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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study, key study used in EU risk assessment report for Zinc metal

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
zinc monoglycerolate

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
no data

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
none
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0%
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0.05% (= male 31.52 mg/kg bw and female 35.78 mg/kg bw)
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0.2% (= male 127.52 mg/kg bw and female 145.91mg/kg bw)
Basis:
nominal in diet
No. of animals per sex per dose:
20 males
20 females
Details on study design:
Groups of 20 male and 20 female Sprague-Dawley rats were fed zinc monoglycerolate at dietary levels of 0, 0.05 or 0.2% (equal to 0, 31.52 or 127.52 mg/kg for males and 0, 35.78 or 145.91 mg/kg bw for females, respectively) for a period of 13 weeks in a study performed according to OECD 408. Asimilar group was fed 1% (equal to 719 and 805 mg/kg bw/day for males and females, respectively) of zinc monoglycerolate up to day 58 of the study when a deterioration in their clinical condition (poor physical health and reduced food intake) necessitated reducing the dietary level to 0.5% (equal to 632 and 759 mg/kg bw/day for males and females, respectively). However, as no improvement occurred these rats were killed on humane grounds on day 64 of the study.

Examinations

Observations and examinations performed and frequency:
according to guideline
Sacrifice and pathology:
according to guideline
Statistics:
according to guideline

Results and discussion

Results of examinations

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
Ophthalmological findings:
effects observed, treatment-related
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Details on results:
The rats fed 1% of test substance for 58 days and then 0.5% to day 64 had were killed before the end of the study due to ill-health developed hypocupremia manifested as a hypochromic microcytic regenerative type anaemia (low haemoglobin and haematocrit, decreased MCV and MCH, and increased MCHC, red blood cell and reticulocyte count). Enlargement of the mesenteric lymph nodes and slight pitting of the surface of the kidneys were noted. Severe pancreatic degeneration and pathological changes in the spleen, kidneys, incisors, eyes and bones were observed. The testes of all males showed hypoplasia of the seminiferous tubules to a varying degree and in addition the prostate and seminal vesicles showed hypoplasia. In all but one female the uterus was hypoplastic.

In the main study, a dietary level of 0.2% increases in plasma ALAT, alkaline phosphatase and creatine kinase were observed in males and in plasma creatine kinase in females. Total plasma cholesterol was reduced in both males and females. The changes were statistically significant but small in absolute terms. No changes in haematological parameters were seen at 0.05 and 0.2%. A dose related reduction in the quantity of abdominal fat was noted in male rats at 0.05 and 0.2%. Enlargement of the mesenteric lymph nodes was apparent in 6 out of 20 rats fed 0.2% and in one male fed 0.05%. Microscopic examination showed a reduction in the number of trabeculae in the metaphysis of the tibia of 5 male and 3 female rats fed 0.2%, 4 males and 1 female had a similar reduction in the metaphysis of the femur. Pancreatic cell necrosis was seen in both sexes at 0.2% and a slight, but statistically not significant increase could be noted at 0.05% (3 males and 1 female). This pancreatic cell necrosis was seen also in 1 control male. A reduction in the number of pigmentated macrophages in the red pulp of the spleen was observed in both sexes at 0.2% and a marginal reduction was also seen in males at 0.05%. In the animals given 0.05 and 0.2% no effects were found on the reproductive organs.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
31.52 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
LOAEL
Effect level:
53.8 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: changes in haemotological parameters, pancreatic cell necrosis; no effects were seen at LOAEL in reproductive organs

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL in this study is 31.52 mg/kg bw (approximately 13.26 mg Zn2+/kg bw)
Executive summary:

Groups of 20 male and 20 female Sprague-Dawley rats were fed zinc monoglycerolate at dietary levels of 0, 0.05 or 0.2% (equal to 0, 31.52 or 127.52 mg/kg for males and 0, 35.78 or 145.91 mg/kg bw for females, respectively) for a period of 13 weeks in a study performed according to OECD 408. A similar group was fed 1% (equal to 719 and 805 mg/kg bw/day for males and females, respectively) of zinc monoglycerolate up to day 58 of the study when a deterioration in their clinical condition (poor physical health and reduced food intake) necessitated reducing the dietary level to 0.5% (equal to 632 and 759 mg/kg bw/day for males and females, respectively). However, as no improvement occurred these rats were killed on humane grounds on day 64 of the study. These rats developed hypocupremia manifested as a hypochromic microcytic regenerative type anaemia (low haemoglobin and haematocrit, decreased MCV and MCH, and increased MCHC, red blood cell and reticulocyte count). Enlargement of the mesenteric lymph nodes and slight pitting of the surface of the kidneys were noted. Severe pancreatic degeneration and pathological changes in the spleen, kidneys, incisors, eyes and bones were observed. The testes of all males showed hypoplasia of the seminiferous tubules to a varying degree and in addition the prostate and seminal vesicles showed hypoplasia. In all but one female the uterus was hypoplastic.

All other rats survived to the end of the 13 weeks treatment. At a dietary level of 0.2% increases in plasma ALAT, alkaline phosphatase and creatine kinase were observed in males and in plasma creatine kinase in females. Total plasma cholesterol was reduced in both males and females. The changes were statistically significant but small in absolute terms. No changes in haematological parameters were seen at 0.05 and 0.2%. A dose related reduction in the quantity of abdominal fat was noted in male rats at 0.05 and 0.2%. Enlargement of the mesenteric lymph nodes was apparent in 6 out of 20 rats fed 0.2% and in one male fed 0.05%. Microscopic examination showed a reduction in the number of trabeculae in the metaphysis of the tibia of 5 male and 3 female rats fed 0.2%, 4 males and 1 female had a similar reduction in the metaphysis of the femur. Pancreatic cell necrosis was seen in both sexes at 0.2% and a slight, but statistically not significant increase could be noted at 0.05% (3 males and 1 female). This pancreatic cell necrosis was seen also in 1 control male. A reduction in the number of pigmentated macrophages in the red pulp of the spleen was observed in both sexes at 0.2% and a marginal reduction was also seen in males at 0.05%. In the animals given 0.05 and 0.2% no effects were found on the reproductive organs.

Since the pancreatic cell necrosis, being without statistical significance at 0.05%, was also apparent in 1 control male and because the reduction in pigmented macrophages in the spleen was only marginal at 0.05% without any haematological changes the dose level of 0.05%, is considered as a NOAEL. This dose level is equal to 31.52 or 35.78 mg zinc monoglycerolate/kg bw for males and females, respectively, so the NOAEL in this study is 31.52 mg/kg bw (»13.26 mg Zn2+/kg bw)