not reported
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
Medium Chain Triglycerides (MCT)
IUPAC Name:
Medium Chain Triglycerides (MCT)
Details on test material:
- Name of test material (as cited in study report): Medium Chain Triglycerides (MCT)
- Physical state: liquid
- Analytical purity: no data
- Composition of test material, percentage of components: a 20% lipid emulsion containing a 3:1 ratio of MCT:LCT (Long Chain Triglycerides) from soybean oil. Medium chain fatty acids are 6 to 12 carbons in length. The 20% lipid emulsion is composed primarily of 8- and 10-carbon fatty acids and a trace of 6- and 12-carbon fatty acids. The same lot of test article was used throughout the studies. Saline (0.9% NaCl for injection, USP) was used as a non-lipid control article.
- Stability under test conditions: stable for the duration of both studies

Test animals

Species:
rat
Strain:
other: Crl:CD BR rats
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage, USA
- Weight at study initiation: 150-200 g
- Housing: animals were housed individually in suspended stainless steel cages
- Diet: Certified Rodent Chow 5002 meal (PMI Feeds, Inc.), ad libitum; except during dose administration
- Water: ad libitum; except during dose administration

ENVIRONMENTAL CONDITIONS
Environmental controls in the animal rooms were set to maintain temperature, relative humidity, and light/dark cycle (no further information).

Administration / exposure

Route of administration:
intravenous
Vehicle:
other: 20% lipid emulsion was created (no further information)
Details on exposure:
ADMINISTRATION OF DOSING SOLUTIONS:
The dose was administered daily to rats by intravenous infusion via a caudal vein using a Quik-Cath Teflon catheter connected to a syringe using an extension set. Doses were delivered using syringe pumps.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: Time-mated Crl:CD BR rats were shipped by the supplier on GD 4.
Duration of treatment / exposure:
Day 6-15 of gestation
Frequency of treatment:
4 h/day, 7 days/week
Duration of test:
15 days; Day 20 of gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
1000 and 4280 mg/kg bw/day
Basis:
nominal conc.
No. of animals per sex per dose:
25 or 29 P females
Control animals:
other: 0.9% saline
Details on study design:
- Dose selection rationale: The dose rate was based on previous preclinical studies (unpublished). The 1000 mg/kg bw/day dose approximates the proposed clinical dosage. The 4280 mg/kg bw/day dose is the highest dose administered in preclinical studies that did not produce narcosis (unpublished).

- Selection of exposure route: The intravenous route of administration was used because the lipid emulsion is intended for intravenous human administration as a component of parenteral nutrition.

- Dose volumes: 5 and 21.4 mL/kg bw

Examinations

Maternal examinations:
CLINICAL SIGNS AND CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were observed twice daily for mortality and moribundity. On dosing days, animals were observed predose, immediately (within 5 min) postdose, and approximately 1 h after completion of dosing.

BODY WEIGHT: Yes
- Time schedule for examinations: daily on GD 5-20

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Food consumption data were collected daily starting on the day of receipt

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


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
Fetal examinations:
- External examinations: Yes, half per litter; live fetuses were weighed, examined externally and sexed
- Soft tissue examinations: Yes, half per litter; soft tissue malformations were preserved in 10% phosphate-buffered formalin
- Skeletal examinations: Yes, half per litter; viscera were removed and discarded, and fetuses were processed and examined for skeletal variations and malformations; skeletal specimens were retained in glycerine
- Head examinations: Yes, half per litter; a mid-coronal slice of the head was made to expose the internal structure of the brain for examination; the eyes were excised and examined.
Statistics:
The litter was the experimental unit for evaluation. All comparisons were made with the control group (Group 1). For rats, feed consumption, dam body weights, and fetal body weights were summarized wim means and standard deviations calculated using an Excel spreadsheet program (Microsoft Corporation). For rabbit data, Levene's test (Levene, H. (1960). Robust tests for equality of variance. Contrib. Prob. Stat. 25, 278-292) was done to test for variance homogeneity. In the case of heterogeneity of variance at p « 0.05, rank transformation was used to stabilize the variance. Analysis of variance [ANOVA (Winer, B.J. (1971a). Design and analysis of single-factor experiments. Stat. Princ. Exp. Design 3, 149-260)] was done on the homogeneous or transformed data. If the ANOVA was significant, Dunnett's t test (Dunnett, 1964) was used for pairwise comparisons between groups. One-way ANOVA was used to analyze body weights, body weight changes, feed consumption, and caesarcan section data. As appropriate, rat and rabbit fetal abnormality data were analyzed by the Cochran-Armitage test (Thakur et al., (1985). A FORTRAN program for testing trend and homogeneity in proportions. Comput. Programs Biomed. 19, 229-233) for trend and departure and by the Fisher-Irwin exact test. One-way analysis of covariance [ANCOVA (Winer, B.J. (1971b). Analysis of covariance. Stat. Princ. Exp. Design 10, 752-812] was used to analyze fetal body weights (males, females, and combined) with the number of fetuses in the litter as the covariate. As appropriate, for values calculated to analyze litter data or mean fetal weight data, values were first derived within the litter, and the group mean values were derived as a mean of individual litter values. Group comparisons were analyzed at the 5.0 and 1.0% two-tailed probability levels.
Indices:
Early and late resorptions
% fetuses dead/live
% postimplantation loss

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: high dose group

Details on maternal toxic effects:
Observed test article-related findings were associated with tail lesions in both test article groups. The tail findings were predominantly those of discoloration and ulceration. Incidences were 1/25, 14/25, and 23/29 for these tail lesions in the control, low-, and high-dose groups, respectively, and ranged from mild to severe with some necrosis and partial loss of the tail. Furthermore, occasional occurrence of red tinged urine (8/29) and vaginal bleeding (1/29) in the high-dose group were noted.
The tail findings were considered to be related to occurrences of observed extravasation of the MCT:LCT lipid test article into perivascular areas. Evaluation of urine collected from one high-dose animal suggested a bacterial infection of the urogenital tract. Clinical observations for this animal included occasional red-tinged urine and vaginal bleeding. This rat was noted as having a large urinary bladder stone and kidney hydronephrosis at necropsy.
No significant differences in mean body weight or feed consumption were observed for the low-dose group compared with those of the control group. However, the high-dose group animals exhibited lower body weights beginning 1 day after dose administration throughout the remainder of the study. Feed consumption was also notably lower in 9/10 days during dosing, with an increase in feed consumption after completion of dose administration (GD 15). The decrease in feed consumption in high-dose animals was expected to be due to the high-caloric nature of the test article.
Necropsy findings were primarily related to tail effects and were observed for most rats in the high-dose group and some rats in the low-dose group. In addition to tail effects, there was a trend toward an increasing incidence of necropsy findings in the high-dose group, including enlarged lymph nodes, enlarged spleen, hydronephrosis/enlarged renal pelvis, small thymus, and small red lung foci. These changes indicated that the high-dose group was likely exhibiting test article effects.
There was a slight trend toward decreasing mean gravid uterine weights in proportion to increasing test article dose; however, due to the large variability between groups, group mean uterine weights appeared to be similar. With the exception of one control dam, all females were pregnant and had at least one viable fetus/litter (i.e., no dams had total resorptions).

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
4 280 mg/kg bw/day
Based on:
other: test mat. (i.v. application)
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
other: test mat. (i.v. application)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
4 280 mg/kg bw/day
Based on:
test mat.
Remarks:
(i.v. application)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No significant group differences in preimplantation or postimplantation loss were observed. No difference in the mean percentage of live or resorbed fetuses and no dead fetuses were present. Mean fetal sex ratios of the treatment groups were comparable with those of controls. There were no apparent effects on mean fetal body weight (combined, males or females). There were no test article-related fetal external, soft tissue, or skeletal observations.
A high incidence of folded retina in control and test article-treated groups was attributed to shrinkage of the retina during storage in alcohol prior to being transferred to Bouin's fixative.
Omphalocele and cleft palate were observed in one fetus each in the control and high-dose groups, respectively. The only fetal skeletal malformation observed (malformed/misshapen skull bones) was present in one fetus each from two control litters. Fetal skeletal variations were present in control and test article-treated groups in a nondose-related pattern.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion