Zinc dimyristate

Endpoint summary

Description of key information

No acute toxicity studies with zinc ditetradecanoate are available, thus the acute toxicity will be addressed with existing data on the dissociation products zinc and tetradecanoic acid. Signs of acute oral or acute dermal toxicity are not expected for zinc ditetradecanoate, since for the moiety zinc, has not shown signs of acute oral toxicity (LD50 > 2000mg/kg)

and acute dermal toxicity is considered to be low in view of the poor absorption by this route. The moiety tetradecanoate has not shown signs of acute oral or acute dermal toxicity in experimental testing (LD50 > 2000mg/kg).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Used in EU risk assessment for zinc oxide, limited study details provided

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

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:

5 per sex

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

single dose by oral gavage in water and observed for 14 days

Doses:

single dose of 5 gZnO/kg bw

No. of animals per sex per dose:

5 per sex

Control animals:

not specified

Details on study design:

no further information

Statistics:

no data

Preliminary study:

no further information

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Mortality:

no mortality

Clinical signs:

no adverse signs of toxicity

Body weight:

no adverse signs of toxicity

Gross pathology:

no adverse signs of toxicity

none

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LD50 > 5000 mg ZnO/kg bw was determined.

Executive summary:

In an acute toxicity test Wistar rats (5/sex) were given a single dose of 5 g ZnO/kg bw (in water) by gavage and observed for 14 days. No mortality and signs of toxicity were observed. The LD₅₀for rats is therefore >5 g ZnO/kg bw.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study is well documented and meets general acceptable scientific principle.

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

no

GLP compliance:

not specified

Remarks:

the publication does not specify GLP compliance

Test type:

other: limit test

Limit test:

yes

Species:

mouse

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: gavage

Vehicle:

DMSO

Details on oral exposure:

- Rationale for the selection of the starting dose: Based on the result of another study (Yamaki & Yoshino 2009).

Doses:

5,000 mg/kg bw for both ZnO nanoparticle and microparticle

No. of animals per sex per dose:

5/sex/dose

Control animals:

yes

Details on study design:

Thirty mice were divided into three groups (five males and five females per group). Mice were fed with vehicle (control group), 5,000 mg/kg bw ZnO-nanoparticle suspension or 5,000 mg/kg bw ZnO-microparticles suspension. Dosed mice were conditioned for 14 d. The mortality and clinical behaviour were observed daily. Body weights were recorded twice weekly. At the end of the study (on Day 14), the mice were anaesthetised with isoflurane and blood (for serum biochemistry analysis) was collected from the orbital sinus, followed by gross necropsy. Tissue samples (for histopathologic examination) were taken and fixed in 10% neutral buffered formalin

Statistics:

All data were expressed as the mean ± SD from at least three independent experiments (N ‡ 3). The significance of the difference between the control and each experimental test condition was analysed by Student’s t-test. Statistically significant differences among groups were determined using one-way analysis of variance (ANOVA). A value of p < 0.05 was taken as statistically significant.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

Not observed

Clinical signs:

Not observed

Body weight:

In comparison with vehicle control group, ZnO microparticles treated group showed a body weight reduction in both males (Days 5 and 10) and females (Days 5, 10, and 14); the body weight changes were unobvious in ZnO nanoparticle treated groups.

Gross pathology:

Decreased wet weights of the spleen, kidney, and liver were observed in ZnO microparticles treated females but not in ZnO nanoparticle treated males. However, no obvious gross pathological signs were found in the study.

Other findings:

All serum biochemistry measures were without any significant alternation except for marginal variations in certain parameters.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on the study details, the LD50 value of both the ZnO nanoparticles and ZnO microparticles can be established at >5,000 mg/kg bw in mice.

Executive summary:

The study was conducted to examine the acute toxicity of both ZnO nanoparticles and ZnO microparticles in mice.

Thirty mice were divided into three groups (five males and five females per group). Mice were fed with vehicle (control group), 5,000 mg/kg bw ZnO-nanoparticle suspension or 5,000 mg/kg bw ZnO-microparticles suspension. Dosed mice were conditioned for 14 d.

All the mice survived throughout the testing period without exhibiting any abnormalities related to the test substances. In comparison with the vehicle control group, ZnO-microparticles treated group showed a body weight reduction in both males (Days 5 and 10) and females (Days 5, 10, and 14); the body weight changes were not obvious in ZnO-nanoparticle treated groups. All serum biochemistry measures were without any significant alterations except for marginal variations in certain parameters.

Based on the study details, the LD50 value of both the ZnO nanoparticles and ZnO microparticles can be established at >5,000 mg/kg bw in mice.

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: According to the OECD guideline, but mice used

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

mouse

Strain:

other: CD-ICR

Sex:

male/female

Details on test animals or test system and environmental conditions:

Age: 8 weeks
Weight: 20-22 g

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Doses:

1000, 2000, 3000, 4000, 5000 mg/kg

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:before begin of study, after 2 and 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology, blood analysis

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Remarks on result:

other: 20 nm ZnO

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 - < 5 000 mg/kg bw

Remarks on result:

other: 120 nm ZnO

Mortality:

One female death occurred in the nano-scale 2000 mg group and one male death in the nano-scale 5000 mg group.
As for 120-nm ZnO treated mice, one and three female mice died in the sub-micro 2000 mg and 5000 mg group.

Combined with the results of zinc accumulation, pathological examination and the biological indicators assays, according to the authors the target organs for 20- and 120-nm ZnO acute oral administration are demonstrated as liver, heart, spleen, pancreas and bone.

The biochemical and pathological investigation shows that the toxic effects between the 20-nm and 120-nm ZnO particles are a little different. For example, the blood viscosity could be induced by low and median dose of 20-nm ZnO but high dose of fine ZnO after oral administration. The edema and degeneration of hepatocytes, and inflammation of pancreas could be observed in most of the 20-nm ZnO treated mice. The 120-nm ZnO treated mice were found having dose-effect pathological damage in gastric, liver, heart and spleen, however, the 20-nm ZnO treated mice presented lessened liver, spleen and pancreas damage with the increase of treated dose.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

According to the authors nano-scale as well as submicro-scale ZnO are both not classified according to the GHS with a LD50 of greater than 5 g/kg and 2g/mg < LD50 < 5 g/kg, respectively.

Executive summary:

In this work, the acute oral toxicity of 20- and 120-nm ZnO powder at doses of 1-, 2-, 3-, 4-, 5-g/kg body weight was evaluated referred to the OECD guidelines for testing of chemicals. As the results, both 20- and 120-nm ZnO belong to non-toxic chemicals according to the Globally Harmonized Classification System (GHS) for the classification of chemicals.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reference 2

Endpoint:

acute toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Zinc ditetradecanoate

No acute toxicity studies with zinc ditetradecanoate are available, thus the acute toxicity will be addressed with existing data on the individual moieties zinc and tetradecanoate.

Signs of acute oral or acute dermal toxicity are not expected for zinc ditetradecanoate, since for the moiety zinc, has not shown signs of acute oral toxicity (LD50 > 2000mg/kg) and acute dermal toxicity is considered to be low in view of the poor absorption by this route. The moiety tetradecanoate has not shown signs of acute oral or acute dermal toxicity in experimental testing (LD50 > 2000mg/kg). Under the assumption that the moieties of zinc ditetradecanoate show their toxicological profile individually upon dissolution, the acute oral and dermal (systemic) toxicity of zinc ditetradecanoate can be calculated using the equation given in regulation (EC) 1272/2008, Annex I, Section 3.1.3.6.1.

A study for acute toxicity via inhalation was not conducted with zinc ditetradecanote, since inhalation of the substance zinc ditetradecanoate is considered negligible based on the outcome of the dustiness testing according to the modified Heubach method, as reported under section particle size distribution (granulometry). Further, in a supporting study with the analogous substance zinc dilaurate, no toxicity was seen in an acute inhalation toxicity test up to the limit concentration of 5mg/L. Thus, acute toxic effects are not likely to occur during manufacture and handling of that substance. For further information on the toxicity of the individual moieties, please refer to the relevant sections in the IUCLID and CSR.

 

The calculated oral and dermal LD50 for zinc ditetradecanoate is > 2000mg/kg, hence the substance is not to be classified according to regulation (EC) 1272/2008 for acute oral and dermal toxicity as well as for specific target organ toxicity, single exposure (STOT SE).

 

Zinc

Acute oral toxicity

- With LD50values consistently exceeding 2,000 mg/kg bw, zinc oxide (LD50ranges between 5,000 and 15,000mg/kg bw), shows very low level of acute oral toxicity.

 

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 in view of the poor absorption by this route.

 

Tetradecanoate

Acute oral toxicity

According to the HERA document on fatty acid salts (2002) “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 (IUCLID, 2000c, 2000e, 2000f, 2000g; Clayton & Clayton, 1982; CIR, 1987)” (HERA, 2002).

“In a study conducted according to the FHSA, groups of five male albino rats were administered myristic acid at doses up to 10,000 mg/kg bw. There were no deaths. There were no clinical signs at 464, 1000, 2150 mg/kg bw. Transient slight diarrhea and excessive salivation was observed at 4640 mg/kg bw. The majority of animals in the 10,000 mg/kg group showed slight depression, mucoid diarrhea, unkempt fur stained with diarrhea, and serum and blood discharge from the nose and eyes the first three days of dosing. There were no findings at gross necropsy. The LD50was > 10,000 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” (EFSA ANS Panel, 2017).

Based on these results, the EFSA ANS Panel concluded that myristic acid has a low acute oral toxicity.

In conclusion, the conduct of any further toxicity studies with acute oral exposure in animals would not contribute any new information and is therefore not considered to be required.

 

Acute dermal toxicity

A registration dossier shall contain information on the human health hazard assessment (regulation 1907/2006, Art.10). However, it is considered that the information requirements for zinc ditetradecanoate (synonym: zinc dimyristate) as laid down in annex VII to IX can be fulfilled by adaptation of the standard testing regime according to Annex XI, points 1.2. and 1.3. as presented in the following:

According to Regulation (EC) No 1907/2006 Annex V substances obtained from natural sources and not modified such as vegetable fats and oils as well as fatty acids from C6 to C24 and their potassium, sodium, calcium and magnesium salts are excluded from the obligation to register.

The substance subjected to registration is a common saturated C14- fatty acid, which is present in bovine milk, breast milk as well as palm kernel oil, coconut oil and butterfat. Based on this, the following endpoint is covered by publicly available data on fatty acids with the same or similar structure.

“As with the acute oral data, 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 LD50values were greater than >2,000 mg/kg (BIBRA, 1996; IUCLID, 2000e; Clayton & Clayton, 1982; CIR, 1982, 1987)” (HERA, 2002).

 “In a subchronic study, no adverse effects were produced from topical application of myristic acid (C14) to rabbit skin. One-half ml of a 30% preparation of myristic acid in ether and propylene glycol (solvents at a 1:1 ratio in concentration) was massaged into the depilated skin of the flanks of 5 rabbits daily for 30 days. The opposite flank of the rabbits was depilated and treated with solvent only. No significant macroscopic changes were observed. Microscopic lesions included thinning of collagen fibres in the superficial layer of the dermis after 10 days and a loose dermal infiltrate of lymphomononuclear cells and histocytes after 20 and 30 days (CIR, 1987)” (HERA, 2002).

No dermal toxicity was reported for similar substances such as sodium stearate. “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).

Justification for classification or non-classification

The calculated oral and dermal LD50 for zinc ditetradecanoate is > 2000mg/kg, hence the substance is not to be classified according to regulation (EC) 1272/2008 for acute oral and dermal toxicity as well as for specific target organ toxicity, single exposure (STOT SE).

 Zinc ditetradecanoate is not classified for acute inhalative toxicity because of lacking data.