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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:
no
GLP compliance:
no
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:
no
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

1
Chemical structure
Reference substance name:
Potassium sodium tartrate
EC Number:
206-156-8
EC Name:
Potassium sodium tartrate
Cas Number:
304-59-6
Molecular formula:
C4H6O6.K.Na
IUPAC Name:
potassium sodium tartrate
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:
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.

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