Butanoic acid, 4-[(2-hydroxyethyl)amino]-4-oxo-2-(pentapropenyl)-, sodium salt, compd. with 2,2',2''-nitrilotris[ethanol] (1:?:?)

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well-performed and well-documented study; recently performed Guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

sodium/triethanolamine 4-((2-hydroxyethyl)amino)-3-pentaproenyl-4-oxobutanoate

EC Number:

800-765-8

Cas Number:

1424149-03-0

Molecular formula:

C21H40NO4.1/2Na.1/2C6H15NO3

IUPAC Name:

sodium/triethanolamine 4-((2-hydroxyethyl)amino)-3-pentaproenyl-4-oxobutanoate

Test animals

Species:

rat

Strain:

Wistar

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

yes

Details on mating procedure:

Mating was performed using a ratio of 1:2 (male to females).At the mornings, the vaginal smear of the female was checked. The day on which sperms were observed in the vaginal smear was considered as gestation day '0'. After getting 100 sperm positive females, the remaining females and males were discarded.

Duration of treatment / exposure:

Gestatation day 5-19

Frequency of treatment:

Once per day

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
There were no mortalities in any of the treated and control groups during the study.
There were no significant clinical signs indicative of significant systemic toxicity. There were moving the bedding and slight to severe salivation in 300 and 1000 mg/kg groups. These were assumed to be due to the local effect of test item treatment. There were also isolated incidences of alopecia, crust, half eye closure, abnormal breathing in treated groups. These were considered to be incidental.
There were no effects on body weight and body weight gain. There were no effects on terminal body weight and adjusted maternal body weight in test item treated groups compared to the corresponding control groups.
There was statistically significantly lower food consumption between GD 5-8 in the 1000 mg/kg group compared to control. Considering no effect on body weight and body weight gain, the minor effect on food consumption was not considered to be adverse.
There were no adverse effects on hematology and clinical biochemistry parameters. There were no statistically significant differences between the control and test item treated group females except for the statistically significantly lower mean ASAT value in 1000 mg/kg group compared to control. This finding was considered to have no toxicological relevance.

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no effects of test item treatment on the parameters of prenatal data. There were no differences in mean gravid uterus weight, number of live foetuses, number of resorptions (early, late and total), number of foetuses (male, female and total foetuses), sex ratio and percent post implantation losses between the control and test item treated group. There were no dead foetuses in the control and test item treated groups.
There were no effects of test item treatment on litter data including mean foetus weight, total litter weight, male litter weight and female litter weight. There were no statistically significant differences between the control and the test item treated groups.
There were no external, craniofacial and skeletal abnormalities considered to be of toxicological relevance noted in any of the treated groups. The statistical analysis showed no significant changes.
The internal examinations of the foetal viscera by the free-hand-microdissection showed dose responsive increase in the incidence of “dilated ureter (bilateral)” in treated groups compared to control attaining statistical significance at HD group. However, this finding is normally seen greater in fetuses than in pups and is considered part of normal aspects of renal development supporting the idea that these changes are transient and considered as variations [1], [2]. Therefore, the finding was not considered to be an adverse effect.

The references used are,
1. Solecki R et al., (2003) Harmonization of rat fetal external and visceral terminology and classification. Report of the Fourth Workshop on the Terminology in Developmental Toxicology, Berlin, 18–20 April 2002. Reprod Toxicol 17: 625-637
2. Teratology. 1972 Oct;6(2):191-6. "Apparent hydronephrosis" as a normal aspect of renal development in late gestation of rats: the effect of methyl salicylate. Woo DC, Hoar RM.

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Key result

Developmental effects observed:

no

Any other information on results incl. tables

Table: Findings of foetal viscera
	Historical [%]	Study 151945 [%]
		Control	100 mg/kg bw	300 mg/kg bw	1000 mg/kg bw
Ureter B	0.25 ± 0.65, max 2.46	0.83	3.67	6.06	8.85
Ureter L	1.00 ± 1.18, max 4.44	8.33	4.59	9.09	8.85
Ureter R	0.46 ± 0.90, max 3.33	1.67	0.92	5.05	0.88
S Dilated ureter either one sided or both sided	1.71	10.83	9.18	20.2	18.59

Applicant's summary and conclusion

Conclusions:

The reproduction toxicity of the registration substance was investigated according to the Guideline OECD 414. Pregnant rats were treated at dose up to 1000 mg/kg bw. No significant maternal and developmental toxicity was found. The NOAEL of 1000 mg/kg bw was obtained.

Executive summary:

The reproduction toxicity of the registration substance was investigated according to the Guideline OECD 414. Pregnant rats were treated at dose up to 1000 mg/kg bw. No significant maternal and developmental toxicity was found. The NOAEL of 1000 mg/kg bw was obtained.