Tall oil, potassium salt

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12 November 1974 to 24 December 1974

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiencies, which do not affect the quality of the relevant results. Study read-across from supporting substance.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1975

Report date:

1975

Materials and methods

Principles of method if other than guideline:

Pregnant female rats received 0, 3.1, 14.4, 66.8 and 310.0 mg/kg bw/day of the test material from day 6 of gestation to day 15 by gavage.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Potassium chloride

EC Number:

231-211-8

EC Name:

Potassium chloride

Cas Number:

7447-40-7

Molecular formula:

KCl or ClK

IUPAC Name:

potassium chloride

Test material form:

solid: crystalline

Details on test material:

- Appearance: fine, white crystalline material

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Animals: Virgin albino rats (Wistar derived stock)
- Age at study initiation: adult
- Weight at study initiation: 215 to 230 g (average group values)
- Housing: Animals were individually housed in mesh bottom cages
- Diet (e.g. ad libitum): free access to food
- Water (e.g. ad libitum): free access to fresh tap water

ENVIRONMENTAL CONDITIONS
Animals were housed in temperature and humidity-controlled quarters.
- Temperature (°C): 22 to 37 °C
- Humidity (%): 40 to 74 % relative

IN-LIFE DATES: From: 12 November 1974 To: 24 December 1974

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The test material was prepared and doses calculated as follows:
Dosage Dose Concentration
(mg/kg) (mL/kg) (mg/mL)
≤250 1 ≤250
251 to 500 2 125 to 250
501 to 750 3 133 to 250
751 to 1000 4 187 to 250
1001 to 1600 5 200 to 250

The controls were sham-treated with the vehicle at a level equivalent to the group receiving the highest dose.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Females were mated with young adult males, and observation of the vaginal sperm plug was considered Day 0 of gestation (One male was not permitted to impregnate more than one female per group).

Duration of treatment / exposure:

Day 6 to day 15 of gestation

Frequency of treatment:

Once daily

No. of animals per sex per dose:

Control group: 25 females
3.1 mg/kg dose group: 21 females
14.4 mg/kg dose group: 23 females
66.8 mg/kg dose group: 23 females
310.0 mg/kg dose group: 28 females
Positive Control group: 24 females

Control animals:

yes, sham-exposed

Details on study design:

Pregnant females were administered aspirin at a dose level of 250 mg/kg bw/day as positive control.

Examinations

Maternal examinations:

Bodyweights were recorded on Days 0, 6, 11, 15 and 20 of gestation. All animals were observed daily for appearance and behaviour with particular attention to food consumption and weight, in order to rule out any abnormalities which may have occurred as a result of anorexic effects in the pregnant female animal.

Ovaries and uterine content:

On Day 20 all dams were subjected to Caesarean Section under surgical anaesthesia, and the sex, numbers of corpora lutea, implantation sites and resorption sites were recorded. The urogenital tract of each dam was examined in detail for anatomical normality.

Fetal examinations:

When the dams were subjected to Caesarean Section, the number of live and dead foetuses was recorded. The bodyweights of the live pups were also recorded.
All foetuses were examined grossly for the presence of external congenital abnormalities. One-third of the foetuses of each litter underwent detailed visceral examinations employing the Wilson technique. The remaining two-thirds were cleared in potassium hydroxide (KOH), stained with alizarin red S dye and examined for skeletal defects.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
The test material had no clearly discernible effect on nidation or maternal survival. 

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

310 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The test material had no clearly discernible effect on foetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the controls.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

310 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects on fetal growth or development at any dose level

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Table 1 Summary of Survival and Pregnancy Data

Dose Level (mg/kg)	Total		Surviving at Term
	Mated	Pregnant	Total	Pregnant*
0 3.1 14.4 66.8 310.0	25 21 23 23 28	23 21 20 20 21	25 21 23 23 28	23 21 20 20 21
Positive Control	24	21	24	21

*Includes all dams examined at term

 

Table 2 Summary of Reproduction Data

Dose Level (mg/kg)	0	3.1	14.4	66.8	310.0	Positive Control
Pregnancies Total number Died or aborted (before day 20) To term (on day 20)	23 0 23	21 0 21	20 0 20	20 0 20	21 0 21	21 0 21
Corpora Lutea Total Number Average/dam mated	285 11.9	262 12.5	257 11.2	246 10.7	274 9.79	260 10.8
Live Litters Total number*	23	20	20	20	21	15
Implant Sites Total Number Average/dam*	275 12.0	229 10.9	228 11.4	223 11.2	239 11.4	217 10.3
Resorptions Total number* Dams with 1 or more sites reabsorbed Dams with all sites reabsorbed Percent partial resorptions Percent complete resorptions	1 1 - 4.35 -	7 2 1 9.52 4.76	6 4 - 20.0 -	- - - - -	- - - - -	57 10 6 47.6 28.6
Live Foetuses Total number Average/dam* Sex ratio (M:F)	274 11.9 0.85	222 10.6 1.07	222 11.1 1.07	221 11.1 0.99	239 11.4 0.96	160 7.62 0.88
Dead Foetuses Total number* Dams with 1 or more dead Dams with all dead Percent partial dead Percent all dead	- - - - -	- - - - -	- - - - -	2 2 - 10.0 -	- - - - -	- - - - -
Average Foetus Weight (g)	3.97	4.03	3.96	4.03	3.96	2.61

*Includes only those dams examined at term

 

Table 3 Summary of Skeletal Findings

Dose Level (mg/kg)	0	3.1	14.4	66.8	310.0	Positive Control
Findings
Live foetuses examined (at term)	190/23	156/20	155/20	154/20	167/21	111/15
Sternebrae Incomplete ossification Scrambled Bipartite Fused Extra Missing	40/15         1/1	29/13   1/1     2/2	31/14         8/6	40/14         17/7	58/15         22/10	77/15   9/7   2/1 57/12
Ribs Incomplete ossification Fused/split Wavy Less than 12 More than 13	19/8	1/1   13/8	12/7   1/1	20/8   1/1	20/6	2/1   26/10   29/10
Vertebrae Incomplete ossification	14/4	1/1	4/2	5/4	12/6	53/14
Skull Incomplete closure	50/13	35/14	23/9	35/14	23/6	55/12
Extremities Incomplete ossification			1/1		1/1	1/1
Miscellaneous Hyoid, missing Hyoid, reduced	19/9 33/13	1/1 26/10	24/12 27/12	34/10 23/8	28/10 25/9	55/14 11/6

Numerator = number of foetuses affected; denominator = number of litters affected

Table 4 Summary of Soft Tissue Abnormalities

Dose Level (mg/kg)	Dam	Number of Pups	Description
66.8	45044	1	Gastroschisis
Positive Control	44832 44841	1 1	Encephalomeningocele Encephalomeningocele, Gastroschisis

Applicant's summary and conclusion

Conclusions:

Under the conditions of this study, the NOAEL for maternal toxicity when administered to pregnant Wistar rats for 10 consecutive days was determined to be 310 mg/kg bw/day. The NOAEL for developmental effects was also determined to be 310 mg/kg bw/day.

Executive summary:

The potential of the test substance to cause reproductive and developmental adverse effects was evaluated in the Wistar rats. Pregnant females were dose with the test material from day 6 to day 10 of gestation at dose levels of 0, 3.1, 14.4, 66.8 and 310.0 mg/kg bw/day by oral gavage. The controls were sham treated with the vehicle at a level equivalent to the group receiving the highest test dose. The test material had no clearly discernible effect on nidation or 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 occurring spontaneously in the controls. Under the conditions of this study, the NOAELs for both maternal and developmental toxicitywas determined to be 310 mg/kg bw/day (FDA, 1975).