Registration Dossier

Administrative data

Description of key information

Oral studies in rats and mice have shown that the repeated dose toxicity of Bisphenol A involves effects on bodyweight gain, liver and kidney. The starting point for the human risk assessment is a BMDL10 for mean relative kidney weight of 8.9 mg/kg/day for systemic toxicity. In rats exposed daily to airborne Bisphenol A for 13 weeks there was a NOAEC of 10 mg/m3, with mild olfactory epithelium inflammation at 50 and 150 mg/m3. There was no evidence of systemic toxicity in this study.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
mouse
Quality of whole database:
Comprehensive sub-acute to chronic studies, including multi-generation studies are available in rats and mice.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
150 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
There is a comprehensive sub-chronic inhalation toxicity study available. Comprehensive sub-acute to chronic oral studies, including multi-generation studies are available in rats and mice.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
10 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
There is a comprehensive sub-chronic inhalation toxicity study available. Comprehensive sub-acute to chronic oral studies, including multi-generation studies are available in rats and mice.

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

The 2003 EU RAR concluded:

"No useful information on the effects of repeated exposure to Bisphenol A in humans is available, but experimental studies in rats, mice, and dogs are available. In rat inhalation studies, the principal effect of repeated exposure was the same as observed following a single exposure: slight upper respiratory tract epithelium inflammation, with a NOAEC of 10 mg/m3and a LOAEC of 50 mg/m3. Dietary studies in rats have reported reductions in reproductive organ weights and testicular toxicity at 235 mg/kg and a NOAEL of 74 mg/kg was established in a two-year study based on marginal effects on body weight gain at the next dose level of 148 mg/kg. In mice, the LOAELs of 120 mg/kg in males for multinuclear giant hepatocytes and 650 mg/kg in females for a reduction in body weight gain of unknown magnitude were identifed in a two-year study. There are no animal data available for repeated dermal exposure."

 

The 2008 updated EU RAR concluded:

"Oral studies in rats and mice have shown that the repeated dose toxicity of Bisphenol A involve[s] effects on bodyweight gain, liver and kidney. A NOAEL of 50 mg/kg/day has been identified in a recent 2-generation study in mice for these effects. This NOAEL rather than the original NOAEL of 120 mg/kg/day for liver effects from the published report is taken forward to the risk characterisation."

 

In 2014 SCOEL published a Recommendation on Bisphenol A:

“To establish a recommended occupational exposure limit (OEL), SCOEL began by considering the available data relating to inhalation exposure. In rats exposed daily to airborne Bisphenol A for 13 weeks there was a NOAEC of 10 mg/m3, with mild olfactoryepithelium inflammation at 50 and 150 mg/m3. There was no evidence of systemic toxicity in this study (Nitschke 1988).”

 

EFSA reevaluated Bisphenol A and published a Scientific Opinion in 2015:

“Bisphenol A was found to affect kidney and liver weight in parental animals and in all the generations of rats and mice examined in multi-generation studies. These effects were considered by EFSA (2006, 2010) as relevant systemic effects for the identification of a NOAEL. In mice the increased kidney weight was associated with nephropathy at the highest Bisphenol A dose. Liver weight was increased in rats (relative weight) and mice (both absolute and relative weight). The latter species also showed hepatocellular hypertrophy. The CEF Panel considered the endpoint “general toxicity” for hazard characterisation, using a reference point from the two-generation study in mice, which provided a BMDL10 for mean relative kidney weight of 8 960 μg/kg bw per day in male mice of the F0 generation.”


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Study was selected by EFSA in 2015 as a starting point for TDI calculation

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Study was selected by SCOEL in 2014 as a starting point for TWA calculation

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Study was selected by SCOEL in 2014 as a starting point for TWA calculation

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; urogenital: kidneys

Justification for classification or non-classification

Bisphenol A is included in Annex VI of Regulation (EC) No 1272/2008. No classification regarding repeated dose toxicity is required.