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Proposition 65

Notice of Intent to List: Bisphenol A
[01/25/13]

Responses to Comments in Response to Notice of Intent to List: Bisphenol A
[04/22/13]

Comments in Response to Notice of Intent to List: Bisphenol A
[04/03/13]

Comment period extended [03/08/13]

Public Comments and Responses to Comments on Request for Information [01/25/13]

Amendment to Section 25805 Specific Regulatory Levels: Chemicals Causing Reproductive Toxicity - BPA [01/25/13]

Download this notice as a pdf file

The California Environmental Protection Agency’s Office of Environmental Health Hazard Assessment (OEHHA) intends to list the chemical Bisphenol A as known to the State to cause reproductive toxicity (developmental endpoint) under the Safe Drinking Water and Toxic Enforcement Act of 1986.1 This action is being proposed under the authoritative bodies listing mechanism.2

Chemical

CAS No.

Endpoint

Reference

Chemical Use

Bisphenol A

80-05-7

Developmental

NTP-CERHR (2008)

Component in polycarbonate plastic used in water bottles, present in epoxy resins used to line food cans.

OEHHA requested information relevant to the possible listing of Bisphenol A in a notice published in the California Regulatory Notice Register on February 12, 2010 (Register 2010, Vol. No. 7-Z). OEHHA received several comments. Responses to those comments are being provided separately.

Background on listing via the authoritative bodies mechanism: Under the Proposition 65 regulations, a chemical must be listed via the authoritative bodies mechanism when two conditions are met:

  1. An authoritative body formally identifies the chemical as causing reproductive toxicity (Section 25306(d)3.
  2. The evidence considered by the authoritative body meets the sufficiency criteria contained in the regulations (Section 25306(g)).

However, the chemical is not listed if scientifically valid data which were not considered by the authoritative body clearly establish that the sufficiency of evidence criteria were not met (Section 25306(h)).

The National Toxicology Program (solely as to final reports of its Center for the Evaluation of Risks to Human Reproduction [NTP-CERHR]) is one of several institutions designated as authoritative for the identification of chemicals as causing reproductive toxicity (Section 25306(l)).

OEHHA is the lead agency for Proposition 65 implementation. After an authoritative body has made a determination about a chemical, OEHHA evaluates whether listing under Proposition 65 is required using the criteria contained in the regulations.

OEHHA’s determination: Bisphenol A meets the criteria for listing as known to the State to cause reproductive toxicity (developmental endpoint) under Proposition 65, based on findings of NTP (NTP-CERHR, 2008).

Formal identification and sufficiency of evidence for BPA: In 2008, the NTP-CERHR published a report on Bisphenol A titled “NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Bisphenol A” (NTP-CERHR, 2008). The report concluded that the chemical causes developmental toxicity in laboratory animals at high levels of exposure. This report satisfies the formal identification and sufficiency of evidence criteria in the Proposition 65 regulations.

OEHHA is relying on the NTP’s conclusion in the report that there is clear evidence of adverse developmental effects in laboratory animals at “high” levels of exposure. NTP found that Bisphenol A caused decreases in litter size or number of live pups/litter in rats (Kim et al. 2001, Tyl et al. 2002b) and in mice (Morrissey et al. 1987, Tyl et al. 2002a, NTP, 1985); effects on prenatal or early postnatal growth in rats (Kim et al. 2001, Tyl et al. 2002b) and in mice (Morrissey et al. 1987, Tyl et al. 2002a, Tyl et al. 2008); and delayed puberty in male mice (Tyl et al. 2008), male rats (Tyl et al. 2002b, Tan et al. 2003) and female rats (Tyl et al. 2002b, Tinwell et al. 2002). These studies are briefly summarized in Table 1. These studies were reviewed by OEHHA with regard to the criteria in the regulation (Section 25306(g)(2)). Information reviewed in these studies included experimental design, route of administration, numbers of test animals, choice of species, choice of dosage levels and maternal toxicity. The table emphasizes data relevant to the criteria in the regulation and does not provide a comprehensive description of all findings in the studies tabulated.

Table 1. Information from studies cited by NTP in concluding that Bisphenol A had clear evidence for developmental toxicity at high levels of exposure.

Study

Design

Observations at the LOAEL

Maternal Toxicity

Developmental Toxicity

Morrissey et al., 1987

CD-1 mice
N=21–26
Exposures -
Period: GD 6–15
Route: gavage
Doses: 0, 500, 750, 1000, or 1250 mg/kg-day

LOAEL: 1250 mg/kg-day
↑ mortality
↓ body weight gain
↑ liver weight
↑ clinical observations
Not reported:
Food intake
Kidney weight
Histopathology

LOAEL: 1250 mg/kg-day
↑ % resorptions/litter
↓ fetal body weight

Kim et al., 2001

SD rats
N=14–20
Exposures -
Period: GD 1–20
Route: gavage
Doses: 0, 100, 300, 1000 mg/kg-day,

LOAEL: 300 mg/kg-day
No mortality
↑ clinical observations
↓ body weight gain
↓ food intake GD4
Not reported:
Organ weights
Histopathology

LOAEL: 300 mg/kg-day
↓ fetal body weight/litter
↓live fetuses/litter

NTP, 1985

CD-1 mice
N=19
Female exposure only, beginning one week prior to mating, for 14 weeks
Route: Diet
Dose: 1920 mg/kg-day

LOAEL: 1920 mg/kg-day
No ↑mortality
↑ liver and kidney weights
↑ liver/kidney histopathology
Not reported:
Clinical observations
Food intake (reported for
mating pairs)

LOAEL: 1920 mg/kg-day
↓ live pups/litter
↓ live male pups/litter
↓ live female pups/litter

Tyl et al., 2002b

SD rats
3-Generation Study
F0 N=30
Male and female exposures
Period: premating through lactation
Route: Diet
Doses: 0, 0.001, 0.02, 0.3, 5, 50, 500 mg/kg-day

LOAEL: 500 mg/kg-day
No mortality
Clinical observations not statistically analyzed
↑ food intake during gestation
↓ postpartum body weight
↑ kidney, liver, brain weight
↓ ovary weight
↑ liver/kidney histopathology

LOAEL: 500 mg/kg-day
↓ live pups/litter
↓ pups/litter
↓ implantation sites
↓ pup body weight pnd 4, 7,
14, 21

LOAEL (FI generation): 50 mg/kg-day
↑ age at vaginal opening
↑ age at preputial separation

Tyl, 2008

CD-1 mice
2-Generation Study

N=55 (control)
19–25 (BPA)
Exposures:
Period: premating through lactation
Route: Diet
Doses: 0, 0.003, 0.03, 0.3,5, 50, 600 mg/kg-day

LOAEL: 600 mg/kg-day
No mortality
Clinical observations not analyzed statistically
No reduced food intake
No body weight effects
↑ liver and kidney weight;
↑ liver/kidney histopathology
LOAEL: 600 mg/kg-day
↓ pup body weight pnd 7,14,21
↑ age at preputial separation
Tyl et al., 2002a

CD-1 mice,
1-Generation Study

N=20
Exposure:
Period: premating through birth
Route: Diet
Doses: 0, 875, 1750 mg/kg-day during gestation

LOAEL: 1750 mg/kg-day
No mortality
Clinical observations not analyzed statistically
No reduced food intake (g/kg)
↓ postpartum body weight
↑ postpartum liver kidney weights
↑ gestation length
↑ liver, kidney histopathology

LOAEL: 1750 mg/kg-day
↓ live pups/litter
↓ total pups/litter

Significant trend test; no pairwise effects ↓female pup weight

Tinwell et al., 2002 SD and Wistar rats, male and female
N=7
Exposure:
Period: GD 6–21
Route: gavage
Doses: 20, 100 μg/kg, 50 mg/kg
LOAEL: 50 mg/kg-day
No mortality
Not reported:
Body weight
Liver /kidney weight
Food intake
Clinical observations
Histopathology
LOAEL: 50 mg/kg-day
No effects litter size, sex ratio, birth weight
↑ age at vaginal opening
(Wistar)
Tan et al., 2003 SD rats, Male
N=12
Exposure:
Period days 23-53 postnatal
Route: gavage
Dose: 100 mg/kg
Not applicable LOAEL: 100 mg/kg
↓ number with preputial separation by day 53

↑ = increase; ↓ = decrease; GD= gestation day; pnd= postnatal day; N=number of animals per exposure group; LOAEL = Lowest Observed Adverse Effect Level for maternal or developmental toxicity

In the table, statistically significant results are presented with the exception of clinical observations and histopathology incidence, which were not statistically analyzed. Organ weights are relative to body weight. Maternal weight effects are reported as corrected gestational weight/weight gain or postpartum weight (weights that do not include fetuses). For multigeneration studies, data are from the F0 generation parents and offspring.

The above-described scientific evidence meets the criteria for listing specified in Section 25306(g)(2). In identifying clear evidence for “high” dose developmental toxicity of Bisphenol A, NTP identified the specific studies of individual endpoints of developmental toxicity that led to its overall conclusion. For all of the studies cited by NTP for decreases in litter size or number of live pups/litter in rats and mice, the exposures resulting in this manifestation of developmental toxicity were entirely prenatal (Kim et al. 2001, Tyl et al. 2002b, Morrissey et al. 1987, Tyl et al. 2002a, NTP, 1985). This endpoint provides a clear basis for listing of Bisphenol A under Proposition 65.

Effects on growth were also identified at birth in some studies (Kim et al. 2001, Morrissey et al. 1987), and early during the postnatal period in others (Tyl et al. 2002b, Tyl et al. 2008). In addition, effects on age at onset of puberty were reported after prenatal exposure only in one study (Tinwell et al. 2002), as well as after perinatal (Tyl et al. 2002b, Tyl et al. 2008) or postnatal exposure (Tan et al. 2003) in others. The formal identification of Bisphenol A as causing developmental toxicity is therefore supported by sufficient evidence of adverse developmental effects resulting from exposure during the prenatal period, and is consistent with findings from studies involving exposure during the postnatal period.

Request for comments: OEHHA is requesting comments as to whether Bisphenol A meets the criteria set forth in the Proposition 65 regulations for authoritative bodies listings. In order to be considered, OEHHA must receive comments by 5:00 p.m. on Monday, February 25, 2013. We encourage you to submit comments via e-mail, rather than in paper form. Comments transmitted by e-mail should be addressed to P65Public.Comments@oehha.ca.gov with “NOIL-Bisphenol A” in the subject line. Hard copy comments may be mailed, faxed, or delivered in person to the addresses below:

Mailing Address: Proposition 65
Office of Environmental Health Hazard Assessment
P.O. Box 4010, MS-19B
Sacramento, California 95812-4010
Fax: (916) 323-8803
Street Address: 1001 I Street
Sacramento, California 95814

Comments received during the public comment period will be posted on the OEHHA web site after the close of the comment period.

If you have any questions, please contact Sam Delson at sam.delson@oehha.ca.gov or at (916) 445‑6900.

References

Kim JC, Shin HC, Cha SW, Koh WS, Chung MK, Han SS (2001) Evaluation of developmental toxicity in rats exposed to the environmental estrogen bisphenol A during pregnancy. Life Sci. 69: 2611 – 2625.

Morrissey RE, George JD, Price CJ, Tyl RW, Marr MC, Kimmel CA (1987) The Developmental Tox­icity of bisphenol A in Rats and Mice. Fun­dam Appl Toxicol. 8: 571 – 582.

NTP-CERHR (2008). NTP-CERHR Monograph on the Potential Human Reproductive And Developmental Effects of Bisphenol A. Research Triangle Park, NC, National Toxicology Program: NIH Publication No. 08 – 5994.

NTP (1985) Bisphenol A: reproduction and fertility assessment in CD-1 mice when administered in the feed. NTP-85-192. Re­search Triangle Park, NC.

Tan BL, Kassim NM, Mohd MA (2003) Assessment of pubertal development in juvenile male rats after sub-acute exposure to bisphenol A and nonyl­phenol. Toxicol Lett. 143:261 – 270.

Tinwell H, Haseman J, Lefevre PA, Wal­lis N, Ashby J (2002) Normal sexual development of two strains of rat exposed in utero to low doses of bisphenol A. Toxicol Sci. 68:339 – 348.

Tyl RW, Myers CB, Marr MC, Sloan CS, Castillo NP, Veselica MM, Seely JC, Di­mond SS, Van Miller JP, Shiotsuka RN, Beyer D, Hentges SG, Waechter JM, Jr. (2008) Two-generation repro­ductive toxicity study of dietary bisphenol A (Bisphenol A) in CD-1(R) (Swiss) mice. Toxicol Sci. 104:362 – 384.

Tyl R, Myers CB, Marr MC. Abbreviated one-generation study of dietary bisphenol A (Bisphenol A) in CD-1® (Swiss) mice (2002a). In. Research Triangle Park, NC: RTI (spon­sored by the Society of the Plastics Indus­try, Inc.).

Tyl RW, Myers CB, Marr MC, Thomas BF, Keimowitz AR, Brine DR, Veselica MM, Fail PA, Chang TY, Seely JC, Joiner RL, Butala JH, Dimond SS, Cagen SZ, Shiot­suka RN, Stropp GD, Waechter JM (2002b) Three-generation reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley rats. Toxicol Sci. 68:121 – 146.

1Commonly known as Proposition 65, the Safe Drinking Water and Toxic Enforcement Act of 1986 is codified in Health and Safety Code section 25249.5 et seq.

2See Health and Safety Code section 25249.8(b) and Title 27, Cal. Code of Regs., section 25306.

3All referenced sections are from Title 27 of the Cal. Code of Regulations.

 
 
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