Registration Dossier

Administrative data

Description of key information

ORAL
In a repeated dose study of sufficient quality conducted using methods comparable to OECD guideline 407, BPA-DA did not cause any toxicity effects after administered to rats in diet at levels up to 4 % (approximately 2750-3160 mg/kg/day) for 30 days. The NOAEL was determined to be equal to or greater than 4 % in this study.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study with sufficient data to evaluate methods and results.
Reference:
Composition 0
Composition 0
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
: no data presented on hematology or clinical chemistry.
GLP compliance:
yes
Test material information:
Composition 1
Species:
rat
Strain:
other: Sprague-Dawley Crl:COBS®, CD®, (SD) Br
Sex:
male/female
Route of administration:
oral: feed
Details on oral exposure:
Groups of 10 rats/sex were fed BPA-DA at concentrations of 0, 1, 2 and 4% in the diet.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
30 days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0, 1, 2, and 4% of BPA-DA in basal diet (approximately 646 – 765, 1277 – 1490, and 2750 – 3160 mg/kg/day, respectively)
Basis:
nominal in diet
No. of animals per sex per dose:
10/sex/group
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
All rats were observed for mortality twice each day. Clinical signs and body weights were recorded at initiation and weekly thereafter. Food consumption was recorded weekly.
Sacrifice and pathology:
After 31 days of treatment, all surviving rats were weighed, killed and a gross necropsy was performed. At necropsy, the liver and kidneys of each animal were weighed and organ to body weight ratios determined. The following tissues were preserved from all animals: brain, pituitary, thoracic spinal cord, eyes, salivary glands, thyroid, parathyroids, thymus, trachea, esophagus, lung, heart, liver, spleen, kidneys, adrenals, stomach, pancreas, duodenum, jejunum, ileum, colon, cecum, mesenteric lymph node, urinary bladder, testes with epididymides and prostate (males), ovaries and uterus (females), femur, costal bone marrow, skeletal muscle, and all gross lesions. Microscopic evaluation was conducted on sections of the lungs, liver, brain and kidneys from rats of all treatment groups. Reproductive organs were not evaluated histologically.
Statistics:
The following statistical tests were utilized to evaluate body weight changes, total food consumption and organ weights: Bartlett’s test for homogeneity of variance and one-way classification analysis of variance (ANOVA). Since the ANOVA proved to be not significant for all of the analyses, no other tests were performed. All analyses were performed at the 5% one-tailed probability level.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
No deaths occurred during the study. No compound-related clinical observations were noted throughout the study. Body weight and food consumption data of the compound-treated males and females were generally comparable to those of their respective controls. Individual and mean terminal body weights, absolute organ weights and organ weights relative to terminal body weight were not affected by treatment. No compound-related organ or tissue changes were evident macroscopically or microscopically.
Dose descriptor:
NOAEL
Effect level:
>= 4 other: %
Sex:
male/female
Basis for effect level:
other: approximately 2750 to 3160 mg/kg/day
Critical effects observed:
not specified
Conclusions:
NOAEL >= 4% (approximately 2750 to 3160 mg/kg/day)
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 750 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
One study conducted under GLP conditions using methodology equivalent to a standardised guideline is available, the quality of the database is therefore considered to be adequate.

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

Mode of Action Analysis / Human Relevance Framework

Additional information

Oral

The repeated dose toxicity via the oral route of BPA-DA was investigated in a dietary-feeding study conducted using methodology similar to OECD guideline 407 under GLP conditions (Hazleton Laboratories America, Inc., 1982). The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

BPA-DA was administered in basal diet to groups of 10 male and 10 female Sprague-Dawley rats per dose at doses of 0, 1, 2, and 4 % (approximately 646 - 765, 1277 - 1490, and 2750 - 3160 mg/kg/day, respectively) for 30 days.

No deaths occurred during the study. No compound-related clinical observations were noted throughout the study. Body weight and food consumption data of the compound-treated males and females were generally comparable to those of their respective controls. Individual and mean terminal body weights, absolute organ weights and organ weights relative to terminal body weight were not affected by treatment. No compound-related organ or tissue changes were evident macroscopically or microscopically. The NOAEL was determined to be equal or greater than 4 % (approximately 2750 - 3160 mg/kg/day) in this study.

 

In accordance with section 1 of REACH Annex XI, it is considered justified to omit the 90 day repeated dose toxicity testing and further chronic toxicity testing on the grounds that the substance is not marketed as such on the EU market, but as a monomer in a polymer only and the residual levels are below 0.1 %. No toxicity was seen in the 30 day study; in conjunction with the lack of exposure, further repeated dose testing is therefore considered to be an inappropriate use of vertebrate animals.

 

Inhalation

In accordance with Column 2 of REACH Annexes VIII and IX, it is considered that the repeated dose toxicity study (required in Sections 8.6.1 and 8.6.2, respectively) by the inhalation route does not need to be conducted as exposure of humans via inhalation is unlikely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size. The substance is not marketed as such on the EU market, but as a monomer in a polymer only and the residual levels are below 0.1 %.

Furthermore, additional long-term repeated toxicity studies by this route as specified in section 8.6.3 of Annex X are considered not to be appropriate given the toxicological profile and use pattern of this substance.

 

Dermal

In accordance with Column 2 of REACH Annexes VIII and IX, it is considered that the repeated dose toxicity study (required in Sections 8.6.1 and 8.6.2, respectively) by the dermal route does not need to be conducted as significant skin contact is not likely, nor do the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin. The substance is not marketed as such on the EU market, but as a monomer in a polymer only and the residual levels are below 0.1 %.

Furthermore, additional long-term repeated toxicity studies by this route as specified in section 8.6.3 of Annex X are considered not to be appropriate given the toxicological profile and use pattern of this substance.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Only one study available.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to repeated dose toxicity.