Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
Species:
other: animal and human data

Additional information

Introduction to read-across matrix

A comprehensive data gap analysis was conducted for the entire substance portfolio of the Metal carboxylates REACH Consortium (MCRC), covering 11 metal carboxylates in total. This literature screening effort included:

 

  • all available proprietary studies from the Metal carboxylates REACH Consortium (MCRC)
  • detailed literature searches in online databases
  • screening of human health review articles
  • rigorous quality and reliability screening according to Klimisch criteria, where those criteria apply

 

During the literature search and data gap analysis it became obvious that the overall database on substance-specific human health hazard data for the metal carboxylates is too scant to cover all REACH endpoints. Therefore, the remaining data gaps had to be covered by either experimental testing or read-across from similar substances.

 

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the organic acid counterion and the metal (or one of its readily soluble salts). This way forward is acceptable, since metal carboxylates dissociate to the organic anion and the metal cation upon dissolution in aqueous media. No indications of complexation or masking of the metal ion through the organic acid were apparent during the water solubility tests (please refer to the water solubility data in section of the IUCLID and chapter of the CSR). Once the individual constituents of the metal carboxylate become bioavailable (i.e. in the acidic environment in the gastric passage or after phagocytosis by pulmonary macrophages), the “overall” toxicity of the dissociated metal carboxylate can be described by the toxicity of the “individual” constituents. Since synergistic effects are not expected for this group of metal carboxylates, the human health hazard assessment consists of an individual assessment of the metal cation and the organic anion.

 

The hazard information of the individual constituents was obtained from existing REACH registration dossiers via a license-to-use obtained by the lead registrant. These registration dossiers were submitted to ECHA in 2010 as full registration dossiers, and are thus considered to contain relevant and reliable information for all human health endpoints. All lead-registrant dossiers were checked for completeness and accepted by ECHA, i.e. a registration number was assigned.

 

Zinc dibenzoate is the zinc metal salt of benzoic acid, which readily dissociates to the corresponding divalent zinc cation and benzoic acid anions. The zinc cation and the benzoic acid anion are considered to represent the overall toxicity of the zinc dibenzoate in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). Based on the above information, unrestricted read-across is considered feasible and justified.

 

Although the term „constituent“ within the REACH context is defined as substance (also being part of a mixture), the term constituent within this hazard assessment is meant to describe either part of the metal carboxylate salt, i.e. anion or cation.

Repeated dose toxicity

No repeated dose toxicity study with zinc dibenzoate is available, thus the repeated dose toxicity will be addressed with existing data on the dissociation products zinc and benzoic acid as detailed in the table below.

 

Table: Summary of repeated dose toxicity data of the zinc dibenzoate and the individual constituents.

 

(slightly soluble) zinc substances

benzoic acid
(CAS# 65-85-0)

Zinc dibenzoate
(CAS# 553-72-0)

Repeated dose
oral toxicity

NOAEL(human data)= 0.83 mg Zn/kg bw/day*

NOAEL(rat; 18-24 mo.)
= 1,000 mg/kg bw/day*


read across (sodium benzoate)

no data

* Identified as most sensitive endpoint in the registration dossier for zinc and benzoic acid, thus has been used for the DNEL derivation of this substance.

 

Zinc

From studies in which humans were supplemented with zinc (as zinc gluconate) it was concluded 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 exposure of 0.83 mg Zn/kg bw. At the LOAEL of 150 mg Zn/day, clinical signs and indications for disturbance of copper homeostasis have been observed. Studies conducted on animals are not discussed here, since information on human experience are considered of higher relevance for risk assessment purposes and should take precedence over animal studies. For further information on the toxicity of zinc, please refer to the relevant sections in the IUCLID and CSR.

 

Benzoic acid

Oral:

No adequate studies with benzoic acid are available. Several studies are available on the structural analogue sodium benzoate.

 

A short-term dietary study (10 days) with sodium benzoate in rats and mice (Fujitani, 1993) showed a NOAEL of 905 mg/kg bw in rats and of 3571 mg/kg bw in mice. Effects included decreased body weight and increased (rel) liver weights with enlarged (glossy) hepatocytes and eosinophilic foci around the portal vein. In high dosed decreased kidney weights were reported without histopathological changes. In addition, in a 35 day study in rats with sodium benzoate (Sodemoto, 1979) animals at the highest dose groups died. Symptoms in descendants were severe decrease in body weight. Morphological effects were limited to atrophy of the spleen and lymph nodes at 4 and 8% in diet. At the NOAEL 2% in diet no morphological changes were reported. In a limited reported 90-day study on sodium benzoate in rats (Weil, 1953) a NOAEL of 2,620 mg/kg bw/day was established based on reduced body weight gain, increased relative liver and kidney weights and pathological changes in liver and kidneys at 6,290 mg/kg bw/day. The overall NOAEL for repeated dose toxicity is based on a chronic toxicity study and is set at 1,000 mg/kg bw/day (Sodemoto, 1979).

 

Dermal:

A 21-day dermal toxicity study with rabbit (Marroquin, 1981) which run on Benzoic acid (65-85-0) is available. No effects were found at the highest dose level, thus the NOAEL was > 2500 mg/kg bodyweight.

 

For further information on the toxicity of benzoic acid, please refer to the relevant sections in the IUCLID and CSR.

 

Zinc dibenzoate

Since no repeated dose toxicity study is available specifically for zinc dibenzoate, information on the individual constituents zinc and benzoic acid will be used for the hazard assessment and when applicable for the risk characterisation of zinc dibenzoate. For the purpose of hazard assessment of zinc dibenzoate, the point of departure for the most sensitive endpoint of each constituent will be used for the DNEL derivation. In case of zinc in zinc dibenzoate, the NOAEL of 0.83 mg/kg bw/day in repeated dose toxicity (human data) will be used. In case of benzoate in zinc dibenzoate, the NOAEL of 1,000 mg/kg bw/day in repeated dose toxicity (animal data) will be used.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Information from read-across substances:
human data for zinc: NOAEL=0.83mg/kg bw/day
animal data for benzoic acid: NOAEL(rat; 18-24 mo.)=1,000 mg/kg bw/day; read across (sodium benzoate)

Justification for classification or non-classification