1,3,4,5-tetrahydroxycyclohexanecarboxylic acid

Endpoint summary

Description of key information

According to the calculation done by ChemProp and the publication of the read across substance salicylic acid, quinic acid is not irritating or corrosive to skin. In the in vitro BCOP test, quinic acid had effects on the cornea of the bovine eye. A mean IVIS of 52.548 (second experiment) and 52.151 (third experiment) was calculated. Therefore, we assumed that quinic acid is moderate irritating to eyes.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation / corrosion

Remarks:

other: estimated by calculation

Type of information:

calculation (if not (Q)SAR)

Remarks:

Migrated phrase: estimated by calculation

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Result is predicted from a model. Thus, it provides an approximation compared to experimental measure.

Principles of method if other than guideline:

The risk of skin irritation/corrosion in terms of R phrases is estimated from chemical structure in a two-step-procedure:
1. Bioavailabilty (Some physicochemical properties (Kow, lipid solubility, Tm, molar weight) will be calculated.)
2. Structural alerts (Particular substructures trigger substructure alert for R phrases)

Ingrid Gerner, Kerstin Schlegel, John D. Walker, and Etje Hulzebosc, Use of Physicochemical Property Limits to Develop Rules for Identifying Chemical Substances with no Skin Irritation or Corrosion Potential, QSAR Comb. Sci. 2004, 23, pp.726-733

GLP compliance:

not specified

Remarks on result:

not measured/tested

#	Result	Unit / range	Property description
1.1	0	Frequency	Structural alerts for skin irritation (R38)
1.2	0	Frequency	Structural alerts for skin corrosion (R34 or R35)
1.3	0	1=bioavailable, 0=save-1 = not appropriate	General bioavail. for skin irritation/corrosion potential (R38)
1.4	0	1=bioavailable, 0=save-1 = not appropriate	General bioavail. for skin irritation/corrosion potential (R34 or R35)
1.5	0	1=bioavailable, 0=save-1 = not appropriate	C – bioavail. for skin irritation/corrosion potential (R38)
1.6	0	1=bioavailable, 0=save-1 = not appropriate	C – bioavail. for skin irritation/corrosion potential (R34 or R35)
1.7	-1	1=bioavailable, 0=save-1 = not appropriate	CN – bioavail. for skin irritation/corrosion potential (R38)
1.8	-1	1=bioavailable, 0=save-1 = not appropriate	CN – bioavail. for skin irritation/corrosion potential (R34 or R35)
1.9	-1	1=bioavailable, 0=save-1 = not appropriate	CNHal – bioavail. for skin irritation/corrosion potential (R38)
1.10	-1	1=bioavailable, 0=save-1 = not appropriate	CNHal – bioavail. for skin irritation/corrosion potential (R34 or R35)
1.11	-1	1=bioavailable, 0=save-1 = not appropriate	CNS – bioavail. for skin irritation/corrosion potential (R38)
1.12	-1	1=bioavailable, 0=save-1 = not appropriate	CNS – bioavail. for skin irritation/corrosion potential (R34 or R35)
1.13	-1	1=bioavailable, 0=save-1 = not appropriate	CHal – bioavail. for skin irritation/corrosion potential (R38)
1.14	-1	1=bioavailable, 0=save-1 = not appropriate	CHal – bioavail. for skin irritation/corrosion potential (R34 or R35)

The default output is either -1, 0, or 1:

-1: Exclusion rule found: Compound is not bioavailable → save

0: No exclusion rule (bioavailable), but no alert → likely save

1: Alert found, and no exclusion rule matched (bioavailable) → not save

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: other: Prediction via calculation

Conclusions:

According to this calculation, quinic acid is not irritating to skin.

Executive summary:

The skin irritating/corrosive properties of quinic acid have been calculated by ChempProp. The calculation shows that quinic acid is not irritating or corrosion to skin since no structural alerts are available.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was done according to OECD guideline 437.

Qualifier:

according to guideline

Guideline:

OECD Guideline 437 (Bovine Corneal Opacity and Permeability Test Method for Identifying Ocular Corrosives and Severe Irritants)

Qualifier:

according to guideline

Guideline:

EU method B.47 (Bovine corneal opacity and permeability test method for identifying ocular corrosives and severe irritants)

Principles of method if other than guideline:

Test System:
Fresh bovine eyes were obtained from the slaughterhouse Müller Fleisch GmbH, Enzstr. 2 - 4, 75217 Birkenfeld, Germany, on the day of the test. The cattle were between 12 and 60 months old. The eyes were transported to the test facility in Hank’s balanced salt solution (supplemented with 0.01 % streptomycin and 0.01 % penicillin). Then, the corneas were dissected and incubated in medium at 32 ± 1 °C in an incubation chamber for 1 hour.

Preparations:
After having carefully cleaned and sterilised the cornea holders, they were kept in the incubation chamber at 32 +-1°C. On the day of the assay, the MEM without phenol red was supplemented with sodium bicarbonate, L-glutamine and 1 % fetal calf serum (= complete MEM) and stored in a water bath at 32 °C ± 1 °C. The same was performed with the MEM with phenol red. After the arrival of the corneas they were examined and only corneas which were free from defects were used. The corneas were excised with a scalpel and cut from the globe with a 2-3 mm ring of sclera around the outside. Each cornea was transferred to a cornea holder in which pre-warmed cMEM without phenol red was filled. The holders were then incubated for one hour in the incubation chamber at 32 °C.

Method Description:
After the initial incubation, the medium was changed and the baseline opacity for each cornea was recorded. None of the corneas showed tissue damage; therefore, all corneas were used. The baseline opacity was measured by placing the holder with the cornea in a spectral photometer and recording the absorption at 570 nm. Opacity is calculated from the measured absorption. For each treatment group (negative control solution, test item suspension and positive control solution), three replicates were used. After removal of the pre-incubation medium, 750 μL negative control solution resp. test item suspension resp. positive control solution were applied to each replicate

According to the characteristics of the test item, the following treatment procedure was performed: Open Chamber Method:
The “open chamber-method” is used for solid substances. In order to apply the test item, the nut was unscrewed to remove the glass disc. The test item could be applied directly on the cornea now. 750 μL of the test item were tested as suspension at 20 % concentration in 0.9 % sodium chloride solution. The test item suspension was given on the epithelium in such a manner that as much as possible of the cornea was covered with test item suspension. Exposition time on the corneas was 4 h ± 5 min. at 32 °C. After thorough rinsing with cMEM with phenol red and final rinsing with cMEM without phenol red, both chambers were filled with cMEM without phenol red, and the final opacity value of each cornea was recorded at once (again by measurement at 570 nm). The cMEM without phenol red was then removed from the front chamber, and 1 mL sodium fluorescein solution (concentration
5 mg/mL) was added to the front chamber. The chambers were then closed again and incubated for 90 ± 5 min at 32 ± 1 °C. After incubation, the content of the posterior chamber was thoroughly mixed. Then, the permeability of the cornea was measured as optical density of the liquid at 490 nm.

GLP compliance:

yes (incl. QA statement)

Species:

other: Bos primigenius Taurus (Fresh bovine corneas)

Vehicle:

physiological saline

Remarks:

0.9 % sodium chloride solution

Amount / concentration applied:

TEST MATERIAL
- Concentration (if solution): 20% in 0.9 % sodium chloride solution

Duration of treatment / exposure:

Incubation time: 4 hours at 32 ± 1 °C

Details on study design:

Negative Control: Sodium chloride solution: 0.9 % NaCl (CAS-No. 7647-14-5), dissolved in demin. water.
Positive Control: Imidazole solution: 20 % C3H4N2 (CAS-No. 288-32-4), dissolved in 0.9 % NaCl.
The test item is a non-surfactant solid substance. It was tested as a suspension at a concentration of 20% in 0.9 % sodium chloride solution.

Irritation parameter:

in vitro irritation score

Run / experiment:

2

Value:

52.548

Vehicle controls validity:

not examined

Negative controls validity:

valid

Positive controls validity:

valid

Irritation parameter:

in vitro irritation score

Run / experiment:

3

Value:

52.151

Vehicle controls validity:

not examined

Negative controls validity:

valid

Positive controls validity:

valid

Opacity and Permeability Values of the Second Experiment. The first experiment was invalid and is not reported.

The absorption (570 nm) and opacity values which were measured before and after exposition are given in the following table:

A) Absorption and Opacity Values Negative Control:

Parameter	Negative Control
Absorption before exposition	0.1534	0.1456	0.1523
Absorption after exposition	0.2548	0.1948	0.2557
Opacity before exposition	1.4236	1.3983	1.4200
Opacity after exposition	1.7980	1.5660	1.8018
Opacity Difference	0.3744	0.1677	0.3817

Mean opacity difference of the negative control is 0.3080.

B) Absorption and Opacity Values Test Item and Positive Control:

Parameter	Test Item Quinic acid			Positive Control
Absorption before exposition	0.1239	0.1380	0.1355	0.1539	0.1389	0.1598
Absorption after exposition	1.673	1.6600	1.8429	1.5211	1.7040	1.5634
Opacity before exposition	1.3301	1.3740	1.3662	1.4253	1.3769	1.4448
Opacity after exposition	47.0977	45.7088	69.6466	33.1971	50.5825	36.5932
Opacity Difference	45.7676	44.3348	68.2805	31.7718	49.2056	35.1484

For the permeability measurement, three replicates for each treatment group were measured. The optical density values at 490 nm are given in the following table:

C) Optical density at 490 nm:

Repl.	Negative Control			Test Item Quinic acid			Positive Control
Meas.	0.0074	0.0059	0.0099	0.0094	0.0048	0.0115	0.5096	0.3197	0.3642
Corr.	0.0370	0.0295	0.0495	0.0470	0.0240	0.0575	2.5480	1.5985	1.8210
Mean	0.0387			--

Note: In order to correct the path length, a factor of 5 was taken into account when calculating the IVIS.

IVIS Values

IVIS was calculated using the values in tables A, B and C and the equation IVIS = (opacity difference – mean opacity difference of the negative controls) + [15 * (corr.OD490 – mean corr. OD490 of the negative controls)]

The calculated IVIS for each replicate and the corresponding means are presented in the following table:

D) IVIS:

Test Group	IVIS	Mean IVIS	Relative Standard Deviation IVIS
Negative Control 0.9% NaCl	0.929
	0.610	0.888	29.2 %
	1.124
Test Item Quinic acid	45.584
	43.806	52.548	25.9 %
	68.254
Positive Control 20% imidazole	69.103
	72.295	67.658	8.1 %
	61.575

Opacity and Permeability Values of the Third Experiment.

The absorption (570 nm) and opacity values which were measured before and after exposition are given in the following table:

A) Absorption and Opacity Values Negative Control:

Parameter	Negative Control
Absorption before exposition	0.1532	0.1552	0.1546
Absorption after exposition	0.3141	0.1982	0.2154
Opacity before exposition	1.4230	1.4296	1.4276
Opacity after exposition	2.0611	1.5783	1.6421
Opacity Difference	0.6381	0.1488	0.2145

Mean opacity difference of the negative control is 0.3338.

B) Absorption and Opacity Values Test Item and Positive Control:

Parameter	Test Item Quinic acid			Positive Control
Absorption before exposition	0.2060	0.1437	0.1516	0.1500	0.1336	0.1624
Absorption after exposition	1.8269	1.6772	1.6654	1.8089	2.0742	2.1406
Opacity before exposition	1.6069	1.3922	1.4178	1.4125	1.3602	1.4534
Opacity after exposition	67.1274	47.5554	46.2807	64.4021	118.6315	138.2293
Opacity Difference	65.5205	46.1632	44.8630	62.9896	117.2713	136.7758

For the permeability measurement, three replicates for each treatment group were measured. The optical density values at 490 nm are given in the following table:

C) Optical density at 490 nm:

Repl.	Negative Control			Test Item Quinic acid			Positive Control
Meas.	0.0043	0.0041	0.0060	0.0150	0.0068	0.0047	0.1856	0.1992	0.1594
Corr.	0.0215	0.0205	0.0300	0.0750	0.0340	0.0235	0.9280	0.9960	0.7970
Mean	0.0240			--

Note: In order to correct the path length, a factor of 5 was taken into account when calculating the IVIS.

IVIS Values

IVIS was calculated using the values in tables A, B and C and the equation IVIS = (opacity difference – mean opacity difference of the negative controls) + [15 * (corr.OD490 – mean corr. OD490 of the negative controls)]

The calculated IVIS for each replicate and the corresponding means are presented in the following table:

D) IVIS:

Test Group	IVIS	Mean IVIS	Relative Standard Deviation IVIS
Negative Control 0.9% NaCl	0.961
	0.456	0.694	36.5%
	0.665
Test Item Quinic acid	65.952
	45.979	52.151	23 %
	44.522
Positive Control 20% imidazole	76.216
	131.518	118.590	31.7 %
	148.037

Interpretation of results:

Category 2A (irritating to eyes)

Remarks:

Migrated information Criteria used for interpretation of results: other: UN GHS

Conclusions:

According to the study report, quinic acid had effects on the cornea of the bovine eye. The calculated IVIS (in vitro irritancy score) is 52.548 and 52.151. Therefore, quinic acid is moderate irritating to eyes.

Executive summary:

This in vitro study was performed to assess serious eye damage of quinic acid by quantitative measurements of changes in opacity and permeability in a bovine cornea. Three experiments were performed. The first experiment was declared invalid, because the value of the positive control was not within the range of the historical data. The second and the third experiment are reported in this report. The test item quinic acid was brought onto the cornea of a bovine eye which previously had been incubated with cMEM without phenol red at 32 ± 1 °C for one hour and whose opacity had been determined. A 20 % suspension of quinic acid was incubated on the cornea for four hours at 32 ± 1 °C. After removal of the test item, opacity and permeability values were measured. Physiological sodium chloride solution was used as negative control and imidazole (20 % solution in 0.9 % sodium chloride solution) was used as positive control. The negative control showed no irritation effects and no serious eye damage, mean IVIS was 0.888 (second experiment) and 0.694 (third experiment). The positive control induced serious eye damage on the cornea, mean IVIS was 67.658 (second experiment) and 118.590 (third experiment). Under this test conditions, quinic acid showed effects on the cornea of the bovine eye. In the second experiment, the calculated IVIS is 52.548 and in the third experiment, the calculated IVIS is 52.151.

According to OECD Guideline no. 437 (Jul. 2013), a substance with an IVIS > 3 and ≤ 55 induces effects on the cornea, that cannot be classified in a UN GHS Category. According to the Background Review Document Current Status of In Vitro Test Methods for Identifying Mild/Moderate Ocular Irritants: Bovine Corneal Opacity and Permeability Test Method, 2010 a substance with an IVIS of 25.1 - 55 is moderate irritant. Therefore, we assumed that quinic acid is moderate irritating to eyes and need to be classified.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The skin irritating/corrosive properties of quinic acid were calculated by ChemProp. The calculation showed that quinic acid is not irritating or corrosive to skin since no structural alerts are available. Furthermore, the read across substance salicylic acid is also not irritating to skin. In conclusion, we assume that quinic acid is not irritating and does not need to be classified.

To assess serious eye damage of quinic acid an in vitro test (BCOP) was performed. A 20 % suspension of quinic acid was brought onto the cornea of a bovine eye for four hours at 32 ± 1 °C. After removal of quinic acid, opacity and permeability were measured. In this study report, quinic acid showed effects on the cornea of the bovine eye. A mean IVIS of 52.548 and 52.151 was calculated. According to OECD Guideline no. 437 (Jul. 2013), a substance with an IVIS > 3 and ≤ 55 induces effects on the cornea, that cannot be classified in a UN GHS Category. According to the Background Review Document Current Status of In Vitro Test Methods for Identifying Mild/Moderate Ocular Irritants: Bovine Corneal Opacity and Permeability Test Method, 2010 a substance with an IVIS of 25.1 - 55 is moderate irritant. Therefore, we assumed that quinic acid is moderate irritating to eyes and need to be classified.

Justification for selection of eye irritation endpoint:

The study was done according to OECD guideline 437.

Effects on eye irritation: moderately irritating

Justification for classification or non-classification

Quinic acid is not irritating / corrosive to skin but moderate irritating to eyes. Therefore, quinic acid has to be classified in Eye Irrit. 2.