Barium dibenzoate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No toxicity data on adverse effects on sexual function and fertility with barium dibenzoate are available, thus the reproductive toxicity will be addressed with existing data on the individual moieties barium and benzoate. The moiety benzoate has not shown adverse effects on fertility or the development in a 4-generation reproductive toxicity study. The moiety barium has not shown effects on fertility or developmental toxicity effects.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Barium

Only two studies (NTP and Dietz) exist in which a dose-response relationship of different adverse effects on fertility after oral administration of barium chloride was investigated. These studies (see section 7.8.1) which were published in peer-reviewed journals were examined with respect to their adequacy for the derivation of NOAEL/LOAEL values for fertility impairment.

Based on these limited investigations with barium chloride as described above, a lack of fully, guideline conform data must be noted. Tentatively, the premating study by Dietz et al. (1992) on rats and mice may be considered as the only acceptable study for the derivation of a preliminary NOAEL for fertility effects of soluble barium compounds. This study investigated the occurrence of different adverse effects in male and female rats and mice and their offspring related to barium chloride exposure via drinking water. A tentative NOAEL for fertility impairment of 4,000 ppm in rats and 2,000 ppm in mice can be derived.

Screening study:

Fertility impairment in female rats: NOAEL of 179.5 mg Ba2+/kg bw/d; relates to 272 mg Barium chloride/kg bw/day (Dietz et al., 1992)

Fertility impairment in male rats: NOAEL of 201.5 mg Ba2+/kg bw/d; relates to 306 mg Barium chloride/kg bw/day (Dietz et al., 1992)

A screening test is available. Based on this study there are no indications of a substantial impairment of fertility in rats up to the highest dose tested. Thus, the NOAEL was 4000 ppm (to average doses of 201.5 and 179.5 mg Ba/kg bw/d to male and female rats, respectively). No-observed-adverse-effect levels (NOAELs) on developmental toxicity for rats of 4000 ppm were derived. However, this NOAEL is of limited value to evaluate the potential for barium to induce developmental effects because there was no exposure of the females during gestation.

For the endpoint developmental toxicity, which is not a Reach Annex VIII (10-100 t/a) requirement, no robust study summaries were obtained. However, the license to use includes information that is included in the endpoint summary of IUCLID section 7.8 “Toxicity to reproduction”. Thus, a conclusion on developmental toxicity can be drawn based on the information stated therein (for detailed information please refer to the registration dossier of barium dichloride):

Developmental toxicity of barium chloride dihydrate was evaluated in a recent prenatal developmental toxicity study by daily administration of the test item at dose levels of 0, 10, 30 or 100 mg BaCl2 * 2 H2O/kg body weight to pregnant rats from gestation day 1 up to and including gestation day 20. No effects on body weights, food consumption and clinical signs were observed. Maternal toxicity was evidenced by the spontaneous deaths of two animals on gestation day 21 only and the conditional decline of another animal on gestation day 21 in the high dose group (100 mg BaCl2 * 2 H2O/kg bw).

No developmental toxicity or treatment-related observations, whatsoever in external, visceral and skeletal foetal examinations were observed in any dose level.

The NOAEL for maternal toxicity was therefore 30 mg/kg body weight barium chloride dihydrate (25.6 mg/kg bw barium chloride)). In absence of developmental effects, the NOAEL for prenatal developmental toxicity in the rat was ≥ 100 mg/kg body weight barium chloride dihydrate (≥85.3 mg/kg bw barium chloride).

Furthermore, tentative NOAEL values for developmental toxicity of 4,000 ppm and 2,000 ppm for rats and mice, respectively, are also reported in the study by Dietz et al. (1992). However, these NOAELs are of limited value to evaluate the potential for barium to induce developmental effects because the study design did not include prenatal exposure of the female animals to barium dichloride dihydrate.

Developmental toxicity: a NOAEL of >=85.3 mg BaCl2/kg was derived in an oral developmental toxicity study according to OECD 414.

No classification is required based on the results of the prenatal developmental toxicity study.

  

Benzoate

In a 4-generation rat study (Kieckebusch 1970), no effects on fertility, reproductive performance and offspring were reported at up to and including 1% the test substance in feed equivalent to 500 mg/kg bw/d (highest dose tested).

Barium dibenzoate

Barium dibenzoate is not expected to show effects on fertility or development of the offspring, since the moiety benzoate has not shown adverse effects on fertility or the development in a 4-generation reproductive toxicity study. For the moiety barium, no classification is required based on the results of the prenatal developmental toxicity study. For the endpoint developmental toxicity, which is not a Reach Annex VIII (10-100 t/a) requirement, no robust study summaries were obtained. However, the license to use includes information that is included in the endpoint summary of IUCLID section 7.8 “Toxicity to reproduction”. Thus, a conclusion on developmental toxicity can be drawn based on the information stated therein. Thus, barium dibenzoate is not to be classified according to regulation (EC) 1272/2008 for reproductive toxicity. Further testing is not required. For further information on the toxicity of the individual moieties, please refer to the relevant sections in the IUCLID and CSR.

 

Information on the individual moieties barium and benzoate will be used for the hazard assessment and, when applicable, for the risk characterisation of barium dibenzoate. For the purpose of hazard assessment of barium dibenzoate, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation. In case of barium dibenzoate, the NOAEL of 61 mg/kg bw/day for repeated dose toxicity of the moiety Barium will be used.

Effects on developmental toxicity

Description of key information

No toxicity data on adverse effects on sexual function and fertility with barium dibenzoate are available, thus the reproductive toxicity will be addressed with existing data on the individual moieties barium and benzoate. The moiety benzoate has not shown adverse effects on fertility or the development in a 4-generation reproductive toxicity study. For the moiety barium, no classification is required based on the results of the prenatal developmental toxicity study.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Barium

A pre-natal developmental toxicity study is not required for the Annex VIII data requirements. The source substance dossier barium dichloride for the assessment entity barium, contains information which allow to conclude on the classification and labelling for the endpoint reproductive toxicity, as follows:

Developmental toxicity of barium chloride dihydrate was evaluated in a recent prenatal developmental toxicity study by daily administration of the test item at dose levels of 0, 10, 30 or 100 mg BaCl2 * 2 H2O/kg body weight to pregnant rats from gestation day 1 up to and including gestation day 20. No effects on body weights, food consumption and clinical signs were observed. Maternal toxicity was evidenced by the spontaneous deaths of two animals on gestation day 21 only and the conditional decline of another animal on gestation day 21 in the high dose group (100 mg BaCl2 * 2 H2O/kg bw).

No developmental toxicity or treatment-related observations, whatsoever in external, visceral and skeletal foetal examinations were observed in any dose level.

The NOAEL for maternal toxicity was therefore 30 mg/kg body weight barium chloride dihydrate (25.6 mg/kg bw barium chloride)). In absence of developmental effects, the NOAEL for prenatal developmental toxicity in the rat was ≥ 100 mg/kg body weight barium chloride dihydrate (≥85.3 mg/kg bw barium chloride).

Furthermore, tentative NOAEL values for developmental toxicity of 4,000 ppm and 2,000 ppm for rats and mice, respectively, are also reported in the study by Dietz et al. (1992). However, these NOAELs are of limited value to evaluate the potential for barium to induce developmental effects because the study design did not include prenatal exposure of the female animals to barium dichloride dihydrate.

Developmental toxicity: a NOAEL of >=85.3 mg BaCl2/kg was derived in an oral developmental toxicity study according to OECD 414.

No classification is required based on the results of the prenatal developmental toxicity study.

  

Benzoate

In a 4-generation rat study (Kieckebusch 1970), no effects on fertility, reproductive performance and offspring were reported at up to and including 1% the test substance in feed equivalent to 500 mg/kg bw/d (highest dose tested).

Barium dibenzoate

Barium dibenzoate is not expected to show effects on fertility or development of the offspring, since the moiety benzoate has not shown adverse effects on fertility or the development in a 4-generation reproductive toxicity study. For the moiety barium, no classification is required based on the results of the prenatal developmental toxicity study. For the endpoint developmental toxicity, which is not a Reach Annex VIII (10-100 t/a) requirement, no robust study summaries were obtained. However, the license to use includes information that is included in the endpoint summary of IUCLID section 7.8 “Toxicity to reproduction”. Thus, a conclusion on developmental toxicity can be drawn based on the information stated therein. Thus, barium dibenzoate is not to be classified according to regulation (EC) 1272/2008 for reproductive toxicity. Further testing is not required. For further information on the toxicity of the individual moieties, please refer to the relevant sections in the IUCLID and CSR.

 

Information on the individual moieties barium and benzoate will be used for the hazard assessment and, when applicable, for the risk characterisation of barium dibenzoate. For the purpose of hazard assessment of barium dibenzoate, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation. In case of barium dibenzoate, the NOAEL of 61 mg/kg bw/day for repeated dose toxicity of the moiety Barium will be used.

Justification for classification or non-classification

Barium dibenzoate is not expected to impair fertility or development, since both moieties namely barium and benzoate did not show any reprotoxic effects. The moiety benzoate has not shown adverse effects on fertility or the development in a 4-reneration reproductive toxicity study. The moiety barium did not show any developmental toxicity effects in a pre-natal developmental toxicity study and no effects on the fertility were seen in a number of repeated dose toxicity studies in rats and mice.Barium dibenzoate is not to be classified according to regulation (EC) 1272/2008 as toxic for reproduction.