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Administrative data

Description of key information

Information is available for the oral and dermal route. The systemic toxicity of zinc lactate via any route can be understood in terms of systemic toxicity of lactic acid and zinc(II). The available information is sufficient for route-to-route extrapolation.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Shizuoka Agriculture Cooperative Association for Laboratory Animals
- Age at study initiation: Four wk
- Weight at study initiation: 120-150 g (male); 90-110 g (female)
- Fasting period before study: No data
- Housing: Stainless cages with a wire-meshed bottom
- Diet: Pulverized chows M (Oriental Yeast Co.), ad libitum, mixed with test material
- Water: Ad libitum
- Acclimation period: One wk


ENVIRONMENTAL CONDITIONS
- Temperature: 24±1 °C
- Humidity: 55±5 %
- Air changes (per hr): No data
- Photoperiod: 10 h dark/14 h light cycle


Route of administration:
oral: feed
Vehicle:
other: Mixed with basic feed
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): Pulverized chows M
- Storage temperature of food: No data


Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
13 wk
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0, 300, 3000, 30000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
12
Control animals:
yes, plain diet
Details on study design:
The animals were divided into four groups, each of which included 12 animals of each sex and fed on diets containing Zinc sulphate at
four different concentration levels 0, 300, 3,000 and 30,000 ppm, for 13 wk.
Positive control:
No
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION: Yes
- Time schedule for examinations: Twice a wk

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: Not applicable
- Dose groups that were examined: Not applicable

HAEMATOLOGY: Yes
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: Yes (under light ether anaesthesia)
- Animals fasted: No data
- How many animals: 48
- Parameters checked: Erythrocyte count, hemoglobin, leukocyte count, differential count of leukocyte

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: 48
- Parameters checked: Total plasma protein, alkaline phosphatase, glucose, urea nitrogen, SGOT, SGPT, cholesterol and calcium.


Sacrifice and pathology:
GROSS PATHOLOGY: Yes
After necropsy at the termination of the study the following organs were weighed: Brain, pituitary, thyroid, heart, thymus, liver, kidney, spleen, adrenals, gonads (testes or ovaries), and muscles (triceps surae).

HISTOPATHOLOGY: Yes (see table)
- For histopathology following organs and tissues were collected: Brain, pituitary, thyroid, heart, thymus, liver, kidney, spleen, adrenals, gonads (testes or ovaries), and muscles (triceps surae), submaxillary glands, lungs, mesenteric lymph nodes, pancreas, stomach, small and large intestine, accessory genital organs, bone and bone marrow (sternum and femur), and lesions of gross abnormalities
- 3 or 4 µm paraffin sections from the specimens were stained with hematoxylineosin, periodic acid Schiff's reaction and azan for microscopic observations.
Other examinations:
None
Statistics:
Student's t-test was used to estimate the statistical differences between controls and treated groups
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
effects observed, treatment-related
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY:
- At 30,000 ppm: Showed symptom of discarding the diet from the food jar by picking it out with their fore-limbs. This symptom began a week
after commencement of the experiment and persisted throughout the study. No moribund animals of either sex were found.
- At ≤ 3,000 ppm: No remarkable signs in either sex. Two females, one of the control and one of the 3,000 ppm group, were killed in extremis due to suppurative pyelitis during the study.

BODY WEIGHT AND WEIGHT GAIN:
- At 30,000 ppm: Depressed weight gain and dwarfism. Weight gain of females in this group was slightly depressed during the study with significant
differences to control animals in the 1st to 5th wk of the study.
- At ≤ 3,000 ppm: Statistically not significant values when compared to control
FOOD & WATER CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- At 30,000 ppm: Food intake of males decreased after the third wk of the study. A similar reduction was seen in females of this group during the 1st to 6th wk but then disappeared. A slightly lower value of average food and water intake was reported only in males.
- At ≤ 3,000 ppm: Statistically not significant values when compared to control

FOOD EFFICIENCY:
There were some fluctuations in food efficiency in each group.
- At 30,000 ppm: Slight reduction in overall average value.
- At ≤ 3,000 ppm: Statistically not significant values when compared to control


HAEMATOLOGY:
-At 30,000 ppm: A moderate reduction in leukocyte count was shown in both sexes. Males showed a slight decrease in hematocrit and hemoglobin concentration.
- At 3,000 ppm: No remarkable changes in animals but there was a slight increment of hemoglobin concentration in females

CLINICAL CHEMISTRY:
Significant reductions or reductive tendencies were seen in rats in the following parameters: SGOT and SGPT in all male groups, total protein, cholesterol and calcium levels in males in the 30,000 ppm group and calcium level in females in both the 3,000 and 30,000 ppm groups.


ORGAN WEIGHTS:
-At 30,000 ppm: A slight or moderate decrease in absolute and relative weights was seen in the liver and kidney among males
- Significant fluctuations of absolute or relative organ weights were seen in various organs from chemically treated groups of both species, no clear relationship with the treatment could be shown.
- At ≤ 3,000 ppm: Statistically not significant values when compared to control

GROSS PATHOLOGY
No remarkable lesions were attributable to the treatment.

HISTOPATHOLOGY: NON-NEOPLASTIC
- At 30,000 ppm: Pancreatic lesions as well as degeneration and necrosis of the acinar cells, clarification of centroacinar cells and interstitial fibrosis. No other lesions attributable to the treatment.
- No histopathological abnormalities were observed in the bone or male genital organs which had elsewhere been reported to have sustained toxic changes due to an overdose of Zinc.




Dose descriptor:
NOEL
Effect level:
3 000 ppm
Sex:
male/female
Basis for effect level:
other: No remarkable clinical signs in either sex at ≤ 3000 ppm diet admix, approximately equivalent to 234 mg/kg/day (male) and 243 mg/kg/day (female)
Critical effects observed:
not specified

See the attached pdf for the following figure and tables:

Fig. 2. Group mean body weights in rats

Table 2. Food, chemical, water intake and food efficiency in rats

Table 4. Hematology-mean values in rats.

Table 6. Blood biochemistry--mean values in rats

Table 8. Absolute and relative organ weights in rats

Conclusions:
Under the test conditions, the NOEL of the test material in rats was determined to be 3000 ppm (approximately equivalent to 234 mg/kg/day in male rats and 243 mg/kg/day in female rats)
Executive summary:

This study was conducted to evaluate the subchronic toxicity (13 weeks) of the test material in Wistar rats. The study followed was equivalent or similar to OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents). Rats of both sexes were fed a diet containing the test material at 0, 300, 3000 and 30000 ppm for 13 weeks. The clinical signs of the animals, body weight, food, chemical and water intake, food efficiency, hematological, biochemical examination, necropsy and organ weight and histopathological examination were performed. Animals in the 30000 ppm group showed retarded growth along with low food intake, abnormal values in a few hematological parameters and regressive changes of the pancreatic exocrine gland. There were no remarkable clinical signs in either sex in groups 3000 ppm. Under the test conditions, NOEL of the test material in rats was determined to be 3000 ppm (approximately equivalent to 234 mg/kg/day in male rats and 243 mg/kg/day in female rats).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
234 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Review
Principles of method if other than guideline:
The dermal toxicity of a face cream containing 0.25% of 85% aq. Lactic Acid was evaluated using two groups of 15 female Sprague-Dawley rats (Avon Products, Inc., 1995b). The test group received daily applications of 886 mg/kg applied 5 days/week for 13 weeks to a shaved dorsal area of the back; the control group was untreated (The dose was determined by applying a factor of 100 x to the average daily human use determined using 1 g/day). Animals were observed daily, and blood and urine samples were collected during weeks 7 and 13 from randomly selected animals.
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Vehicle:
other: cosmetic cream
Details on exposure:
Route of administration: dermal
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily, 5 days/week
Dose / conc.:
886 mg/kg bw/day (nominal)
No. of animals per sex per dose:
15 (female only)
Control animals:
yes, concurrent no treatment
Details on study design:
The dermal toxicity of a face cream containing 0.25% of 85% aq. Lactic Acid was evaluated using two groups of 15 female Sprague-Dawley rats (Avon Products, Inc., 1995b). The test group received daily applications of 886 mg/kg applied 5 days/week for 13 weeks to a shaved dorsal area of the back; the control group was untreated (The dose was determined by applying a factor of 100 x to the average daily human use determined using 1 g/day). Animals were observed daily, and blood and urine samples were collected during weeks 7 and 13 from randomly selected animals.
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
All animals survived to study termination. No significant gross observations, with the exception of minimal skin irritation throughout the study, could be attributed to dosing. During week 7, the blood urea nitrogen value was significantly increased for test animals as compared to controls; no other hematological effects were seen, and urinary parameters were normal. Absolute brain weight and kidney-to-body weight ratios were statistically significantly increased for the test animals. No lesions were observed at necropsy or at microscopic exammation.
Dose descriptor:
LOAEL
Effect level:
886 mg/kg bw/day
Critical effects observed:
not specified
Conclusions:
Formulation (face cream containing 0.25% lactic acid) is safe in terms of cumulative toxicity. Based upon the exaggerated dose levels used in this study for skin care products, dermal applicaton is not likely to produce adverse effects under conditions of consumer use.
Executive summary:

All animals survived to study termination. No significant gross observations, with the exception of minimal skin irritation throughout the study, could be attributed to dosing. During week 7, the blood urea nitrogen value was significantly increased for test animals as compared to controls; no other hematological effects were seen, and urinary parameters were normal. Absolute brain weight and kidney-to-body weight ratios were statistically significantly increased for the test animals. No lesions were observed at necropsy or at microscopic exammation. The investigators concluded this formulation is "safe in terms of cumulative toxicity" and that "based upon the exaggerated dose level used in this study for skin care products, dermal application is not likely to produce adverse effects under conditions of consumer use."

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Information is available for the oral and dermal route. The systemic toxicity of zinc lactate via any route can be understood in terms of the systemic toxicity of lactic acid and zinc(II). The available information is sufficient for route-to-route extrapolation.

Lactic acid can be considered non-toxic; the only deleterious effects of lactic acid are local irritation as a result of decreased pH, which is not relevant in the case of zinc lactate, a salt not releasing protons.

The biological activities of zinc compounds are determined by their ability to release zinc under the respective exposure conditions. Therefore, information on the effects of systemically available zinc allows the repeated dose toxicity assessment of zinc lactate.

Non-human information

The repeated dose toxicity of water soluble zinc sulphate was examined in oral feeding studies. The NOAEL in the feeding studies with zinc sulphate (heptahydrate) was determined to be 458 mg/kg bw/d in mice and 234 mg/kg bw/d in rats (corresponding to 198 mg/kg bw/d zinc lactate). At higher doses the most important effects in rats were the development of hypocupremia, and significant changes in the pancreas (i.e., focal acinar degeneration and necrosis) and a decreased number of pigmented macrophages in spleen.

Human information

Information from the EU risk assessment report on zinc chloride, Part II (2004): Upon supplementing men and women with 150 mg Zn/d (as zinc sulphate capsules), women appeared to be more sensitive than men to the effects of high zinc intake: Clinical signs such as headache, nausea and gastric discomfort were more frequent among women, and women but not men had decreased activities of serum ceruloplasmin and ESOD. In some earlier oral studies in which humans were supplemented with moderately high amounts of zinc (50 mg Zn/d), a reduction in ESOD activity was also observed and again women appeared to be more sensitive to this effect. Hence, a reduction in ESOD was thought to be a sensitive indicator of copper status. However, in more recent and more sophisticated studies using the same dose level, ESOD was only marginally reduced (without being correlated to changes in copper balance), while findings on more specific copper deprivation signs (decreased serum ceruloplasmin and platelet cytochrome c oxidase) indicated that a sub-optimal intake of zinc was more effective than a moderately high intake of zinc in inducing changes associated with a decreased copper status in postmenopausal women. Given this, and in view of the degree of the observed ESOD reduction in comparison to the natural variability in its activity, the zinc-induced decrease in ESOD activity is considered to have marginal biological significance, if any, and also because it may not have been caused by an interference with copper metabolism as deep tissue SOD increases as a function of zinc exposure was observed.

Overall, it can be concluded from studies in which humans were supplemented with zinc (as zinc gluconate) that women are more sensitive to the effects of high zinc intake and that a dose of 50 mg Zn/day is the human NOAEL. This corresponds to a daily dose of 0.83 mg/kg bw. At the LOAEL of 150 mg Zn/d, clinical signs and indications for disturbance of copper homeostasis were observed.

Justification for classification or non-classification

Based on the available data from the read-across partners, the target substance does not warrant classification for specific target organ toxicity in accordance to CLP.