Potassium sodium tartrate - Registration Dossier

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Toxicological information

Developmental toxicity / teratogenicity

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Endpoint:: developmental toxicity
Type of information:: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:: key study
Study period:: 1973
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: test procedure in accordance with national standard methods
Justification for type of information:: Although no GLP declaration accompanies the original 1973 report for this study, the level of detail contained threin, the fact that it has been sponsored and reviwed by the US
FDA and that it is the key development study for the consideration of tartaric acid as GRAS, warrants its classification a Klimisch 1.

Cross-reference

Reason / purpose for cross-reference:: read-across source

Reference

Endpoint:

developmental toxicity

Type of information:

other: publication

Adequacy of study:

key study

Study period:

1973

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods

Justification for type of information:

Although no GLP declaration accompanies the original 1973 report for this study, the level of detail contained threin, the fact that it has been sponsored and reviwed by the US
FDA and that it is the key development study for the consideration of tartaric acid as GRAS, warrants its classification a Klimisch 1.

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.31 (Prenatal Developmental Toxicity Study)

Deviations:

GLP compliance:

Specific details on test material used for the study:

L(+) Tartaric acid. Reported as a fine white crystalline material.

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

Test animals: Virgin adult female albino rats (Wistar derived stock).
Housed individually in mexh bottom cages
Environmental conditions not stated but report indicates "temperature and humidity controlled quarters"
Food and water access: ad libitum
Average weights of pregnant females at day cero (at start of gestation) is 205-212 g.

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

1 ml / kg bw was administered on each dosing, containing the appropriate concentration to achieve the desired dose.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No information on analytical verificatipn provided.

Details on mating procedure:

Females mated with youn adult males of the same species.
Observation of vaginal sperm plug is considered day 0 of gestation.

Duration of treatment / exposure:

Dosage by oral intubation (gavage) of test substance dissolved in water.
Dosing takes place daily between day 6 and trough to day 15 of gestation.

Frequency of treatment:

Daily

Duration of test:

10 days

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

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

No. of animals per sex per dose:

22 - 25 females were mated per dose group and control. Of these a total of between 19 and 24 (average 21) animals survived at term.

Control animals:

yes, concurrent vehicle

Details on study design:

Body weights were recoirded at 0, 6, 11, 15 and 20 days of gestation.
All animals were observed daily for appearance and hehaviour, with particular attention to food consumption and weight.
On day 20 all dams were subjected to Caesarean section under surgical anaesthesia and the numbers of implantation sites, resorption sites and live and dead foetuses was recorded. Body weights of live pups were also recorded.
The urogenital tract of each dam was examined in detail for anatomical abnormality.
All foetuses were examined grossly for the presence of external congenital anomalies. One third of the foetuses of each litter were subjected to detailed visceral examination employing the Wilson technique.
The remaining two-thirds were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.
A positive control was used in the study. A group of 22 pregnant animals was treated with 250.0 mg/kg aspirin. This control resulted in a high incidence of encephalomyolecele, meningoencephalocele and, to a lesser extent exophthalmos, hydrocephalus and other abnormalities.

Maternal examinations:

All animals were observed daily for appearance and hehaviour, with particular attention to food consumption and weight.

Ovaries and uterine content:

The urogenital tract of each dam was examined in detail for anatomical abnormality.

Fetal examinations:

All foetuses were examined grossly for the presence of external congenital anomalies. One third of the foetuses of each litter were subjected to detailed visceral examination employing the Wilson technique.
The remaining two-thirds were cleared in potassium hydroxide, stained with alizarin red S dye and examined for skeletal defects.

Dose descriptor:

NOAEL

Effect level:

> 181 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

clinical signs

dead fetuses

food consumption and compound intake

gross pathology

number of abortions

Remarks on result:

not determinable

Abnormalities:

no effects observed

Developmental effects observed:

Lowest effective dose / conc.:

181 mg/kg bw/day (nominal)

TABLE 1. FATE

SUMMARY (RATS)

GROUP	MATERIAL	DOSE**	TOTAL		SURVIVING AT TERM
		(mg/Kg)	Mated	Pregnant	Total	Pregnant(1)
271	Sham	0	25	22	25	22
272	Aspirin*	250	22	21	22	21
273	FDA 71 -55	1.81	25	19	25	19
274	FDA 71 -55	8.41	24	19	24	19
275	FDA 71 -55	39.1	25	23	25	23
276	FDA 71 -55	181.1	25	24	25	24

* Positive Control: 250,0 mg/kg

** Administered as a water solution (See Appendix I)

(1) Includes all dams examined at term

TABLE 2: REPRODUCTION DATA (RATS)

GROUP	271	272	273	274	275	276
DOSE (mg/Kg)	Sham	Aspirin**	1.81	8.41	39.1	181

Pregnancies
Total No.	22	21	19	19	23	24
Died or aborted (before Day 17)	0	0	0	0	0	0
To Term (on day 17)	22	21	19	19	23	24

Live Litters
Total No.	22	20	19	19	23	24

Implant Sites
Total No.	251	225	225	235	274	273
Average/dam*	11,4	10,7	11.8	12.4	11.9	11.4

Resorptions
Total No.	6	27	3	4	2	4
Drams with all sites resorbed	4	9	2	3	2	3
Drams with all sites resorbed	-	1	-	-	-	-
Per cent partial resorptions	-	4.76	-	-	-	-

Live Fetuses
Total No.	245	198	222	231	272	269
Average/dam*	11.1	9.43	11.7	12.2	11.8	11.2
Sex ratio (M/F)	0.9	1.06	1	0.85	1.11	1.05

Dead fetuses
Total*
Drams with 1 or more dead	-	-	-	-	-	-
Drams with all dead	-	-	-	-	-	-
Per cent patrial dead	-	-	-	-	-	-
Per cent all dead	-	-	-	-	-	-

Average Fetus Weight, g	9.39	2.68	3.97	3.77	3.83	3.97

*Includes only those dams examined al term
**Positive Control: 150.0 mg/Kg

TABLE 3: SUMMARY OF SKELETAL FINDINGS* (RATS)

GROUP No.	271	272	273	274	275	276
DOSE (mg/Kg)	Sham	Aspirin**	1.81	8.41	39.1	181

Finding
Live Fetuses Examined (at term)	173/22	137/20	152/19	161/19	186/23	188/24
Sternebrae
Incomplete oss.	82/20	91/20	78/15	42/13	52/14	46/15
Scrambled
Bispartite	3/3	5/4	1/1	1/1	1/1	1/1
Fused	-	-	-	-	1/1	-
Extra	-	-	1/1	-	-	-
Missing	2/2	86/19	7/4	5/2	8/ 5	6/4
Other	-	-	-	-	-	-
Ribs	-	-	-	-	-	-
Incomplete oss	-	1/1	-	-	3/2	-
Fused/split	-	1/1	-	-	-	-
Wavy	1/1	46/16	22/7	13/7	18/10	18/9
Less than 12	2/2	2/1	-	-	-	-
Les Than 13	7/3	91/19	-	1/1	-	5/5
Other	-	-	-	-	-	-
Vertebrae
Incomplete oss.	-	101/19	2/2	8/6	5/4	10/7
Srambied	-	-	-	-	-	-
Fused	-	-	-	-	-	-
Extra ctrs. Oss	-	-	-	-	-	-
Scoliosis	1/1	-	-	-	-	-
Tail defects	-	-	-	-	-	-
Other	-	-	-	-	-	-
Skull
Incomplete closure	26/14	47/16	49/14	19/9	40/17	32/16
Missing	-	6/2	-	-	-	-
Extra	-	-	-	-	-	-
Miscellaneous
Hyoid; missing	15/8	65/18	17/9	19/10	15/10	31/13
Hyoid; reduced	20/9	19/10	22/9	17/8	29/15	13/10

* Numerator = Number of fetuses affected; Denominator = number of litters affected

** Possitive control: 150,0 mg/kg

TABLE 3-A: SUMMARY OF SOFT TISSUE ABNORMALITIES (RATS)

GROUP	MATERIAL	DOSE LEVEL	DAM	NUMBER OF	DESCRIPTION
		mg/Kg		PUPS
272	Apirin*	250	A 4882	6	Encephalomyelocele
				2	Exophthalmos
				1	Gastroschisis
			A4888	1	Meningeoncephalocele
			A4892	1	Encephalomyelocele
				3	Meningeoncephalocele
			A4899	1	Hydrocephalus
				1	Encephalomyelocele
273	FDA 71 -55	1.81	I 4006	1	Subcutaneous hematoma
			I 4009	1	Umbilical hernia
275	FDA 71 -55	39.1	I 4064	1	Umbilical hernia

*Positive control: 250,0 mg/kg

TABLE 4: AVERAGE BODY WEIGHTS* (RATS)

GROUP	MATERIAL	DOSE LEVEL			DAY
		(mg/Kg)	0	6	11	15	20**
271	Sham	0	212	232	250	268	331 (22)
272	Aspirin***	250	212	282	246	265	215 (21)
273	FDA 71 -55	1.81	213	234	253	274	340 (19)
274	FDA 71 -55	8.41	211	232	250	272	345 (19)
275	FDA 71 -55	39.1	205	225	243	266	333 (23)
276	FDA 71 -55	181	218	235	256	278	345 (24)

* Of pregnant dams

**Number of surviving dams in parentheses (c.f. Table 1)

*** Positive control: 250,0 mg/kg

Conclusions:

The administration of up to 181 mg/kg bw of L(+) tartaric acid to groups of 20 pregnant female rats for 10 consecutive days starting on day 6 after gestation had no clear discernible effect on nidation or on maternal or foetal survival. The number of anomalies seen either in soft or skeletal tissues in the test groups did not differ from those occuring spontaneously in the control group.It is concluded that tartaric acid is not a developmental toxicant to the rat.

Executive summary:

The administration of up to 181 mg/kg bw of L(+) tartaric acid to groups of 20 pregnant female rats for 10 consecutive days starting on

day 6 after gestation had no clear discernible effect on nidation or on maternal or foetal survival. The number of anomalies seen either in

soft or skeletal tissues in the test groups did not differ from those occuring spontaneously in the control group.It is concluded that tartaric

acid is not a developmental toxicant to the rat.

This test, performed essentially according to EU test method B.31 (although no test method is not quoted) is considered of full relevance

to the reference substance Potassium Sodium Tartrate, as the salt dissociates fully at physiological pH.

Data source

Materials and methods

Test material

Test material information

Test material form:: solid: crystalline

Administration / exposure

Duration of treatment / exposure:: .

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:: NOAEL
Effect level:: > 181 mg/kg bw/day (nominal)
Based on:: test mat.
Basis for effect level:: behaviour (functional findings); body weight and weight gain; dead fetuses; food consumption and compound intake; gross pathology; number of abortions

Results (fetuses)

Effect levels (fetuses)

Remarks on result:: not determinable

Fetal abnormalities

Abnormalities:: no effects observed

Overall developmental toxicity

Developmental effects observed:: no
Lowest effective dose / conc.:: 181 mg/kg bw/day (nominal)

Any other information on results incl. tables

TABLE 1. FATE

SUMMARY (RATS)

GROUP	MATERIAL	DOSE**	TOTAL		SURVIVING AT TERM
		(mg/Kg)	Mated	Pregnant	Total	Pregnant(1)
271	Sham	0	25	22	25	22
272	Aspirin*	250	22	21	22	21
273	FDA 71 -55	1.81	25	19	25	19
274	FDA 71 -55	8.41	24	19	24	19
275	FDA 71 -55	39.1	25	23	25	23
276	FDA 71 -55	181.1	25	24	25	24

* Positive Control: 250,0 mg/kg

** Administered as a water solution (See Appendix I)

(1) Includes all dams examined at term

TABLE 2: REPRODUCTION DATA (RATS)

GROUP	271	272	273	274	275	276
DOSE (mg/Kg)	Sham	Aspirin**	1.81	8.41	39.1	181

Pregnancies
Total No.	22	21	19	19	23	24
Died or aborted (before Day 17)	0	0	0	0	0	0
To Term (on day 17)	22	21	19	19	23	24

Live Litters
Total No.	22	20	19	19	23	24

Implant Sites
Total No.	251	225	225	235	274	273
Average/dam*	11,4	10,7	11.8	12.4	11.9	11.4

Resorptions
Total No.	6	27	3	4	2	4
Drams with all sites resorbed	4	9	2	3	2	3
Drams with all sites resorbed	-	1	-	-	-	-
Per cent partial resorptions	-	4.76	-	-	-	-

Live Fetuses
Total No.	245	198	222	231	272	269
Average/dam*	11.1	9.43	11.7	12.2	11.8	11.2
Sex ratio (M/F)	0.9	1.06	1	0.85	1.11	1.05

Dead fetuses
Total*
Drams with 1 or more dead	-	-	-	-	-	-
Drams with all dead	-	-	-	-	-	-
Per cent patrial dead	-	-	-	-	-	-
Per cent all dead	-	-	-	-	-	-

Average Fetus Weight, g	9.39	2.68	3.97	3.77	3.83	3.97

*Includes only those dams examined al term
**Positive Control: 150.0 mg/Kg

TABLE 3: SUMMARY OF SKELETAL FINDINGS* (RATS)

GROUP No.	271	272	273	274	275	276
DOSE (mg/Kg)	Sham	Aspirin**	1.81	8.41	39.1	181

Finding
Live Fetuses Examined (at term)	173/22	137/20	152/19	161/19	186/23	188/24
Sternebrae
Incomplete oss.	82/20	91/20	78/15	42/13	52/14	46/15
Scrambled
Bispartite	3/3	5/4	1/1	1/1	1/1	1/1
Fused	-	-	-	-	1/1	-
Extra	-	-	1/1	-	-	-
Missing	2/2	86/19	7/4	5/2	8/ 5	6/4
Other	-	-	-	-	-	-
Ribs	-	-	-	-	-	-
Incomplete oss	-	1/1	-	-	3/2	-
Fused/split	-	1/1	-	-	-	-
Wavy	1/1	46/16	22/7	13/7	18/10	18/9
Less than 12	2/2	2/1	-	-	-	-
Les Than 13	7/3	91/19	-	1/1	-	5/5
Other	-	-	-	-	-	-
Vertebrae
Incomplete oss.	-	101/19	2/2	8/6	5/4	10/7
Srambied	-	-	-	-	-	-
Fused	-	-	-	-	-	-
Extra ctrs. Oss	-	-	-	-	-	-
Scoliosis	1/1	-	-	-	-	-
Tail defects	-	-	-	-	-	-
Other	-	-	-	-	-	-
Skull
Incomplete closure	26/14	47/16	49/14	19/9	40/17	32/16
Missing	-	6/2	-	-	-	-
Extra	-	-	-	-	-	-
Miscellaneous
Hyoid; missing	15/8	65/18	17/9	19/10	15/10	31/13
Hyoid; reduced	20/9	19/10	22/9	17/8	29/15	13/10

* Numerator = Number of fetuses affected; Denominator = number of litters affected

** Possitive control: 150,0 mg/kg

TABLE 3-A: SUMMARY OF SOFT TISSUE ABNORMALITIES (RATS)

GROUP	MATERIAL	DOSE LEVEL	DAM	NUMBER OF	DESCRIPTION
		mg/Kg		PUPS
272	Apirin*	250	A 4882	6	Encephalomyelocele
				2	Exophthalmos
				1	Gastroschisis
			A4888	1	Meningeoncephalocele
			A4892	1	Encephalomyelocele
				3	Meningeoncephalocele
			A4899	1	Hydrocephalus
				1	Encephalomyelocele
273	FDA 71 -55	1.81	I 4006	1	Subcutaneous hematoma
			I 4009	1	Umbilical hernia
275	FDA 71 -55	39.1	I 4064	1	Umbilical hernia

*Positive control: 250,0 mg/kg

TABLE 4: AVERAGE BODY WEIGHTS* (RATS)

GROUP	MATERIAL	DOSE LEVEL			DAY
		(mg/Kg)	0	6	11	15	20**
271	Sham	0	212	232	250	268	331 (22)
272	Aspirin***	250	212	282	246	265	215 (21)
273	FDA 71 -55	1.81	213	234	253	274	340 (19)
274	FDA 71 -55	8.41	211	232	250	272	345 (19)
275	FDA 71 -55	39.1	205	225	243	266	333 (23)
276	FDA 71 -55	181	218	235	256	278	345 (24)

* 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:

Executive summary:

The administration of up to 181 mg/kg bw of L(+) tartaric acid to groups of 20 pregnant female rats for 10 consecutive days starting on

day 6 after gestation had no clear discernible effect on nidation or on maternal or foetal survival. The number of anomalies seen either in

soft or skeletal tissues in the test groups did not differ from those occuring spontaneously in the control group.It is concluded that tartaric

acid is not a developmental toxicant to the rat.

This test, performed essentially according to EU test method B.31 (although no test method is not quoted) is considered of full relevance

to the reference substance Potassium Sodium Tartrate, as the salt dissociates fully at physiological pH.

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