Potassium (E,E)-hexa-2,4-dienoate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, reasonably well documented publication

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1975

Report date:

1975

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.31 (Prenatal Developmental Toxicity Study)

Version / remarks:

, 1988

Deviations:

no

Principles of method if other than guideline:

The conduct of the sutdy was consistent to EC method B.31 (88/302/EEC) in all important aspects.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Potassium (E,E)-hexa-2,4-dienoate

EC Number:

246-376-1

EC Name:

Potassium (E,E)-hexa-2,4-dienoate

Cas Number:

24634-61-5

Molecular formula:

C6H8O2.K

IUPAC Name:

potassium (E,E)-hexa-2,4-dienoate

Details on test material:

- Name of test material: Potassium sorbate
- Physical state: Off-white powder
- Stability: the test substance was considered to be stable for the duration of the study.

Specific details on test material used for the study:

not specified

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: a precise statement on the age of the test animals is lacking. Rats are transcribed as virgin adult females and young adult males.
- Weight at study initiation: 214-230 g

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

VEHICLE
- Concentration in vehicle: 0, 3.4, 15.8, 73.3, 170 mg/mL

TOTAL VOLUME APPLIED: 1 mL (0, 3.4, 15.8, 73.3 mg of test substance)
2 mL (340 mg of test substance)

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Mating procedures: with young adult males (1:1); the day of copulation was considered as day 0 of pregancy.

Duration of treatment / exposure:

Duration of expsoure: Day 6-15 post mating

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

3.4 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

15.8 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

55 mg/kg bw/day

Doses / concentrations 4

Dose / conc.:

340 mg/kg bw/day

No. of animals per sex per dose:

Number of animals per group: 25 females

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: 5 days

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: clinical signs

BODY WEIGHT: Yes
- Time schedule for examinations: On day 0, 6, 11, 15 and 20 of gestation

FOOD CONSUMPTION: Yes

Ovaries and uterine content:

Parameters assessed during Caesarean section on day 20: sex, numbers of corpora lutea, implantation sites, resoption sites, live and dead fetuses, body weight of the live pups, and anatomical normality of the urogenital tract of each dam. 

Blood sampling:

Not specified

Fetal examinations:

Examinations on fetuses: presence of external cogenital abnormalities, visceral examinations (Wilson technique) 

Statistics:

Stastistical methods: not stated

Historical control data:

Not specified

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Description (incidence and severity):

Not specified

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Endocrine findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Maternal developmental toxicity

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

no effects observed

Changes in number of pregnant:

no effects observed

Details on maternal toxic effects:

Details on maternal toxic effects:
The administration of up to 340 mg/kg bw of potassium sorbate had no clearly discernible effect on nidation or on maternal or foetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occuring spontaneously in the sham-treated controls.

Effect levels (maternal animals)

1

Key result

Dose descriptor:

LOAEL

Effect level:

> 340 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Key result

Dose descriptor:

NOAEL

Effect level:

340 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Anogenital distance of all rodent fetuses:

not specified

Changes in postnatal survival:

no effects observed

External malformations:

effects observed, non-treatment-related

Skeletal malformations:

effects observed, non-treatment-related

Visceral malformations:

no effects observed

Details on embryotoxic / teratogenic effects:

Details on embryotoxic / teratogenic effects:
The administration of up to 340 mg/kg bw of potassium sorbate had no clearly discernible effect on nidation or on maternal or foetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occuring spontaneously in the sham-treated controls.

Effect levels (fetuses)

1

Key result

Dose descriptor:

LOAEL

Effect level:

> 340 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: embryotoxicity

2

Key result

Dose descriptor:

LOAEL

Effect level:

> 340 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

external malformations

skeletal malformations

visceral malformations

3

Key result

Dose descriptor:

NOAEL

Effect level:

340 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: embryotoxicity

4

Key result

Dose descriptor:

NOAEL

Effect level:

340 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Key result

Abnormalities:

effects observed, non-treatment-related

Description (incidence and severity):

These were not different than the number reported in the sham-treated controls

Overall developmental toxicity

Key result

Developmental effects observed:

no

Any other information on results incl. tables

TEST MATERIALS (POTASSIUM SORBATE) AND DOSES
Dosage (mg/kg)	Dose (ml/kg)	Concentration (mg/ml)
> 250	1	> 250
251- 500	2	125 – 250
501 – 750	3	133 – 250
751 – 1000	4	187 – 250
1001 - 1600	5	200 – 250

Groups: 51 through 56 RATS Materia: FDA 73-4 Date: December 30, 1974 Laboratory No.: 2123 (18)			Total		Total
Group	Material	Dose mg/kg	Mated	Pregnant	Total	Pregnant^1
51	Sham	0.0	25	20	24	19
52	Aspirin*	250.0	25	20	28	20
53	FDA 73-4	3.4	23	20	27	20
54	FDA 73-4	15.8	25	20	26	20
55	FDA 73-4	73.3	23	20	25	20
56	FDA 73-4	340.0	25	20	25	20
*Positive Control: 250 mg/kg **Administered as water suspension (10 ml per kg BW) ^1 Includes all dams examined at term

REPRODUCTION DATA (RATS)
RATS Group: Dose mg/kg BW	51 Sham	52 Aspirin**	53 3.4	54 15.8	55 73.3	56 340.0
Pregnancy Total No. Died or aborted (before day 20) To term(on Day 20)	22 0 22	22 0 22	20 0 20	19 0 19	20 0 20	20 0 20
Corpora Lutea Total No. Average/dam mated	282 11.3	299 12.0	265 11.5	259 10.4	273 11.9	242 9.68
Live Litters Total No.*	22	22	20	19	20	20
Implant Sites Total No. Average/dam*	257 11.7	251 11.4	244 12.2	222 11.7	240 12.0	233 11.7
Resorptions Total No.* Dams with 1 or more sites resorbed Dams with all sites resorbed Percent partial resorptions Percent complete resorptions	-- -- -- -- --	51 9 -- 40.9 --	1 1 -- 5.00 --	7 4 -- 21.2 --	1 1 -- 5.00 --	4 4 -- 20.0 --
Live Fetuses Total No. Average/dam* Sex ratio (M/F)	253 11.5 0.93	199 9.05 0.90	243 12.2 0.94	215 11.3 1.24	238 11.0 1.00	228 11.4 1.00
Dead Fetuses Total No.* Dams with 1 or more dead Dams with all dead Percent partial dead Percent all dead	4 1 -- 4.55 --	1 1 -- 4.55 --	-- -- -- -- --	-- -- -- -- --	1 1 -- 5.00 --	1 1 -- 5.00 --
Average Fetus Weight, g	3.93	2.40	4.03	4.08	4.02	0.86
*Includes only those dams examined at team **Positive Control: 250 mg/kg

SUMMARY OF SKELETAL FINDINGS (RATS)
	51	52	53	54	55	56
	sham	Aspirin**	4.6	21.4	99.1	460.0
Live Fetuses Examined (at term)	177/22	145/22	171/20	150/19	165/20	163/20
Sternebrae Incomplete oss. Scramble Bipartite Fused Extra Missing Other	37/14   1/1     1/1	96/19   11/5   1/1 130/21	54/16         9/5	58/18   1/1     2/2	14/9	34/16   1/1     12/8
Ribs Incomplete oss. Fused/split Wavy Less than 12 More than 13 Other	14/7	7/4 91/20   131/22	13/9   5/4	15/6   1/1	7/3	22/9   1/1
Vertebrae Incomplete oss. Scrambled Fused Extra ctrs. oss. Scoliosis Tail defects Other	9/6	106/22	1/1	3/2		3/3
Skull Incomplete closure Missing Craniostosis Other	43/15	72/19 1/1	18/10	31/12	19/11	27/9
Extremities Incomplete oss. Missing Extra		19/8		1/1
Miscellaneous Hyoid; missing Hyoid; reduced	16/10 37/16	79/21 10/6	26/10 15/11	8/4 29/11	10/5 28/16	26/11 26/12
*Numerator = Number of fetuses affected; Denominator = Number of litters affected. **Positive control: 250.0 mg/kg

SUMMARY OF SOFT TISSUE ABNORMALITIES (RATS)
Group	Material	Dose level (mg/kg)	Dam	Number of Pups	Description
52	Aspirin*	250.0	44534 44538 44551	1 1 1	Umbilical hernia Encephalomeningocele Umbilical hernia
53	FDA 73-4	3.4	44571	1	Cleft palate
*Positive control: 250.o mg/kg

AVERAGE BODY WEIGHTS* (RATS)
Group	Material	Dose Level Mg/kg	0	6	11	15	20**
51	Sham	0.0	219	232	248	269	335 (22)
52	Aspirin***	250.0	231	236	248	262	319 (22)
53	FDA 73-4	3.4	230	242	259	282	361 (20)
54	FDA 73-4	15.8	218	230	247	265	334 (19)
55	FDA 73-4	73.3	221	233	249	270	344 (20)
56	FDA 73-4	340.0	214	225	243	262	332 (20)
*Of pregnant dams **Number of surviving dams in parentheses (c.f. Table 1) ***Positive control: 250.0 mg/kg

Applicant's summary and conclusion

Conclusions:

LO(A)EL maternal toxic effects > 340 mg/kg b.w./day
NO(A)EL maternal toxic effects: 340 mg/kg b.w./day
LO(A)EL embryotoxic/ teratogenic effects > 340 mg/kg b.w./day
NO(A)EL embryotoxic/ teratogenic effects: 340 mg/kg b.w./day

The administration of up to 340 mg/kg bw of potassium sorbate had no clearly discernible effect on nidation or on maternal or foetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occuring spontaneously in the sham-treated controls.

The extrapolation from sorbic acid to potassium sorbate or vice versa is considered not to be restricted in any way, since the determinant of potential toxicity is on the "sorbate" anion.

Executive summary:

Potassium sorbate was not teratogenic in rats under the conditions of the study.