BPA CLH report / proposal for harmonised classification and labelling

BPA
CLH report / proposal for harmonised
CLH report / proposal
for harmonised classification classification
and labelling
29, October 2012
Jean Nicolas Ormsby (DER, anses)
1
Background
2009 : ministry of health requests Anses to assess health risks
in connection with consumer goods,
goods products and articles – BPA being
one in a list of 50 chemical substances/ endocrine disrupters
2010 : ministry
y of ecology
gy requests
q
Anses targeting
g
g BPA and
substitutes : summary of risks, identification of uses and exposure, HRA
feasibility, substitutes, recommendations in the framework of REACh.
-> Registry of Intentions (RoI) 21, July 2011
2
Background
•
Classification of BPA is harmonised in annex VI of CLP : Repr. Cat.3; R 62 /
Xi; R 37-41/ R 43 / R52
•
2002 : classification of BPA as reprotoxic cat.3 for fertility – though the initial
proposal from UK was to classify as reprotoxic cat. 2; R60. Member states
decided to take up discussions concerning the effects on development
when more studies would be available
available.
•
Since 2002 new studies have been published not yet evaluated by the CT
C&L.
•
The aim of the proposal is to harmonise the classification for fertility with
the conclusions of the sept.2011
p
report
p on health effects of BPA: key
y
studies identified in the report irrespective of their publication date together
with all new data published since 2002 on fertility (until 31 Dec 2011)
3
Current classification
CLP/GHS (29th ATP, 2002)
• Eye Dam. 1/H318 : Category 1/ causes serious eye damage • Skin Sens. A/H317 : C t
Category
1/
1/ may cause an allergic skin reaction.
ll i ki
ti
• Repr. 2/H361 : Category 2/ suspected of damaging fertility or the unborn child.
2/ suspected of damaging fertility or the unborn child
• STOT SE 3/H335 : Category 3/ may cause respiratory irritation
3/ may cause respiratory irritation
4
CLH report Low dose effects of BPA is controversial and could suggest the need to review
the current TDI. However the CLH report circumvents this obstacle as the
identification of health effects for « reproductive toxicity» does not depend on a
specific
f dose.
d
New data needed to this end : ‐adverse affects on reproduction and fertility / development
adverse affects on reproduction and fertility / development
‐effects on or via lactation
Studies :
ANSES 2011 Health effects report
Studies with doses > TDI ((5 mg/kg
g/ g p
pc/j)
/j)
Literature search for more recent studies
Æ Completeness ?
5
Effects on the female reproductive system
Animal studies :
Health effects of BPA (Anses, 2011) Inserm report 2010 on BPA and reproduction
Other studies since 2003
literature review : 40 academic studies + 2 studies OECD guidelines (Tyl.et al.)
Prenatal, perinatal, neonatal, prepuberty:
Effects on the reproductive tract and ovarian morphology
Effects on the meiosis and the oocyte development
Effects on the implantations
Effects on the age of puberty Effects on the estrous
ff
h
cycle
l
Effects on the hypothalamic‐hypophyseal axis
Effects on the female reproductive capacities Exposure during adulthood
Decrease in the number of pregnancies and implantations
Multigeneration exposure
6
Conclusion on animal female reproductive system Recognized effects in animals
Increased occurrence of ovarian cysts after prenatal and/or postnatal exposure
Early onset of puberty after prenatal and/or postnatal exposure
Adverse effects on the estrous cycle after prenatal and/or postnatal exposure
Adverse effects on the estrous
cycle after prenatal and/or postnatal exposure
Decline in the female reproductive capacities Suspected
p
effects in animals
Increased occurrence of endometrial hyperplasia Effects on oocytes development Decrease in LH concentration
‐> Only 2 negative studies out of 42 studies y
g
‐> Complex mode of action 7
Epidemiological studies – women
Population
Femmes suivant un protocole de
stimulation ovarienne Æ FIV
N = 84 (1121 cycles)
Results
Augmen. de conc. urinaire de BPA associée à :
- dim. du nbr d’ovocytes
-Dim du pic d’oestradiol
Ref.
Mok-Lin, 2010
Femmes subissant des FIV
N = 58
Association positive significative entre le conc. en BPA et la baisse
du succès de la FIV (serait du à une moindre qalité des ovocytes)
Fujimoto, 2010
femmes souffrant d’infertilité et
avec endométriose
N = 140
Pas d’association significative entre le taux urinaire de BPA et le
stade de l’endométriose
Itoh, 2007
Femmes, couple en évaluation de
leur fertilité
N = 137
Risque accru de perte implantatoire avec des conc. BPA croissante
Fillettes
Agées de 9 ans
N = 186
Ehrlich, 2012
Wolff, 2008
Pas de changement dans l’âge de la puberté
Fillettes
Agees de 6-8
6 8 ans
N =1151
Wolff 2010
Wolff,
8
Conclusion on the effects in women
Effects of BPA on oocyte maturation:
Decrease in the number of oocytes after ovarian stimulation and
i
impaired
i d oocyte
t quality
lit (one
(
study)and
t d ) d Fujimoto
F ji t ett al.,
l 2010)
Effects of BPA on the uterus, ovaries and outcome of pregnancies:
Endometriosis, endometrial hyperplasia, polycystic ovary syndrome,
miscarriages, and premature birth are reported in a few epidemiological studies
with however limitations (size of population, selection of participants, statistical
analysis, confounding factors) and require further investigations
Æ Human data to be considered with caution which nevertheless converge with
effects observed in animals
9
Conclusion on effects on male reproductive tract
IIn utero
t
and
d lactation
l t ti exposure per os (6 studies),
di ) subcutaneous
b
(3 studies)
di )
Neonatal and prepubertal exposure (10 studies)
Adult exposure (5 studies)
Multigeneration and transgeneration exposure ( 2 studies)
ÆVarious effects are observed with some discrepancies between studies.
However converging data concerning a decrease of testis weight,
weight sperm
count, and testosterone levels)
.Effects on sperm production linked to 5 week exposure during adulthood
(per os and subcutaneous).
.Effects on the male reproductive system due to exposure during puberty
(decrease of testosterone serum levels, alteration of sexual behaviour)
.Effects on the male reproductive system due to exposure during the pre‐
natal, neo‐natal and post‐natal (lactation) periods of exposure
Additional studies on mode of action suggest a possible reversible
disruption of Sertoli cell tight junction barrier by BPA
10
Epidemiological studies – men
Population
BPA urinary
concentration
Results
Ref.
Travailleurs
N = 218
Mediane = 39 (6-354)
µg/g creatinine
P concentration, motilité, vitalité des spermatozoïdes
Li, 2011
Hommes dans un couple
infertile
N = 190
ND – 36,4 ng/mL
P Concentration de spermatozoïdes et % de formes
typiques
N Fragmentation AND dans le noyau des
spermatozoïdes
Meeker, 2010b
travailleurs
Mediane = 53,7 µg
BPA/g Cr
Hommes impliqués dans une
FIV
N= 27
Expo pro au BPA
N = 153
3,7- 72,3 µg/g Cr
N Risque de dysfonctionnent sexuel/ baisse fonction
sexuelle mâle
Li, 2010a et
2010b
Baisse du nbr d’embryons et de leur qualité
Bloom, 2011
Dim de l’AGD chez petits garçons dont parents exposés
au BPA
Miao, 2011
11
Epidemiological studies – men
Population
BPA urinary
concentration
Results
Ref.
General
N = 715
1,3 – 11,5 ng/mL (24h)
Hommes : N total testosterone (N=316)
Galloway, 2010
Hommes dans un couple
infertile
N = 167
< 0,4– 36,4 ng/mL
N FSH, FSH/inhibin B et oestradiol/testosterone,
P inhibin B
Meeker, 2010a
< 0.4– 6.5 ng/mL
Pas de relation entre expo au BPA exposure et qualité
des gametes
P Index de T libre (testosterone totale/SHBG) ; N
SHBG
Mendiola, 2010
Hommes fertiles
N = 375
Æ relevance to general population ?
Æ preliminary results which call for further investigations Æconvergence with results from animal studies g
12
Animal studies
•
Reduction of the sperm production after an exposure of adults to BPA for 5
weeks ( 2 studies)(. 2004)
•
Suspected effects on the male reproductive system (decrease of plasmatic
concentrations
t ti
off testosterone,
t t t
changes
h
i sexuall behaviour)
in
b h i ) following
f ll i
an
exposure during pubertal age (Della Seta et al. 2006)
•
In female animals (converging results from studies undertaken during
development pre- and postnatal exposure), to be considered as recognized
effects : increased occurrence of ovarian cysts, early on onset of puberty
after prenatal and postnatal exposure, effects on the hypothalamic-pituitarygonadal axis after in utero or early postnatal exposure resulting in changes
of sex hormone levels and the expression of these hormones receptors.
•
IIn animals,
i l effects
ff
related
l d to exposure in
i adulthood
d l h d are related
l d (e.g.
(
number
b
of implantation sites, histological changes in the uterine wall, morphology of
the genital tract
13
Human studies
•
In women, effects of BPA on oocyte maturation (decrease in the
number of oocytes after ovarian stimulation and alteration of the
quality of collected oocytes) in a context of assisted reproductive
technology, are suspected on the basis of a high quality study and
another
th study
t d having
h i non major
j methodological
th d l i l limitations
li it ti
(F ji t
(Fujimoto
et al. 2010)
•
There are few other epidemiological studies available and they
present methodological limitations (study population size, selection
of participants, statistical analyses, confounding factors, etc.).
•
Experts consider that on the basis of human data related to the
effects of BPA on the endometrium (endometriosis, hyperplasia), the
ovaries (polycystic ovary syndrome) and the outcome of pregnancy
(miscarriages and prematurity) in women, it is not possible to draw a
conclusion.
14
Conclusion Many effects on the male and female reproductive systems are observed Need for to be confirmed in a number of cases There is overall evidence that BPA has reproductive toxicity • Classification cat. Repr. 2 : some evidence from humans or experimental animals and when results non sufficiently convincing to place under cat 1.
• Cat Repr. 1B : clear evidence of adverse effects from animal studies and a strong presumption in humans • Repr. 1A : clear evidence of adverse effects in humans
Æ Proposed classification Repr. 1B –
Proposed classification Repr 1B H360f H360f
… but open discussion regarding a classification Repr.1A according to the epidemiological evidence
15
Thank you for your attention
h k
f
i
16