Fatty acids, C14-18 and C16-18-unsatd., zinc salts

Endpoint summary

Description of key information

No acute toxicity studies with Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts are available, thus the acute toxicity will be addressed with existing data on the dissociation products zinc and fatty acids, C14 -18 and C16 -18 unsatd. and with existing data on structurally similar or shorter-chained zinc salts of fatty acids.

 

Signs of acute oral, inhalation and dermal toxicity are not expected for Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts, since no acute oral, dermal or inhalation toxicity was observed in reliable studies with the strucurally similar substance Fatty acids, C16 -18, zinc salts and shorter-chained zinc salts of fatty acids.

Moreover, the moiety zinc has not shown signs of acute oral or inhalation toxicity in experimental testing and the acute dermal toxicity for the moiety zinc can be considered low in view of the poor absorption by this route. For the moiety fatty acids, C14 -18 and C16 -18 unsatd. there were no toxicological findings reported in peer-reviewed publicly available assessment reports, neither by the oral nor by the dermal route.

 

The calculated oral and dermal LD50 for fatty acids, C14 -18 and C16 -18 unsatd., zinc salts is > 2000mg/kg and the LC50 is expected to be higher than 50 mg/L based experimental data available with Fatty acids, C16 -18, zinc salts. Hence the substance is not to be classified according to regulation (EC) 1272/2008 and its subsequent amendments for acute oral, inhalation and dermal toxicity as well as for specific target organ toxicity, single exposure (STOT SE).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study report reliable with restrictions. No original document, a translated German summary without signature and raw data, purity of test item is missing. The study was peer-reviewed and rated reliable within the framework of the EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004". In accordance with Section 1 (0.5), Annex I of Regulation (EC) No 1907/2006 (REACH), this study was considered reliable with restrictions.

Justification for type of information:

Fatty acids, C14-18 and C16-18-unsatd., zinc salts (CAS 67701-12-6) is a zinc salt of a fatty acid containing 14-18 C-atoms. Thus, read-across of data available for zinc salts of shorter-chained (C8, 12) and similar chained (C16-18) fatty acids based on structural similarity, water solubility and zinc content in a conservative, worst-case approach is assumed to adequately describe the toxicological potential of Fatty acids, C14-18 and C16-18-unsatd., zinc salts.

Acute toxicity is addressed with data read-across from relevant zinc soaps (zinc salts of shorter-chained (C8, C12) and similar chained (C16-18) fatty acids) as well as supporting information from slightly soluble/insoluble zinc compounds. Thus, read-across of toxicological data of (i) zinc oxide; (ii) octanoic acid, zinc salt, basic; (iii) zinc dilaurate; and (iv) Fatty acids, C16-18, zinc salts is applied to Fatty acids, C14-18 and C16-18-unsatd., zinc salts.
Regarding acute oral toxicity, read-across data from different reliable studies conducted with (i) zinc oxide; (ii) Fatty acids, C16-18, zinc salts; (iii) Zinc bis [12-hydroxyoctadecanoate] and (iv) octanoic acid, zinc salt, basic are addressed. The LD50 for Fatty acids, C14-18 and C16-18-unsatd., zinc salts was estimated to be greater than 2000 mg/kg bw.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

, see "Rationale for reliability"

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: "Nossan" in Correzzana, Milan
- Age at study initiation: young healhty animals
- Weight at study initiation: mean weight 200 +/- 20 g
- Fasting period before study: Overnight fasting; 3 -4 hours after administration food supply is restored.
- Housing: Cages were made from translucent polycarbonate, Model 1290 (425 x 260 x 150 mm) from the firm Techniplast, Gazzada (Varese); The stable has an overpressure opposed to the atmosphere outside.
- Diet: Food pellets (Firm Nossan, Correzzana)
- Water (ad libitum): Filtered water from the municpal water supply; Filtered with Seitz-Filter
- Quarantine period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature: 20 °C +/- 2°C
- Humidity: 55 % +/- 10 %
- Air changes: minimal 8 times per hour
- Photoperiod (hrs dark / hrs light): 12/12
No further information on the test animals was stated.

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

The test substance is administered in its pure form or in a medium. If needed the test substance will be solved in either a suitable medium or in a suspension. Preferably in an aqueous medium, followed by a solution in vegetable oil, solution in other media and lastly a suspension. For nonaqueous media toxic characteristics should be considered.
The volume administered is either smaller or equal to 10 ml/kg body weight. Exceptionally up to 20 ml/kg body weight can be administered if a aqueous solution is used.
No further information on the oral exposure was stated.

Doses:

5000 mg/kg body weight

No. of animals per sex per dose:

Test group: 5 males / 5 females
Control animals: 5 males / 5 females (administered medium or physiological solution)

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Careful clinical observations were made several times during the first day and afterwards once daily. For every animal the time of death will be noted. Signs of toxication are among others: weight variations, diarrhoea, general condition, every variation from the norm. Rats were weighed prior to administration and if they survived at the end of observation. The weight will be compared to the control animals.
- Necropsy of survivors performed: Yes
All rats that survive the observation period and all rats that died during the observation period will be subject to autopsy.
No further information on the study design was stated.

Statistics:

no data

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: No signs of intoxication was observed.

Gross pathology:

no data

Other findings:

no data

Interpretation of results:

GHS criteria not met

Conclusions:

According to the results of the study, zinc stearate has an LD50 (male and female rats) > 5000 mg/kg bw.
According to the Regulation (EC) No. 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the oral route.

This conclusion is in accordance with the EU RAR.
Conclusions of EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004: "Zinc distearate does not need to be classified on the basis of its acute toxicity according to the EC criteria."

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2012-01-13 to 2012-02-09

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Fatty acids, C14-18 and C16-18-unsatd., zinc salts (CAS 67701-12-6) is a zinc salt of a fatty acid containing 14-18 C-atoms. Thus, read-across of data available for zinc salts of shorter-chained (C8, 12) and similar chained (C16-18) fatty acids based on structural similarity, water solubility and zinc content in a conservative, worst-case approach is assumed to adequately describe the toxicological potential of Fatty acids, C14-18 and C16-18-unsatd., zinc salts.

Acute toxicity is addressed with data read-across from relevant zinc soaps (zinc salts of shorter-chained (C8, C12) and similar chained (C16-18) fatty acids) as well as supporting information from slightly soluble/insoluble zinc compounds. Thus, read-across of toxicological data of (i) zinc oxide; (ii) octanoic acid, zinc salt, basic; (iii) zinc dilaurate; and (iv) Fatty acids, C16-18, zinc salts is applied to Fatty acids, C14-18 and C16-18-unsatd., zinc salts.
Regarding acute oral toxicity, read-across data from different reliable studies conducted with (i) zinc oxide; (ii) Fatty acids, C16-18, zinc salts; (iii) Zinc bis [12-hydroxyoctadecanoate] and (iv) octanoic acid, zinc salt, basic are addressed. The LD50 for Fatty acids, C14-18 and C16-18-unsatd., zinc salts was estimated to be greater than 2000 mg/kg bw.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

adopted December 17, 2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

May 30, 2008

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

signed 2009-11-12

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Crj: CD(SD)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS:
- Source: Charles River Laboratories, Research Models and Services, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: approx. 8 weeks
- Weight at study initiation: 167 - 182g
- Fasting period before study: feeding was discontinued approx. 16 hours before administration; only tap water was then available ad libitum.
- Housing: during the 14-day observation period the animals were kept in groups of 3 animals in MAKROLON cages (type III plus). Granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt, Germany) was used as bedding material for the cages.
- Diet (ad libitum): commercial diet, ssniff R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water (ad libitum): drinking water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS:
- Temperature: 22°C ± 3°C (maximum range)
- Relative humidity: 55% ± 15% (maximum range)
- Air exchanges: 12 to 18- fold air change per hour
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: 0.8% aqueous hydroxypropylmethylcellulose

Details on oral exposure:

VEHICLE
- Methocel; batch no. 11 A 27-N27, Fagron GmbH & Co., 22885 Barsbüttel, Germany

MAXIMUM DOSE VOLUME APPLIED: the administration volume was 10 mL/kg bw.

DOSAGE PREPARATION: the test substance was diluted to the appropriate concentration in the vehicle.

Doses:

2000 mg/ kg bw

No. of animals per sex per dose:

6 female rats

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical observations were made 5, 15, 30 and 60 min, as well as 3, 6 and 24 hours after dosing and then daily for fourteen days. Observations on deaths were made at least once daily to minimize loss of animals during the study. Individual body weights were recorded before administration of the test item and thereafter in weekly intervals up to the end of the study. Changes in weight were calculated and recorded.
- Necropsy of survivors performed: yes
At the end of the experiments, all animals were sacrificed, dissected and inspected macroscopically. All gross pathological changes were recorded. Autopsy and macroscopic inspection of animals which died prematurely would have been carried out as soon as possible after exitus.
Histopathology was not carried out as no macroscopical findings were noted at autopsy.

Statistics:

No statistical analysis could be performed (the method used is not intended to allow a calculation of a precise LD50 value).

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: mortality: 0/6, no signs of toxicity

Mortality:

No death was recorded within the test period.

Clinical signs:

other: Under the present test conditions, a single oral administration of 2000 mg octanoic acid, zinc salt, basic/kg bw to female rats did not reveal any signs of toxicity.

Gross pathology:

No pathological changes were observed at necropsy.

Interpretation of results:

GHS criteria not met

Conclusions:

LD50 (female rats) > 2000 mg/kg bw
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the oral route.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Signed translation of an original well documented report; purity of test item is missing

Justification for type of information:

Fatty acids, C14-18 and C16-18-unsatd., zinc salts (CAS 67701-12-6) is a zinc salt of a fatty acid containing 14-18 C-atoms. Thus, read-across of data available for zinc salts of shorter-chained (C8, 12) and similar chained (C16-18) fatty acids based on structural similarity, water solubility and zinc content in a conservative, worst-case approach is assumed to adequately describe the toxicological potential of Fatty acids, C14-18 and C16-18-unsatd., zinc salts.

Acute toxicity is addressed with data read-across from relevant zinc soaps (zinc salts of shorter-chained (C8, C12) and similar chained (C16-18) fatty acids) as well as supporting information from slightly soluble/insoluble zinc compounds. Thus, read-across of toxicological data of (i) zinc oxide; (ii) octanoic acid, zinc salt, basic; (iii) zinc dilaurate; and (iv) Fatty acids, C16-18, zinc salts is applied to Fatty acids, C14-18 and C16-18-unsatd., zinc salts.
Regarding acute oral toxicity, read-across data from different reliable studies conducted with (i) zinc oxide; (ii) Fatty acids, C16-18, zinc salts; (iii) Zinc bis [12-hydroxyoctadecanoate] and (iv) octanoic acid, zinc salt, basic are addressed. The LD50 for Fatty acids, C14-18 and C16-18-unsatd., zinc salts was estimated to be greater than 2000 mg/kg bw.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

, adopted 1996-03-22

Deviations:

yes

Remarks:

, see "rational for reliability"

GLP compliance:

not specified

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann GmbH, Gartenstraße 27, D- 33178 Borchen, Germany
- Weight at study initiation:mean weight males: 217.7 g; mean weight females: 208 g
- Fasting period before study: Food was withheld overnight before the day of administration. Food was withheld for further 4 hours after administration.
- Housing: The rats housed individually in Makrolon cages (area 800 cm^2, height 19 cm) with bedding
- Diet: Haltungsdiät "ALMA 0813 A H 1003", 8 g twice daily (Manufacturer: Meika Kraftfutter)
- Water (ad libitum): Community tap water of the city of Karlsruhe; daily changing of watering bottles
- Acclimation period: After randomization the animals were acclimated to the test conditions for 5 days prior to administration.
- Veterinary preliminary examination: Animals without morbid signs; females are nulliparous and non-pregnant

ENVIRONMENTAL CONDITIONS
- Temperature: 19 - 24 °C
- Relative humidity: 30 -70 %
- Photoperiod (hrs dark / hrs light): 12/12
No further information on the test animals was stated.

Route of administration:

oral: gavage

Vehicle:

other: sesame oil

Details on oral exposure:

Calculated amounts of "Zinc 12-hydroxystearate" according to the dosage of 2000 mg/kg bw were administered with the aid of a stomach tube to rats.

VEHICLE: Sesame oil
- Batch no. : 36834458 (Carl Roth GmbH & Co.)

DOSAGE PREPARATION: Weighed amounts of "Zinc 12-hydroxystearate" were dissolved in 2 ml sesame oil immediatly before administration.

No further information on the oral exposure was stated.

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

3 males / 3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Necropsy of survivors performed: Yes, at the end of the observation period. The anaesthesia and euthanasia of all surviving animals were performed in an atmosphere of approx. 80 % CO2 at the end of the observation period.
- Examinations performed: Mortality, body weight (daily, except day 5 and day 12), behaviour, and toxicological symptoms (daily, except day 5 and day 12)(The criteria of judgement were changes of the fur, of the skin, the nose and the mouth and their mucus membranes eyes, anal region, faeces, urine (macroscopically), breathing, circulatory, and nervous system)
No further information on the study design was stated.

Statistics:

not stated

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

After oral application of 2000 mg "Zinc 12-hydroxystearate" per kg body weight none of the 6 tested animals died during the observation period of 15 days.

Clinical signs:

other: No toxicological symptoms were observed.

Gross pathology:

No pathological findings were noted.

Other findings:

no data

Interpretation of results:

GHS criteria not met

Conclusions:

"Zinc 12-hydroxystearate" has a LD50 (male and female rats) > 2000 mg/kg bw.
According to the Regulation (EC) No. 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the oral route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

No guideline study, methodological deficiencies (intratracheal instillation), purity of test item, number of test animals per group at necropsy and raw data are missing The study was peer-reviewed and rated reliable within the framework of the EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004". In accordance with Section 1 (0.5), Annex I of Regulation (EC) No 1907/2006 (REACH), this study was considered reliable with restrictions.

Justification for type of information:

Fatty acids, C14-18 and C16-18-unsatd., zinc salts (CAS 67701-12-6) is a zinc salt of a fatty acid containing 14-18 C-atoms. Thus, read-across of data available for zinc salts of shorter-chained (C8, 12) and similar chained (C16-18) fatty acids based on structural similarity, water solubility and zinc content in a conservative, worst-case approach is assumed to adequately describe the toxicological potential of Fatty acids, C14-18 and C16-18-unsatd., zinc salts.

Acute toxicity is addressed with substance-specific information and data read-across from relevant zinc soaps (zinc salts of shorter-chained (C8, C12) and similar chained (C16-18) fatty acids) as well as supporting information from slightly soluble/insoluble zinc compounds. Thus, read-across of toxicological data of (i) zinc oxide; (ii) octanoic acid, zinc salt, basic; (iii) zinc dilaurate; and (iv) Fatty acids, C16-18, zinc salts is applied to Fatty acids, C14-18 and C16-18-unsatd., zinc salts.
Regarding acute inhalative toxicity, different reliable studies conducted with different zinc compounds are read-across to address this endpoint, including (i) zinc oxide; (ii) Fatty acids, C16-C18, zinc salts; and (iii) zinc dilaurate. Based on the lack of an acute inhalative toxicity potential of zinc salts of similar chained (C16-18) and shorter-chained (C12) fatty acids, a similar lack of acute inhalative toxicity is considered for Fatty acids, C14-18 and C16-18-unsatd., zinc salts. The LC50 for Fatty acids, C16-18, zinc salts was estimated to be greater than 50 mg/L and is thus magnitudes higher than the value reported for metal fume fever. A similar conclusion can be drawn for the structural analogue zinc dilaurate for which a LC50 of greater than 5.08 mg/L (actual concentration) was determined. In sum, metal fume fever is not relevant for zinc salts of fatty acids at all.

Principles of method if other than guideline:

Two experiments with zinc stearate powder were conducted. 50 mg or approximately 100 mg zinc stearate in vehicle were administrated by intratracheal instillation to rats. Mortality and clinical signs were reported. Also, macroscopic changes and microscopic changes of the lungs were reported.

GLP compliance:

not specified

Test type:

other: non standard test with intratracheal application

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Rats were used.
No further information on the test animals was stated.

Route of administration:

other: intratracheal

Type of inhalation exposure:

other: intratracheal instillation

Vehicle:

other: water or skimmed milk and saline

Details on inhalation exposure:

Experiment 1:
Zinc stearate powder was suspended in tap water and autoclaved. Approximately 100 mg of the zinc stearate powder suspended in 1 ml water was injected into the lungs through the larynx of rats anaesthetised with ether.

Examination of the suspension showed that the stearate was difficult to keep suspended in water, and the fluid was notably acid. All further experiments were therefore done with zinc stearate suspended and autoclaved in a mixture of skimmed milk and saline, and the dose was halved.

Experiment 2:
Rats were given approximately 50 mg of zinc stearate suspended in 1 ml and injected into the lungs through the larynx under ether anaesthesia.
No further information on the inhalation exposure was stated.

Analytical verification of test atmosphere concentrations:

no

Concentrations:

Experiment 1: approx. 100 mg of zinc stearate
Experiment 2: 50 mg of zinc stearate

No. of animals per sex per dose:

Experiment 1: 6 rats
Experiment 2: 50 rats

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: up to 259 days
- Examinations performed: mortality and clinical signs were reported, macroscopic and microscopic changes were reported.
No further information on the study design was stated.

Statistics:

not stated

Sex:

not specified

Dose descriptor:

other: Intratracheal instillation: No LC50 was determined.

Effect level:

other: not applicable

Remarks on result:

other: The route of exposure is not relevant for classification and labelling.

Mortality:

Experiment 1:
All the animals died within 10 minutes.
Experiment 2:
Twenty animals died within less than 24 hours, most of them within an hour.

Clinical signs:

other: Animals that survived more than 24 hours appeared quite normal until the time they were killed.

Body weight:

not stated

Gross pathology:

The animals that were examined showed severe oedema and congestion of the lungs and sometimes small haemorrhages. Animals killed 14 days or later after the injection showed no abnormalities in the lungs. Rats were killed up to 259 days after the injection and in none was any fibrosis detected in the lungs.

Other findings:

- Histopathology: Animals killed seven days after injection showed small cellular islands of histocytes scattered through the lungs. None of the injected dust was visible in ordinary paraffin sections, but it is possible that some was still present, since it was later found that the stearate is moderately soluble in fat solvents.

Interpretation of results:

other: No LC50 was determined. The route of exposure is not relevant for classification and labelling.

Conclusions:

It appears that zinc stearate in suspension in tap water or in a mixture of skimmed milk and physiological saline is acutely irritant, and dose of 50 mg kills nearly half the animals after injection through the larynx into the lungs.
No fibrosis was seen in the lungs of the rats after a single injection through the larynx.

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study was peer-reviewed and rated reliable within the framework of the EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004. In accordance with Section 1 (0.5), Annex I of Regulation (EC) No 1907/2006 (REACH), this study was considered reliable with restrictions.

Justification for type of information:

Fatty acids, C14-18 and C16-18-unsatd., zinc salts (CAS 67701-12-6) is a zinc salt of a fatty acid containing 14-18 C-atoms. Thus, read-across of data available for zinc salts of shorter-chained (C8, 12) and similar chained (C16-18) fatty acids based on structural similarity, water solubility and zinc content in a conservative, worst-case approach is assumed to adequately describe the toxicological potential of Fatty acids, C14-18 and C16-18-unsatd., zinc salts.

Acute toxicity is addressed with substance-specific information and data read-across from relevant zinc soaps (zinc salts of shorter-chained (C8, C12) and similar chained (C16-18) fatty acids) as well as supporting information from slightly soluble/insoluble zinc compounds. Thus, read-across of toxicological data of (i) zinc oxide; (ii) octanoic acid, zinc salt, basic; (iii) zinc dilaurate; and (iv) Fatty acids, C16-18, zinc salts is applied to Fatty acids, C14-18 and C16-18-unsatd., zinc salts.
Regarding acute inhalative toxicity, different reliable studies conducted with different zinc compounds are read-across to address this endpoint, including (i) zinc oxide; (ii) Fatty acids, C16-C18, zinc salts; and (iii) zinc dilaurate. Based on the lack of an acute inhalative toxicity potential of zinc salts of similar chained (C16-18) and shorter-chained (C12) fatty acids, a similar lack of acute inhalative toxicity is considered for Fatty acids, C14-18 and C16-18-unsatd., zinc salts. The LC50 for Fatty acids, C16-18, zinc salts was estimated to be greater than 50 mg/L and is thus magnitudes higher than the value reported for metal fume fever. A similar conclusion can be drawn for the structural analogue zinc dilaurate for which a LC50 of greater than 5.08 mg/L (actual concentration) was determined. In sum, metal fume fever is not relevant for zinc salts of fatty acids at all.

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

A single 1-hr exposure of rats to 200 mg/l zinc stearate. The rats were observed for two weeks.

GLP compliance:

no

Test type:

other: not stated

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Albino rats were used.
No further information on the test animals was stated.

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

not specified

Details on inhalation exposure:

Rats were exposed to zinc stearate for one hour.

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

1 h

Concentrations:

200 mg/l zinc stearate (Chamber concentration)

No. of animals per sex per dose:

10 rats

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Examinations performed: moratlity was reported.
No further information on the study design was stated.

Statistics:

not stated

Sex:

not specified

Dose descriptor:

LC50

Effect level:

> 200 other: mg/l

Based on:

test mat.

Exp. duration:

1 h

Sex:

not specified

Dose descriptor:

LC50

Effect level:

> 50 other: mg/l

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: This LC50 was recalculated from the LC50 (1 hr) by using Haber's law.

Mortality:

1/10 rats died during the 2-week observation period.

Clinical signs:

other: All animals appeared depressed for the first six hours. From 24 hrs. until day 14, they appeared normal.

Body weight:

not stated

Gross pathology:

not stated

Other findings:

not stated

Interpretation of results:

GHS criteria not met

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LC50 (4 h) > 50 mg/l (recalculated from LC50 (1h) by using Haber's law)
According to the Regulation (EC) No. 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the inhalation route.

This conclusion is in accordance with the conclusion of the EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004:
"Zinc distearate does not need to be classified on the basis of its acute toxicity according to the EC criteria."

Reference 3

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

No guideline study, but well documented; with methodological deficiencies (intratracheal instillation), the study was not intended to investigate acute inhalational toxicity The study was peer-reviewed and rated reliable within the framework of the EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004". In accordance with Section 1 (0.5), Annex I of Regulation (EC) No 1907/2006 (REACH), this study was considered reliable with restrictions.

Justification for type of information:

Fatty acids, C14-18 and C16-18-unsatd., zinc salts (CAS 67701-12-6) is a zinc salt of a fatty acid containing 14-18 C-atoms. Thus, read-across of data available for zinc salts of shorter-chained (C8, 12) and similar chained (C16-18) fatty acids based on structural similarity, water solubility and zinc content in a conservative, worst-case approach is assumed to adequately describe the toxicological potential of Fatty acids, C14-18 and C16-18-unsatd., zinc salts.

Acute toxicity is addressed with substance-specific information and data read-across from relevant zinc soaps (zinc salts of shorter-chained (C8, C12) and similar chained (C16-18) fatty acids) as well as supporting information from slightly soluble/insoluble zinc compounds. Thus, read-across of toxicological data of (i) zinc oxide; (ii) octanoic acid, zinc salt, basic; (iii) zinc dilaurate; and (iv) Fatty acids, C16-18, zinc salts is applied to Fatty acids, C14-18 and C16-18-unsatd., zinc salts.
Regarding acute inhalative toxicity, different reliable studies conducted with different zinc compounds are read-across to address this endpoint, including (i) zinc oxide; (ii) Fatty acids, C16-C18, zinc salts; and (iii) zinc dilaurate. Based on the lack of an acute inhalative toxicity potential of zinc salts of similar chained (C16-18) and shorter-chained (C12) fatty acids, a similar lack of acute inhalative toxicity is considered for Fatty acids, C14-18 and C16-18-unsatd., zinc salts. The LC50 for Fatty acids, C16-18, zinc salts was estimated to be greater than 50 mg/L and is thus magnitudes higher than the value reported for metal fume fever. A similar conclusion can be drawn for the structural analogue zinc dilaurate for which a LC50 of greater than 5.08 mg/L (actual concentration) was determined. In sum, metal fume fever is not relevant for zinc salts of fatty acids at all.

Principles of method if other than guideline:

Pathological changes in lung tissue of Sprague Dawley rats after single intratracheal administration of 1 mg, 5 mg or 10 mg of zinc stearate were examined to ascertain whether lung fibrosis is caused by exposure to this dust (Method of King et al. (1953)).

GLP compliance:

not specified

Test type:

other: non standard test with intratracheal application

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 4-month old
- Weight at study initiation: 250 - 300 g
- Housing: the animals were housed in an air-conditioned room.
- Diet (ad libitum): pellets
- Water (ad libitum): water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +/- 1 °C
No further information on the test animals was stated.

Route of administration:

other: intratracheal

Type of inhalation exposure:

other: intratracheal instillation

Vehicle:

other: 10 % alcohol solution

Details on inhalation exposure:

The zinc stearate was ground in a ball mill, with a final particle size range of 1 - 5 µm in diameter. The grinding time for zinc stearate was less than six hours in order not to damage the physical properties and the structure of the particulates. The samples were suspended in 10 % alcohol solution, because zinc stearate cannot be suspended well with physiological saline or distilled water.
One ml of the suspended sample mixed with 2000 IU of penicillin G potassium were administered once intratrachealy according to the method of King et al. (King, E.J., Mohanty, G.P. and Harrison, C.V. (1953). The action of flint of variable size injected at constant weight and constant surface into the lungs of rats, Brit. J. Industr. Med., 10, 76.).
Because of the physical properties of zinc stearate, namely water-insolubility, low gravity and cohesiveness in solution, it was difficult to administer zinc stearate powder into the rats lung at concentrations over 10 mg/rat.
No further information on the inhalation exposure was stated.

Analytical verification of test atmosphere concentrations:

no

Concentrations:

The following doses were given:
Group I: 1 mg of zinc stearate/rat (2.8 mg/kg bw zinc stearate)
Group II: 5 mg of zinc stearate/rat (14 mg/kg bw zinc stearate)
Group III: 10 mg of zinc stearate/rat (28 mg/kg bw zinc stearate)
Group IV: only 1 ml of 10 % alcohol solution
Group V: no treatment

No. of animals per sex per dose:

six to 23 rats

Control animals:

yes

Details on study design:

- Necropsy of survivors performed: Yes
The rats were sacrificed at the end of nine months after the injection. Six animals of group III and three of group V were killed soon after the injection. Five animals of group III were killed one week after the injection.
The lungs were removed and fixed with 10 % buffered formalin. The left lung was used for histological examination, and the right one for chemical analysis. The mediastinal lymph nodes and the liver were also examined.
After the usual dehydration and embedding, a slice of the left lung was stained with hematoxylineosin, silver and Van Gieson's method.
Thirty mg of dried tissue of the right lung, after being hydrolyzed at 140 °C by 6N HCl for 10 hours, was assayed for hydroxyproline (HOP) according to the method of Stacy et al. (Stacy, B.D. and King, E.J. (1957). Die Bestimmung von Kollagen im fibrotischen Gewebe, Die Staublungenerkrankungen, Bd. 3, p. 189, Münster/Westf, berlin.). and Kivirikko et al. (Kivirikko, K. I., Laitinen, O. and Prokopp, D.J. (1967). Modifications of a specific assay for hydroxyproline in urine, Ann. Biochem., 19, 249.)
The residue of 100 - 200 mg of dried tissue was wet-ashed by conc-HNO3, H2SO4 and HClO4 in turn with heating, and Zn was determined by atomic absorption spectrometry (Pharmaceutical Society of japan (1980). Standard methods of analysis for hygienic chemist - with commentary-, Kanehara Schuppan, Tokyo.) In this method, the percentage of recovery was 97.2 +/- 30.0 (N = )).
No further information on the study design was stated.

Statistics:

The concentrations (µg/mg of dried tissue) of HOP and Zn were converted to total lung content by the following formula:
Y (HOP or Zn content in total lung) = Concentration in dried tissue X Dried weight of right lung (g) X wet weight of the total lung (g)/wet weight of the right lung (g)

Sex:

male

Dose descriptor:

other: Intratracheal instillation; No LC50 was determined

Effect level:

other: not applicable

Remarks on result:

other: One death was reported in the 10 mg zinc stearate/rat group. Route of exposure is not relevant for classification and labelling.

Mortality:

One death was reported in the 10 mg zinc stearate/rat group.

Clinical signs:

other: not stated

Body weight:

not stated

Gross pathology:

Nine months after the injection there was no nodular formation through the surface of the lungs of groups I, II and III administered 1 - 10 mg of zinc stearate. Pneumonia or a reddening change was observed in the lungs of the zinc stearate groups. Swelling of the mediastinal lymph nodes was seen in the zinc stearate groups.
The lungs of the group VI administered alcohol and group V as controls were almost normal.

Other findings:

- Histopathology: No evident dust foci or lymphocytic granulomatous lesions were found in the lungs of the zinc stearate groups. Thickening of intra-alveolar septa, moderately proliferating reticulin fibers and /or overdistention of alveoli were generally found in the lungs of the zinc stearate groups. In the mediastinal lymph nodes, no change was found in the zinc stearate groups.
One week after the injection, the lungs of group III (10 mg of zinc stearate/rat) were congested and extensive interstitial cellular infiltration was found as a result of the injection of the dust.

- Zinc content of the lung tissue: Higher concentrations per milligram of dried tissue and total lung content were observed in the 1- to 10-mg zinc stearate groups than in the other control groups. The difference between the amounts in the control group and those in the zinc stearate group was assumed to be the amount of deposited zinc resulting from zinc stearate administration. Therefore, the excess of 30 - 50 µg of Zn in the 1- to 10-mg zinc stearate groups nine months after the injection was thought to have been retained from the inital dose. The retention of Zn in group III had a tendency to decrease with time, from 641 µg after one week and 53 µg, 8.3 % of the initial concentration, after nine months.
There was a positive but not statistically significant coefficient of correlation (r = 0.366) between HOP and Zn content in the zinc stearate groups. No relationship was found among the zinc stearate groups between the intensity of histological change and the Zn content of the lung.

Interpretation of results:

other: No LC50 was determined. The route of exposure is not relevant for classification and labelling.

Conclusions:

One death was reported in the 10 mg zinc stearate/rat group.

Reference 4

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2012-04-24 to 2012-05-22

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Fatty acids, C14-18 and C16-18-unsatd., zinc salts (CAS 67701-12-6) is a zinc salt of a fatty acid containing 14-18 C-atoms. Thus, read-across of data available for zinc salts of shorter-chained (C8, 12) and similar chained (C16-18) fatty acids based on structural similarity, water solubility and zinc content in a conservative, worst-case approach is assumed to adequately describe the toxicological potential of Fatty acids, C14-18 and C16-18-unsatd., zinc salts.

Acute toxicity is addressed with substance-specific information and data read-across from relevant zinc soaps (zinc salts of shorter-chained (C8, C12) and similar chained (C16-18) fatty acids) as well as supporting information from slightly soluble/insoluble zinc compounds. Thus, read-across of toxicological data of (i) zinc oxide; (ii) octanoic acid, zinc salt, basic; (iii) zinc dilaurate; and (iv) Fatty acids, C16-18, zinc salts is applied to Fatty acids, C14-18 and C16-18-unsatd., zinc salts.
Regarding acute inhalative toxicity, different reliable studies conducted with different zinc compounds are read-across to address this endpoint, including (i) zinc oxide; (ii) Fatty acids, C16-C18, zinc salts; and (iii) zinc dilaurate. Based on the lack of an acute inhalative toxicity potential of zinc salts of similar chained (C16-18) and shorter-chained (C12) fatty acids, a similar lack of acute inhalative toxicity is considered for Fatty acids, C14-18 and C16-18-unsatd., zinc salts. The LC50 for Fatty acids, C16-18, zinc salts was estimated to be greater than 50 mg/L and is thus magnitudes higher than the value reported for metal fume fever. A similar conclusion can be drawn for the structural analogue zinc dilaurate for which a LC50 of greater than 5.08 mg/L (actual concentration) was determined. In sum, metal fume fever is not relevant for zinc salts of fatty acids at all.

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Version / remarks:

adopted September 7, 2009

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: OECD Series on Testing and Assessment No. 125, Document No. ENV/JM/MONO (2010) 16, June 01, 2010.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

signed 2009-11-12

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: males: 7 weeks; females: 9 weeks
- Weight at study initiation: males: 242 - 256 g; females: 217 - 240 g
- Fasting period before study: feeding was discontinued approx. 16 hours before exposure; only tap water was then available ad libitum.
- Housing: granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt, Germany) was used as bedding material for the cages. During the 14-day observation period, the animals are kept by sex in groups of 2 - 3 animals in MAKROLON cages (type III plus).
- Diet (e.g. ad libitum): commercial diet, ssniff® R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water (ad libitum): drinking water
- Acclimation period: at least 5 adaptation days

The animals were randomised before use. They were acclimatised to the test apparatus for approx. 1 hour on 2 days prior to testing. The restraining tubes did not impose undue physical, thermal or immobilization stress on the animals.

ENVIRONMENTAL CONDITIONS
- Temperature: 22°C ± 3°C (maximum range)
- Relative humidity: 55% ± 15% (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

clean air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: the study was carried out using a dynamic inhalation apparatus (RHEMA-LABORTECHNIK, 65719 Hofheim/Taunus, Germany) (air changes/h (≥ 12 times)) with a nose-only exposure of the animals according to KIMMERLE & TEPPER. The apparatus consists of a cylindrical exposure chamber (volume 40 L) which holds 10 animals in pyrex tubes at the edge of the chamber in a radial position.

- System of generating particulates/aerosols: the dust of the test material was generated with a rotating brush dust generator (RBG 1000, PALAS GmbH Partikel und Lasermesstechnik,76229 Karlsruhe, Germany).
The generator was fed with compressed air (5.0 bar) from a compressor (ALUP Kompressorenfabrik, 73257 Köngen, Germany) (air was taken from the surrounding atmosphere of the laboratory room and filtered using at in-line disposable gas-filter).
At the bottom of the exposure chamber, the air was sucked off at a lower flow rate than it was created by the dust generator in order to produce a homogenous distribution and a positive pressure in the exposure chamber (inflow 900 L/h, outflow 800 L/h).
A manometer and an air-flow meter (ROTA Yokogawa GmbH & Co. KG, 79664 Wehr/Baden, Germany) were used to control the constant supply of compressed air and the exhaust, respectively. Flow rates were checked hourly and the corrected if necessary.
The exhaust air was drawn through gas wash-bottles.

- Method of particle size determination: an analysis of the particle size distribution was carried out twice during the exposure period using a cascade impactor according to MAY (MAY, K. R. Aerosol impaction jets, J. Aerosol Sci. 6, 403 (1975), RESEARCH ENGINEERS Ltd., London N1 5RD, UK.).
The dust from the exposure chamber was drawn through the cascade impactor for 5 minutes at a constant flow rate of 5 L/min. The slides were removed from the impactor and weighed on an analytical balance (SARTORIUS, type 1601 004, precision 0.1 mg). Deltas of slides’ weight were determined.
The mass median aerodynamic diameter (MMAD) was estimated by means of non-linear regression analysis. The 32 μm particle size range and the filter (particle size range < 0.5 μm) were not included in the determination of the MMAD in order not to give undue weight to these values.
The Geometric Standard Deviation (GSD) of the MMAD was calculated from the quotient of the 84.1%- and the 50%-mass fractions, both obtained from the above mentioned non-linear regression analysis.
In addition, a sample of approx. 10 g test material was taken from the exposure chamber to determine the median physical particle size with a CILAS 715 by My-Tec, 91325 Adelsdorf, Germany. This determination was non-GLP.

- Temperature, humidity, pressure in air chamber, oxygen content and carbon dioxide concentration: the oxygen content in the inhalation chamber was 21%. It was determined at the beginning and at the end of the exposure with a DRÄGER Oxygen-analysis test set (DRÄGER Tube Oxygen 67 28 081). Carbon dioxide concentration did not exceed 1%.
Temperature (22.5°C ± 0.4°C (main study) or 20.5°C ± 0.1°C (satellite group)) and humidity (61.9% ± 0.9% (main study) or 66.8% ± 0.1% (satellite group)) were measured once every hour with a climate control monitor (testo 175-HZ data logger).

The whole exposure system was mounted in an inhalation facility to protect the laboratory staff from possible hazards.

Exposition started by locating the animals into the exposure chamber after equilibration of the chamber concentration for at least 15 minutes (t95 approximately 8 minutes).

Before initiating the study with the animals, a pre-test was carried out with the exposure system in order to verify that under the experimental settings chosen, the limit concentration of 5 mg/L air could be achieved by gravimetric analysis.

The tests with the main study animals and the recovery animals were conducted in the same inhalation chamber but on different days. Between the exposure times the chamber was cleaned carefully.

TEST ATMOSPHERE
- Brief description of analytical method used: the actual dust concentration in the inhalation chamber was measured gravimetrically with an air sample filter (Minisart SM 17598 0.45 μm) and pump (Vacuubrand, MZ 2C (Membrane Pump,Vacuubrand GmbH + Co. KG, 97877 Wertheim/Main, Germany)) controlled by a rotameter. Dust samples were taken once every hour during the exposure. For that purpose, a probe was placed close to the animals' noses and air was drawn through the air sample filter at a constant flow of air of 5 L/min for 1 minute. The filters were weighed before and after sampling (accuracy 0.1 mg).
Individual chamber concentration samples did not deviate from the mean chamber concentration by more than 1%.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.):
Main study: 1.953 µm (GSD: 2.94)
Satellite group: 2.037 µm (GSD: 3.06)
No smaller GSDs could be obtained with the test item supplied.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

see above ("Details on inhalation exposure")

Duration of exposure:

4 h

Concentrations:

Main study (limit test):
- actual concentration: 5.08 ± 0.03 mg/L air
- nominal concentration: 6.67 mg/L air
Satellite group:
- actual concentration: 5.05 ± 0.04 mg/L air
- nominal concentration: 6.67 mg/L air

No. of animals per sex per dose:

Main study (limit test):
3 males / 3 females
Satellite group:
3 males / 3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 24 hours (satellite group) and 14 days (main study)

- Frequency of observations and weighing: during and following exposure, observations were made and recorded systematically; individual records were maintained for each animal. Careful clinical examinations were made at least once daily until all symptoms subsided, thereafter each working day. Observations on mortality were made at least once daily (in the morning starting on test day 2) to minimize loss of animals to the study, e.g. necropsy or refrigeration of those animals found dead and isolation or sacrifice of weak or moribund animals.
Cageside observations included, but were not limited to: changes in the skin and fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, as well as somatomotor activity and behaviour pattern.
Particular attention was directed to observation of tremor, convulsions, salivation, diarrhoea, lethargy, sleep and coma. The animals were also observed for possible indications of respiratory irritation such as dyspnoea, rhinitis etc.
Individual weights of animals were determined once during the acclimatisation period, before and after the exposure on test day 1, on test days 3, 8 and 15. Changes in weight were calculated and recorded when survival exceeded one day. At the end of the test, all animals were weighed and sacrificed.

- Necropsy of survivors performed: yes
Necropsy of all main study and satellite animals (3 + 3 males and 3+3 females) was carried out and all gross pathological changes were recorded:
- Satellite animals: necropsy at 24 hours after cessation of exposure, as this is likely to be the time at which any signs of respiratory irritation would have manifested;
- Main study animals: necropsy at the end of the 14-day observation period, also to assess whether any respiratory tract irritation persists or abates.

- Histopathology:
All main study and satellite animals were subjected to the same level of histopathological examination upon necropsy at the end of the respective observation period. During histopathology, attention was paid to alterations that might be indicative of respiratory irritation, such as hyperaemia, oedema, minimal inflammation, thickened mucous layer.
The following organs of all animals were fixed in 10% (nose, i.e. head without brain, eyes and lower jaw) or 7% (other organs) buffered formalin for histopathological examination:
- Nasal cavity, nasopharynx and paranasal sinus:
The tip and level 1 of the nose were taken from a cut just anterior to the incisor teeth. With tip removed, level 2 was taken approximately 2 mm posterior to free tip of the incisor teeth. Level 3 was cut through the incisive papilla. Level 4 was cut through the middle of the second palatal ridge, which is located just anterior to the molar teeth. Level 5 was cut through the middle of the molar teeth. All sections were embedded face down to yield a section from the anterior section, except the nose tip was embedded posterior surface down.
- Larynx
- Trachea
- Lungs (five levels)
Paraffin sections were prepared of all above mentioned organs and stained with haematoxylin-eosin.

Statistics:

Since no animal died prematurely, the calculation of an LC50 was not required.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.08 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: mortality: 0/10; temporary slight clinical signs attributed to inert dust exposure, no clinical signs of substance specific irritation, macroscopic findings (marbled lungs associated with small black foci) without histopathological correlation

Mortality:

No animal died prematurely.

Clinical signs:

other: Under the present test conditions, a 4-hour inhalation exposure to zinc dilaurate at a concentration of 5.08 mg/L air revealed slightly reduced motility, slight ataxia and slightly reduced muscle tone on test day 1 immediately after the end of exposure un

Body weight:

No influence on body weight gain was observed.

Gross pathology:

Macroscopic changes in the nasal cavity and lungs. Marbled lungs were observed in all animals of the main study (14-day sacrifice) and in all satellite animals (24-hour sacrifice). Small black foci were observed in 2 of 3 male and 1 of 3 female satellite animals.

Other findings:

- HISTOPATHOLOGY
Microscopic changes in the nasal cavity and lungs:
1. Test item-related histopathological changes: the histomorphological examination of the trachea, larynx, lungs and the nose of male and female rats after inhalation of zinc dilaurate did not reveal any morphological changes, considered to be related to the inhalation of the test item, in the main study animals and in the satellite animals.
2. Non-test item-related histopathological changes:
Male and female animals of the main study and the satellite group:
- Observations made for the nose (five levels): the nasal cavity of level 1 showed a normal squamous epithelium and a normal respiratory epithelium with goblet cells. A mild congestion was noted in all animals.
The level 2 and 3 showed a similar normal morphological finding with congestion compared to level 1.
The normal respiratory epithelium partially with cilia contained three major cell types, the basal cells above the basement membrane, the ciliated epithelial cells and the secretory goblet cells.
A normal olfactory epithelium with 5 to 7 nuclear layers, normal basal cells, olfactory sensory cells and sustentacular cells was noted in the male and female animals.
The level 4 and 5 of the nose showed focally an olfactory epithelium with mild vacuolization and a loss of epithelial cells (artefacts) on the nasal surface in the dorsal region of the nasal cavity. A normal olfactory epithelium was noted in the other region of the nasal cavity.
Minimal to mild lympho-histiocytic infiltrations or follicular lymphoid hyperplasia in the subepithelial region of the respiratory epithelium (naso-pharynx region) was observed as a normal finding.
- Observations made for the lungs (five levels): the most localisations of the lungs in the main study (14-day sacrifice) and in the satellite group (24-hour sacrifice) were morphologically normal without pathological findings.
Some localisations showed minimal to mild alveolar pulmonary emphysema and mild congestion. In some animals a focal haemorrhage was observed.
The larynx showed in some rats a minimal subepithelial lympho-histiocytic infiltration.
In the trachea some animals showed a focal mild lympho-histiocytic infiltration or a tracheal gland dilatation.
Only in 7 from 30 lung localisations a focal minimal inflammatory oedema with few lymphocytes and neutrophilic granulocytes and a mild congestion was observed.

Interpretation of results:

GHS criteria not met

Conclusions:

LC50 (rats; 4 hours) > 5.08 mg/L air (actual concentration)
Based on the results of the histopathological and macroscopic investigations, zinc dilaurate does not require classification for respiratory irritation.
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is not classified as acute toxic via the inhalation route or as specific target organ toxicity - single exposure.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

50 000 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study was peer-reviewed and rated reliable within the framework of the EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004". In accordance with Section 1 (0.5), Annex I of Regulation (EC) No 1907/2006 (REACH), this study was considered reliable with restrictions.

Justification for type of information:

Fatty acids, C14-18 and C16-18-unsatd., zinc salts (CAS 67701-12-6) is a zinc salt of a fatty acid containing 14-18 C-atoms. Thus, read-across of data available for zinc salts of shorter-chained (C8, 12) and similar chained (C16-18) fatty acids based on structural similarity, water solubility and zinc content in a conservative, worst-case approach is assumed to adequately describe the toxicological potential of Fatty acids, C14-18 and C16-18-unsatd., zinc salts.

Acute toxicity is addressed with substance-specific information and data read-across from relevant zinc soaps (zinc salts of shorter-chained (C8, C12) and similar chained (C16-18) fatty acids) as well as supporting information from slightly soluble/insoluble zinc compounds. Thus, read-across of toxicological data of (i) zinc oxide; (ii) octanoic acid, zinc salt, basic; (iii) zinc dilaurate; and (iv) Fatty acids, C16-18, zinc salts is applied to Fatty acids, C14-18 and C16-18-unsatd., zinc salts.

Regarding acute dermal toxicity, a key study with the structurally similar substance Fatty acids, C16-18, zinc salts is available showing no acute dermal toxicity and an LD50 >2000 mg/kg bw. Thus, is is assumed that Fatty acids, C14-18 and C16-18 unsatd., zinc salt does not show dermal toxicity either.

Reason / purpose for cross-reference:

reference to same study

Principles of method if other than guideline:

10 % zinc stearate in eyeshadow form was applied dermally to rabbits.

GLP compliance:

not specified

Test type:

other: in vivo

Species:

rabbit

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Rabbits were used.
No further information on the test animals was stated.

Type of coverage:

not specified

Vehicle:

not specified

Details on dermal exposure:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 % zinc stearate in eyeshadow form was applied dermally to rabbits.
No further information on dermal exposure was stated.

Duration of exposure:

Not stated

Doses:

Not stated

No. of animals per sex per dose:

10 rabbits

Control animals:

not specified

Details on study design:

No information on the study design was stated.

Statistics:

Not stated.

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No mortality was reported.

Clinical signs:

other: Not stated

Gross pathology:

Not stated

Other findings:

Not stated

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 for 10 % zinc stearate in eye shadow form (formulation) is > 2000 mg/kg bw for rabbits.
According to the Regulation (EC) No 1272/2008 and subsequent regulations, the test item is not classified.

This conclusion is in accordance with the EU RAR.
Conclusions of EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004: "Zinc distearate does not need to be classified on the basis of its acute toxicity according to the EC criteria."

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts

 

Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts is a zinc salt of a fatty acids containing 14 -18 C-atoms. Thus, read-across of data available for zinc salts of shorter-chained (C8,12) and similar chained (C16-18) fatty acids based on structural similarity, water solubility and zinc content in a conservative, worst-case approach is assumed to adequately describe the toxicological potential of Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts.

  

Acute oral toxicity

Regarding acute oral toxicity, read-across data from different reliable studies conducted with the structurally similar substances (i) Fatty acids, C16 -18, zinc salts and

(ii) Zinc bis [hydroxyoctadecanoate] and the shorter-chained substance (iii) Octanoic acid, zinc salt, basic are available. In all studies no acute oral toxicity was observed and the LD50 is greater than 2000 mg/kg bw. Thus, Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts is not expected to be acutely toxic via the oral route and the calculated LD50 for Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts is greater than 2000 mg/kg bw.

 

Acute inhalation toxicity

Regarding acute inhalation toxicity, several reliable studies conducted with the struturally similar substance Fatty acids, C16-18, zinc salts and the shorter-chained substance Zinc dilaurate are available. Based on the lack of an acute inhalative toxicity potential of Fatty acids, C16-18, zinc salts and the shorter-chained fatty acids Zinc dilaurate, for which a LC50 of greater than 5.08 mg/L (actual concentration) was determined, no acute inhalative toxicity potential is expected for Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts.

 

Acute dermal toxicity

Regarding acute dermal toxicity, a study with the structurally similar substance Fatty acids, C16-18, zinc salts is available. The LD50 of Fatty acids, C16-18, zinc salts was estimated to be greater than 2000 mg/kg bw. Further, following the HERAG guidance for metals and metal salts (see section 7.1.2 of the technical dossier: dermal absorption), negligible percutaneous uptake based on minimal penetration, i.e. a dermal absorption rate in the range of maximally 0.1 - 1.0 %, can be anticipated. Dermal absorption in this order of magnitude is not considered to be “significant”.

Moreover, signs of acute oral, inhalation and dermal toxicity are not expected for Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts, since the moiety zinc has not shown signs of acute oral and inhalation toxicity in experimental testing and the acute dermal toxicity can be considered low in view of the poor absorption of zinc by this route. For the moiety fatty acids, C14 -18 and C16 -18 unsatd. there were no toxicological findings reported in peer-reviewed publicly available assessment reports, neither by the oral nor by the dermal route.

 

Conclusion

Overall, the calculated oral and dermal LD50 for fatty acids, C14 -18 and C16 -18 unsatd., zinc salts is > 2000 mg/kg and the inhalation LC50 is expected to be greater than 50 mg/L, hence the substance is not to be classified according to regulation (EC) 1272/2008 and its subsequent amendments for acute oral, inhalation and dermal toxicity as well as for specific target organ toxicity, single exposure (STOT SE).

This conclusion is in line with the EU risk assessment carried out on the structurally similar substance Fatty acids, C16-18, zinc salts (i.e. zinc stearate) within the framework of EU Existing Chemicals Regulation 793/93 (EU RAR Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II-Human Health. EUR 21168 EN {http://echa.europa.eu/documents/10162/08799aec-42c5-44e0-9969-baa022c66db1): "Zinc distearate does not need to be classified on the basis of its acute toxicity according to the EC criteria."

Moieties liberated upon dissolution, zinc and fatty acids, C14 -18 and C16 -18 unsatd.

Please refer to the respective assessment entity section for data on the moieties zinc and fatty acids C14 -18 and C16 -18 unsatd. In brief:

Zinc

 

Acute oral toxicity

- With LD50 values consistently exceeding 2,000 mg/kg bw, zinc oxide (LD50 ranges between 5,000 and 15,000mg/kg bw), shows very low level of acute oral toxicity.

Acute inhalation toxicity

- Key study carried out according to OECD guideline no 403 indicating for micro zinc oxide LC50 > 5.7 mg/L/4hrs

Metal fume fever is not relevant for Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts. The LC50 for Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts is expected to be greater than 50 mg/L and is thus magnitudes higher than the value reported for metal fume fever. A similar conclusion can be drawn for the structural analogue zinc dilaurate for which a LC50 of greater than 5.08 mg/L (actual concentration) was determined.

Acute dermal toxicity

-There are no available data on which to evaluate acute dermal toxicity for ZnO micromaterial. However, acute dermal toxicity can be considered to be low taking into account the poor percutaneous absorption of zinc oxide or the zinc cation.

Fatty acids, C14 -18 and C16 -18 unsatd.

 

Acute oral toxicity

Fatty acids, C14-18 and C16-18 unsatd., zinc salts is a mixture naturally occurring C14-18 saturated and C16-18 unsaturated fatty acids. They are naturally produced by a wide range of plants and organisms. They are naturally present in butter, cheese, milk and meat and some of them are common food additives or involved in essential biochemical processes. Thus, the following endpoint is covered by publicly available data on fatty acids with the same or similar structure.

According to a very recent ECHA report, non-branched aliphatic fatty acids (C5-C24) “are expected to be of low toxicity by their nature (similar to high purity fatty acids of natural origin which do not need to be registered as included in Annex V to REACH). […] From a human health perspective, substances in this group are considered to have a low systemic toxicity profile with no specific target organ toxicity or CMR properties. Some have irritant and/or corrosive properties that are reflected in the classification and labelling. Risk from these properties can be avoided by implementing risk management measures in supply chains based on the correct classification and labelling products. Therefore, there is no need for further action on the substances belonging to the group of aliphatic fatty acids non-branched (C5-C24)” (ECHA, 2020: Integrated Regulatory Strategy Annual Report May 2020).

Further, according to the HERA document on fatty acid salts “the available data for fatty acids provide a clear picture of low acute toxicity for this class of chemicals. All oral LD50values were greater than 2,000 mg/kg, with little mortality being observed even at the highest doses tested in the studies (HERA, 2002 and references therein; Clayton & Clayton, 1982; CIR, 1987). The available data for the fatty acid salts also indicate that these are of low acute toxicity. For example, an acute oral LD50value of >5,000 mg/kg (highest dose tested) has been reported for sodium soap. This test was done according to GLP and OECD Guideline 401 (HERA, 2002 and references therein), while in another study also done to GLP and according to Directive 84/449/EEC, B.1, an LD50value of >2,000 mg/kg (highest dose tested) was reported for fatty acids, C16-18 and C18-unsatd., sodium salts.” (HERA, 2002 and references therein)

Based on in vivo data it was reported that “In an OECD TG 401 study, a group of five rats/sex was administered octadecanoic acid (as a 50% suspension in DMSO) at a dose of 5000 mg/kg bw. There was one death. Animals exhibited transient piloerection, excessive salivation, and diminished activity. At necropsy, the male animal that died exhibited a stomach full of test substance; surviving animals showed remnants of test substance in the stomach with swelling of the mucous membrane. The LD50 was > 5000 mg/kg bw” (OECD SIDS, 2014).

“International-BioResearch (1974, as referred to by CIR, 1987) determined the acute oral toxicity in groups of five male albino rats. Animals were administered by gavage lauric-, myristic-, palmitic- or stearic acid with increasing doses of up to 10,000 mg/kg bw and oleic acid up to 20,000 mg/kg bw. It was observed that for all these fatty acids the LD50value was above the maximum level tested. No mortality was observed in five albino rats gavaged with 5 g/kg bw oleic acid (commercially supplied); clinical signs were not reported during the 7-day post-exposure period (CTFA, 1978, as referred to in CIR, 1987)” (EFSA NDA Panel, 2017).

“Any toxic effects, such as excessive salivation, diarrhoea, central nervous system depression, loss of reflex actions or coma, shown at higher doses, decrease in severity with an increase in the chain length of the fatty acid (Pi-Sunyer et al., 1969). These reported effects are a result of the high doses administered and the fact that unlike humans rats don’t have a vomiting reflex. Therefore, these high dose effects are not considered relevant for human exposure” (HERA, 2002 and references therein).

  

Acute dermal toxicity

Fatty acids, C14-18 and C16-18 unsatd., zinc salts is a mixture naturally occurring C14-18 saturated and C16-18 unsaturated fatty acids. They are naturally produced by a wide range of plants and organisms. They are naturally present in butter, cheese, milk and meat and some of them are common food additives or involved in essential biochemical processes. Thus, the following endpoint is covered by publicly available data on fatty acids with the same or similar structure.

The HERA document on fatty acids salts concluded that “the available acute dermal toxicity data for the fatty acids (and their salts) provide a clear picture of low acute toxicity for this group of chemicals. All dermal LD50 values were greater than >2,000 mg/kg (BIBRA, 1996; HERA, 2002 and references therein; Clayton & Clayton, 1982; CIR, 1982, 1987).

In a dermal study in which concentrations of sodium stearate (C18) ranged between 10-25% in a 20% bath soap detergent form, the LD50was >3000 mg/kg (highest dose tested) (CIR, 1982). In a dermal study in guinea pigs, application of commercial grade oleic acid (3,000 mg/kg) produced no deaths and no signs of toxicity. The number of applications was not stated (CIR, 1987)” (HERA, 2002 and references therein).

Additionally, fatty acids as C14 -18 and C16 -18 unsatd. obtained from natural sources are generally not considered to represent a risk to humans, which is reflected in their exclusion from REACH registration requirements (c.f. REACH Annex V (Regulation (EC) No 987/2008)).

Justification for classification or non-classification

Based on available data on structurally similar or shorter-chained zinc salts of fatty acids, no acute oral, dermal or inhalation toxicity potential is to be expected for Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts. The calculated oral and dermal LD50 for Fatty acids, C14 -18 and C16 -18 unsatd., zinc salts is > 2000mg/kg and the LC50 is expected to be higher than 50 mg/L. Hence the substance is not to be classified according to regulation (EC) 1272/2008 and its subsequent amendments for acute oral, inhalation and dermal toxicity as well as for specific target organ toxicity, single exposure (STOT SE).