Zinc bis(benzenesulphinate)

Endpoint summary

Description of key information

Systemic toxicity in male and female rats dosed for at least 49 days: LOAEL = 50 mg/kg/day, NOAEL < 50 mg/kg/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

50 mg/kg bw/day

Study duration:

subacute

Species:

rat

System:

other: hepatobiliary and haematopoietic

Organ:

blood

liver

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

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity of target substance was evaluated in a combined repeated dose toxicity study with reproduction/developmental toxicity screening test in male and female Wistar rats. The study was based on OECD guideline 422.

 

In a dose-range finding experiment (DRFE), male and female rats were dosed with 150, 300, 600 and 1000 mg/kg bw/day for 21 days. The following observations were done: no treatment-related mortality was seen; no adverse changes of health condition and no clinical symptoms of intoxication; no treatment-related changes of basic haematological parameters in both sexes; no serious macroscopic changes in females.

Pathological examination of males of all dose levels revealed changes of colour of kidneys. Enlarged kidneys were observed in males of the dose levels 300, 600 and 1000 mg/kg/day. Enlarged liver and spleen were observed at the highest dose level in one male. Body weight of treated males was affected by treatment at the highest dose level.

   

On the basis of the DRFE results, dose levels for main study were 0, 50, 200 and 400 mg/kg/day, tested in groups of 12 rat/sex; satellite groups at doses of 0 and 400 mg/kg/day following a 14 -day recovery period after dosing were also included, using 6 rat/sex.

Tested doses were prepared in olive oil and administered by gavage. The treated groups were dosed daily for at least 49 days as follows:

males and females – 2 weeks prior to the mating period and during the mating period,

pregnant females  – during pregnancy and till the 12th day of lactation,

males  –  after mating period – totally for 49 days,

non pregnant females (mated females without parturition) – for 25 days after the confirmed mating,

non-mated females – for 25 days after the end of mating period.

No mortality, no clinical signs and no effects on growth were noted.

Male rats showed more pronounced effects than females. In particular, haematological examination in males revealed irreversible decrease of total erythrocyte count associated with decreased haemoglobin concentration and value of haematocrite, increase of value of reticulocytes in treated group of males. Haematological parameters were changed in a dose-dependent manner.

Females showed only decrease of haemoglobin concentration in satellite treated group, also at the end of recovery period. Non-significant (but dose-dependent) decrease of haemoglobin and haematocrite was recorded in treated females.

Changes in biochemical parameters of males were noted showing a dose dependency. In particular, an increase in concentration of total protein (T-Pro), total cholesterol (T-Chol), albumin (ALB), alanine aminotransferase (ALT) concentration of calcium (Ca), phosphorus (IP) and cholinesterase (CHE) was recorded; decrease in concentration of total bilirubin (T-Bil) and glucose (GLU) was noted.  

An increase of urea (BUN) concentration and glucose (GLU) was seen in satellite treated males.

In females, changes were: increase in concentration of total protein (T-Pro), total cholesterol (T-Chol) and alanine aminotranferase (ALT) as well as decrease of creatinine (Crea) at all dose levels (dose dependent, irreversible).

In satellite treated females, changes were: increase of alkaline phosphatase (ALP), triglycerides (TG), glucose (GLU); decrease of creatinine (Crea).

Absolute and relative weights of liver and kidneys were increased in males in a dose-dependent and irreversible manner. Also in females increased weight of kidneys and liver was recorded; relative weight of liver was increased in a dose dependent manner; absolute and relative weight in kidneys was increased in a dose dependent manner.

In males, macroscopical findings were enlarged liver and kidneys with light colour and irregular ochre foci. In females no macroscopical findings were seen.

Histological examination in males showed: hepatocellular hypertrophy (hypertrophic hepatocytes present in centrilobular area) of various intensity in liver at all dose levels; hyaline droplets in tubular epithelium of kidneys at all dose levels and this finding was accompanied by chronic progressive nephropathy; suspected decreased volume of colloid and/or suspected condensation of colloid in thyroid gland. Chronic progressive nephropathy (very early, early or advanced stage) occurred in kidneys of satellite males related to the test substance treatment.

In treated females, hepatocellular hypertrophy (hypertrophic hepatocytes present in centrilobular area) of various intensity in liver was seen; no changes were detected in kidneys and thyroid gland. 

Justification for classification or non-classification

According to the CLP Regulation (EC 1272/2008), classification in category 1 for repeated dose toxicity applies to substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure. Substances are classified in category 1 for target organ toxicity (repeat exposure) on the basis of:

— reliable and good quality evidence from human cases or epidemiological studies; or

— observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations.

As for classification in category 2, it applies to substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following repeated exposure. Substances are classified in category 2 for target organ toxicity (repeated exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations.

The decision on classification was based on dose-dependent toxic responses seen starting at dose of 50 mg/kg/day upon a 49 days exposure. In particular, main findings in males already seen at 50 mg/kg/day were:

- absolute and relative changes in weight of liver and kidneys

- macroscopical changes in liver and kidneys

- histological changes in liver and kidneys

- increase of reticulocytes (haematology); decrease of total bilirubin (biochemistry)

In females, main findings already seen at dose of 50 mg/kg/day were:

- decrease of creatinine (biochemistry)

- relative changes in weight of liver and kidneys

- histological changes in liver

Overall, based on such effects, the lowest tested dose of 50 mg/kg was identified as a LOAEL.

Based on the study duration, i.e. at least 49 days of dosing, and on the Haber's rule, classification in cat.1 applies for effective doses below ca. 20 mg/kg/day and classififcation in cat. 2 applies for effective doses below 200 mg/kg/day.

An effective dose of 50 mg/kg/day was found, while no NOAEL could be identified.

Based on available data, no conclusion could be drawn whether the NOAEL value is above or below the threshold of 20 mg/kg/day. If above, classification in cat. 2 would apply; if below, interpolation would be required to determine whether an effect at or below the threshold would imply a classififcation in cat. 1. However, considering:

- a clear dose-dependency showed by toxic responses

- a decrease of toxic responses seen at the dose 400 mg/kg/day, upon a 14 -day recovery period, reasonably suggesting an almost complete reversiblibility upon dosing at 50 mg/kg (not tested)

- the lack of adverse effects in the reproduction toxicity part of the study

a classification in cat. 1 was reasonably excluded as considered as too precautionary. A classification in category 2 (H373) was considered as appropriate.