Potassium phenylacetate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Documentation insufficient for assessment

Data source

Reference

Reference Type:

publication

Title:

The Embryotoxic Action of Some Food Aromatisers

Author:

Zaitsev AN & Magenova NB

Year:

1975

Bibliographic source:

Voprosy Pitaniya.3:64-68

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

In the present article the results are cited of investigation into the action of phenylacetic acid on the embryo when they had been administered daily and perorally to female rats throughout the course of their pregnancy.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Phenylacetic acid

EC Number:

203-148-6

EC Name:

Phenylacetic acid

Cas Number:

103-82-2

IUPAC Name:

phenylacetic acid

Details on test material:

No data

Test animals

Species:

rat

Strain:

not specified

Details on test animals or test system and environmental conditions:

No data

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

not specified

Details on exposure:

No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Details on mating procedure:

No data

Duration of treatment / exposure:

Administered daily and perorally to female rats throughout the course of their pregnancy.

Frequency of treatment:

Daily

Duration of test:

From the start of pregnancy to the first month of the post-natal period.

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
45 mg/kg bw
Basis:
no data

Doses / concentrations 2

Remarks:

Doses / Concentrations:
5 mg/kg bw
Basis:
no data

No. of animals per sex per dose:

In Experimental and control groups there were 14-15 female rats

Control animals:

yes

Details on study design:

- Other: Studies were carried out of the possible embryotoxic action of several synthetic fragment substances that go into the composition of an essence which is set aside for the aromatising of foodstuffs. It was established that phenylacetic acid which has been introduced into pregnant rats in large doses (0.2 LD50) during the critical periods of embryogenesis (the periods of implantation and organogenesis), while giving rise to no obvioud anomalies in the development of the embryos, showed some embryotoxic action, the degree of expression expression of which varied in te presence of the various substances. Phenylacetic acid showed the most marked result. In light of this, experiments were conducted using very large doses, exceeding by 2 -3000 times the actual addition of aromatisers to human food. The findings gave no basis on which to conclude on either the danger or safety of the given synthetic substances in relation to their embryotoxicity, but they did point to the advisability of carrying out further investigations.

Examinations

Maternal examinations:

No data

Ovaries and uterine content:

No data

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: No data

Statistics:

No data

Indices:

No data

Historical control data:

No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Details on embryotoxic / teratogenic effects:
Investigation in 20-day old embryos in all groups observed no anomaly in the structure of the body and internal organs in comparison to the control.The number of live embryos belonging to one female and their weights were close in the experimental and control animals. Essentially, there was no difference in the indices of embryonal mortality in the two groups. Table (1). The content of nucleic acids in the liver of embryos from rats which recieved phenylacetic acid in a quantity equivalent to 0.02 LD50, and also in embryos from control animals fluctuated between identical limits and averaged; ribonucleic acid - 55.06 mg % in the experimental groups and 52.71 mg % in the control; deaoxyribonucleic acid -28.88 mg % (experimental) and 29.98 mg % (control).
On studying the indices which characterise the production and development of progeny, there were no verifiable distinctions. The length of prognancy, the number of live young belonging to one female, and the average weight at birth in the experimental and control groups could not be distinguished. Instances of stillbirth were not recorded. The development of hairy coats and the opening of eyes took place at the same time in both groups. Their weights after a month were also close. (Table 2).
Examination of the skeletons of 15 embryos from each group (in each group the centres of ossification in 570 bones were measured) showed that the centres of ossifications of the lower jaw, humerus and pelvic girdle in embryos from rats that had recieved phenylacetic acid in a dose equal to 0.02 LD50, were smaller in size than in embryos from control animals. Where the female rat had recieved a dose of 0.02 LD50 of phenylacetic acid, the differences in the size of the centres of ossification between the two groups were not in evidence. (Table 3).
Both the results of earlier investigations and the present study bear witness to the fact that phenylacetic acid exerts a breaking effect on the process of ossification of the skeleton of the embryos and this action depends both on the dose and on the period of its administration to the pregnant rats. The largest expression of this was observed when a single large dose (0.2 LD50) of phenylacetic acid was introduced during the critical periods of pregnancy; and the least expression when frequent doses equal to 0.2 LD50 were administered to the organism, and were not expressed at all when frequent doses equal to 0.002 LD50 were given.
Work by Creave and Parke and other researchers, have shown that because of the increased levels in the tissues of the pregnant animal of progesterone and pregnanediol, the conjugation with glucuronic acid of foreign substances significantly decreases. Therefore, phenylacetic acid being introduced into the organism of the rat during pregnancy when conjugation with glucuronic acid is lower, is capable in certain dosages of having a negative effect on progeny.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Table 1 Indices of fertility and state of foetus

  

Experiment	Aromatizer	LD50	Overall foetal mortality (in parts of a unit)	Difference	Average number of young	Average embryo weight
Experiment I	Phenylacetic acid	0.02	0.17±0.08	>0.1	12	2.3
	Control		0.26±0.04		11	2.4
Experiment II	Phenylacetic acid	0.002	0.24±0.09		11	2.3
	Control		0.28±0.03		11	2.2

  

Table 2. Indices characterising production and development of rat progeny

 

Experiment	Aromatizer	LD50	Average length of pregnancy in days	Average number of offspring per female	Average weight of young at birth	Average weight after one month	Development of coat (in days)	Opening of eyes ( in days)
Experiment I	Pl henylacetic acid	0.02	22	12	6.9	69	7-9	17-18
	Control		23	11	6.8	70	7-9	17-19
Experiment II	Phenylacetic acid	0.002	22	10	6.2	82	9-10	16-17
	Control		22	8	6.7	86	9-10	16-17

 

Table 3. Size of centres of ossification in the skeletons of embryos subjected to the action of phenylacetic acid and control embryos.

 

Bone	Experiment I		Difference	Experiment II
	Control	Phenylacetic acid 0.02 LD50		Control	Phenylacetic acid 0.002 LD50
Lower Jaw
Left	7144±46.22	6877±46.22	<0.001	6880±100	6917±26
Right	7138±46.22	6917±46.22	<0.01	6904±92	6981±62
Parietal
Left	5160±30.82	5120±62.23		5120±107	5221±123
Right	5160±46.22	5120±46.22		5133±108	5208±31
Clavicle
Left	2834±15.40	2736±27.73	<0.01	2752±43	2736±31
Right	2829±21.60	2720±27.73	<0.01	2757±43	2749±49
Scapula
Left	2476±21.55	2386±21.57	<0.01	2346±22	2400±25
Right	2480±6.39	2720±27.73	<0.001	2328±28	2405±25
Humerus
Left	2666±30..82	2533±27.73	<0.01	2560±40	2605±63
Right	2672±30.82	2528±30.82	<0.01	2586±46	2631±46
Ulna
Left	2797±43.58	2589±30.74	<0.01	2600±59	2605±63
Right	2810±43.99	2578±40.06	<0.01	2610±52	2658±46
Radius
Left	2101±33.90	1976±21.57	<0.01	1965±46	1985±37
Right	2112±30.84	1974±27.73	<0.01	2002±40	1986±31

 

Table 3 Continued.

 

Bone	Experiment I		Difference	Experiment II
	Control	Phenylacetic acid 0.02 LD50		Control	Phenylacetic acid 0.002 LD50
Metacarpals
Left II	205±15.4	176±12.32		162±9	166±12
III	328±15.4	288±15.4	<0.05	262±12	274±12
IV	253±12.33	213±9.24	<0.05	198±6	200±9
Metacarpals
II	208±15.4	181±15.40		165±12	164±12
III	328±15.4	288±15.41		275±15	289±9
IV	250±20.8	221±15.41		205±12	208±9
Ilium
Left	1734±27.72	1594±33.90	<0.01	1656±31	1640±18
Right	1741±28.50	1608±33.90	<0.05	1648±31	1640±21
Ischium
Left	934±15.41	778±15.41	<0.05	744±22	748±25
Right	829±9.24	744±18.49	<0.01	746±22	786±31
Pubic
Left	496±21.57	389±33.9	<0.02	434±28	455±18
Right	520±30..82	397±33.9	<0.01	450±34	469±25
Femur
Left	1885±33.9	1778±46.23		1794±38	1792±50
Right	1901±30.84	1792±46.23		1816±46	1808±46
Tibia
Left	2256±46.23	21.17±46.23	<0.05	2048±34	2112±49
Right	2176±33.49	21.09±46.23		2050±40	2120±55
Fibula
Left	2106±43.23	19.68±46.23		1941±46	1973±43
Right	2080±40.06	19.38±43.15		2050±40	2120±55
Metatarsals
Left II	210±15.41	189±15.41		162±17	125±13
III	277±12.33	237±15.41		226±15	200±12
IV	320±18.49	269±21.57		264±15	216±12
Right II	208±15.41	186±15.41		160±12	128±12
III	264±15.41	242±12.33		210±12	200±15
IV	314±15.41	269±15.41	<0.05	248±15	226±15

Applicant's summary and conclusion

Conclusions:

Phenylacetic acid, administered orally to rats throughout pregnancy at a dosage of 45 mg/kg, did exhibit some embryotoxic action which was expressed by the slowing down of the process of ossification of separate centres in the skeletons of progeny. There were no other visible external or internal anomalies in development, having observed the progeny for the first month after birth, there did not appear to be any verifiable differences between the experimental and control animals. However, phenylacetic acid administered to rats in the same conditions but at a dose of 5 mg/kg, exhibited no embryotoxic action.