Neodecanoic acid, zinc salt, basic

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

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 2004

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Zinc

EC Number:

231-175-3

EC Name:

Zinc

Cas Number:

7440-66-6

Molecular formula:

Zn

IUPAC Name:

zinc

Details on test material:

zinc monoglycerolate

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system 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 / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0%
Basis:
nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0.05% (= male 31.52 mg/kg bw and female 35.78 mg/kg bw)
Basis:
nominal in diet

Doses / concentrations 3

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

Dose descriptor:

NOAEL

Effect level:

31.52 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: see 'Remark'

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)