Sodium 4-propoxycarbonylphenoxide

Specific investigations: other studies

Administrative data

Endpoint:

endocrine system modulation

Type of information:

other: Publicataion

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Data source

Reference

Reference Type:

publication

Title:

Application of grouping and read-across for the evaluation of parabens of different chain lengths with a particular focus on endocrine properties

Author:

Susann Fayyaz, Reinhard Kreiling, Ursula G. Sauer

Year:

2021

Bibliographic source:

Clariant Produkte (Deutschland) GmbH, Sulzbach, Germany / Scientific Consultancy – Animal Welfare, Neubiberg, Germany

Results and discussion

Details on results:

Fayyaz et al evaluated all available and reliable in vivo data (especially level 4 and 5 of according to OECD CF for Testing and Assessment of Endocrine Disrupting Properties (OECD 2012) to address human health concerns with respect to 90-day repeated-dose toxicity, developmental and reproductive toxicity (DART), and endocrine disrupting potential for methyl, ethyl and propyl paraben.
For methyl paraben and propyl paraben, all higher-tier studies of relevance for the determination of repeated-dose toxicity, DART and endocrine disrupting potential have been requested under REACH. For both methyl paraben and propyl paraben, the NOAEL with regard to repeated-dose toxicity and DART was set at 1000 mg/kg bw/day. For ethyl paraben, a NOAEL of 1000 mg/kg bw/day for repeated-dose toxicity and DART was estimated by interpolation from methyl paraben and propyl paraben,i.e. the two category members on both sides of the target substance (ECHA 2008; OECD 2014). Additionally, for the sodium salts of methyl paraben, ethyl paraben and propyl paraben, read-across of the NOAEL of 1000 mg/kg bw/day for repeated-dose toxicity and DART also appears justifiable on account of their very high similarities (Tc0.98) as compared to the respective paraben.
Taking all this information together no ED concern can be expected or he test item Na-propyl paraben.

Any other information on results incl. tables

Outcomes of acute toxicity, local toxicity and genotoxicity studies assessing Na-methyl paraben, Na-ethyl paraben, Na-propyl paraben

Endpoint	Na-Methyl paraben	Na-Ethyl paraben	Na-Propyl paraben
CAS Number	5026-62-0	35285-68-8	35285-69-9
Acute oral toxicity studies using rats: LD50[mg/kg bw] (in brackets: OECD TG and date of study)
Acute toxicity	> 5000 (OECD 401; 1982)	3100 OECD 401; 1982)	> 5000 OECD 401; 1982)
Local toxicity studies using rats: Classification (in brackets: OECD TG and date of study)
Skin irritation / corrosion	Skin irritating[a] (OECD 439; 2012)	Not irritating (OECD 404; 1981)	Not irritating (OECD 404; 1982)
Eye irritation / corrosion	Serious eye damage (CFR, Title 16, 1500.42)	Irritating (OECD 405; 1982)	Serious eye damage (OECD 405; 1983)
Skin sensitisation	Not sensitising (read-across from methyl paraben)	Not sensitising (read-across from ethyl paraben)	Not sensitising (read-across from propyl paraben)
In vitroandin vivogenotoxicity studies: Classification (in brackets: OECD TG and date of study)
Mutagenicity in bacteria	Not mutagenic[a] (OECD 471; 2012)	Not mutagenic (read-across from ethyl paraben)	Not mutagenic (read-across from propyl paraben)
Mutagenicity in mammalian cells	Not mutagenic[a] (OECD 476; 2012)	Not a REACH information requirement for this tonnage (1-10 tonnes / year)	Not a REACH information requirement for this tonnage (1-10 tonnes / year)
Genetic toxicityin vivo	Not a REACH information requirement for this tonnage (10-100 tonnes / year)

Higher-tier test results for methyl paraben and propyl paraben: Parameters as per Table 14 in EFSA and ECHA (2018) that allow determining if a substance is, or is not, an endocrine disruptor

Parameter	Indicative of which modality?	OECD TG 408 (P0)	OECD TG 414 (foetus) [a]	OECD TG 421 (P0, F1) [b]	OECD TG 422 (P0, F1) [b]	OECD TG 443 (P0, F1, (F2))	NOAEL for MP / NOAEL for PP (mg/kg bw/day)
		Findings for methyl paraben / findings for propyl paraben
"In vivomechanistic" parameters as per EFSA and ECHA (2018)
Estradiol level	E, A, S	Optional: n. e.	n. r.	n. r.	n. r.	n. r.	Not applicable
Follicle stimulating hormone level	E, A, S	Optional: n. e.	n. r.	n. r.	n. r.	n. r.	Not applicable
Luteinising hormone level	E, A, S	Optional: n. e.	n. r.	n. r.	n. r.	n. r.	Not applicable
Triiodothyronine / thyroxine level	T	NAE / NAE	NAE / NAE (dams)	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Testosterone level	E, A, S	Optional: n. e.	n. r.	n. r.	n. r.	n. r.	Not applicable
Thyroid stimulating hormone level	T	NAE / NAE	NAE / NAE (dams)	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
"EATS-mediated" parameters as per EFSA and ECHA (2018)
Accessory sex organs HP	E, A, S	NAE / NAE	n. r.	n. a. / NAE	n. r.	n. r.	1000 / 1000
Age at first oestrus	E, A	Not addressed in any OECD TG, but only in the non-internationally accepted U.S. EPA guidance OPPTS 890.1450
Age at balano-preputial separation	E, A, S	n. r.	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Age at vaginal opening	E, A, S	n. r.	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Anogenital distance	E, A, S	n. r.	NAE / NAE	n. a. /NAE	NAE / NAE	NAE / NAE	1000 / 1000
Cervix HP	E, A, S	NAE / NAE	n. r.	n. r.	NAE / NAE	NAE / NAE	1000 / 1000
Coagulating gland HP	E, A, S	NAE / NAE	n. r.	n. r.	NAE / NAE	NAE / NAE	1000 / 1000
Coagulating gland weight	E, A, S	n. r.	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Colloid area (thyroid HP)	T	n. r.	n. r.	n. r.	Optional: n. e.	NAE / NAE	1000 / 1000
Cowper’s gland weight	E, A, S	n. r.	n. r.	Optional:n. e.	Optional:n. e.	n. r.	Not applicable
Epididymis HP	E, A, S	NAE / NAE	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Epididymis weight	E, A, S	NAE / NAE	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Oestrus cyclicity	E, A, S	NAE / NAE	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Glans penis weight	E, A, S	n. r.	n. r.	Optional:n. e.	Optional:n. e.	n. r.	Not applicable
Genital abnormalities	E, A, S	n. r.	NAE / NAE	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
HDL/LDL ratio [c]	T	NAE / NAE	n. r.	n. r.	n. r.	n. r.	1000 / 1000
LABC muscle weight	E, A, S	n. r.	n. r.	Optional:n. e.	Optional:n. e.	n. r.	Not applicable
Liver weight [c]	T	NAE / NAE	n. r.	n. r.	NAE / NAE	NAE / NAE	1000 / 1000
Mammary gland HP; males	E, A, S	NAE / NAE	n. r.	n. r.	NAE / NAE	NAE / NAE	1000 / 1000
Mammary gland HP; females	E, A, S	NAE / NAE	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Nipple development	A	n. r.	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Ovary HP	E, A, S	NAE / NAE	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Ovary weight	E, A, S	NAE / NAE	n. r.	Optional:n. e.	NAE / NAE	NAE / NAE	1000 / 1000
Oviduct HP	E, A, S	NAE / NAE	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Prostate HP [d]	E, A, S	NAE / NAE	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Prostate weight	E, A, S	NAE / NAE	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Seminal vesicles HP	E, A, S	NAE / NAE	n. r.		NAE / NAE	NAE / NAE	1000 / 1000
Seminal vesicles weight	E, A, S	NAE / NAE	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Sperm morphology	E, A, S	Optional: n. e.	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Sperm motility	E, A, S	Optional: n. e.	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Sperm numbers	E, A, S	Optional: n. e.	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Testis HP	E, A, S	NAE / NAE	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Testis weight	E, A, S	NAE / NAE	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Thyroid HP	T	NAE / NAE	NAE / NAE (dams)	Optional: n. e.	Optional:n. e.	NAE / NAE	1000 / 1000
Thyroid weight	T	NAE / NAE	NAE / NAE (dams)	Optional: n. e.	Optional: n. e.	NAE / NAE	1000 / 1000
Uterus HP (with cervix)	E, A, S	NAE / NAE	n. r.	Optional: n. e.	NAE / NAE	NAE / NAE	1000 / 1000
Uterus weight (withcervix)	E, A, S	NAE / NAE	NAE / NAE	Optional:n. e.	NAE / NAE	NAE / NAE	1000 / 1000
Vagina HP	E, A, S	NAE / NAE	n. r.	n. r.	NAE / NAE	NAE / NAE	1000 / 1000
Vaginal smears	E, A, S	NAE / NAE	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
"Sensitive to but not diagnostic of EATS" as per EFSA and ECHA (2018)
Adrenals HP	N	NAE / NAE	n. r.	n. r.	NAE / NAE	NAE / NAE	1000 / 1000
Adrenals weight	N	NAE / NAE	n. r.	n. r.	NAE / NAE	NAE / NAE	1000 / 1000
Auditory startle	N	n. r.	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Brain HP	N	n. r.	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Brain morphometric evaluation [e]	N	n. r.	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Brain weight	N	NAE / NAE	n. r.	n. r.	NAE / NAE	NAE / NAE	1000 / 1000
Dystocia	N	n. r.	n. r.	n. a. / NAE	n. r.	NAE / NAE	1000 / 1000
Fertility	N	n. r.	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Foetal development [f]	N	n. r.	NAE / NAE	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Functional observation battery [g]	N	n. r.	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Gestation length	N	n. r.	NAE / NAE	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Offspring: learning & memory	N	n. r.	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Litter size	N	n. r.	NAE / NAE	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Litter viability	N	n. r.	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Litter / pup weight	N	n. r.	NAE / NAE	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Motor activity	N	n. r.	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Motor and sensory function	N	This parameter is addressed in the OECD TG 426 DNT study only. The OECD TG 426 was not conducted since the findings from the EOGRTS DNT cohort provide at least comparable information.
No. of implantations,corpora lutea	N	n. r.	NAE / NAE	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
No. of live births	N	n. r.	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
No. of foetal deaths; viable foetuses	N	n. r.	NAE / NAE	n. r.	n. r.	n. r.	550, highest dose [a] / 1000
No. of ovarian follicles	N	n. r.	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Pituitary HP	N	NAE / NAE	n. r.	n. r.	NAE / NAE	NAE / NAE	1000 / 1000
Pituitary weight	N	NAE / NAE	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Postimplantation loss	N	n. r.	NAE / NAE	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Pre-implantation loss	N	n. r.	NAE / NAE	n. a. / NAE	NAE / NAE	n. r.	1000 / 1000
Presence of anomalies [h]	N	n. r.	NAE / NAE	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Pup development	N	n. r.	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Pup survival index	N	n. r.	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Reproduction	N	n. r.	n. r.	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Sex ratio	N	n. r.	NAE / NAE	n. a. / NAE	NAE / NAE	NAE / NAE	1000 / 1000
Time to mating	N	n. r.	n. r.	n. r.	n. r.	NAE / NAE	1000 / 1000
Tumour types	N	This information can potentially to be obtained from 2-year rodent bioassays. There is no evidence for carcinogenic potential of propyl paraben, or any other paraben.

Footnote to Table: Abbreviations: A: Androgen modality; bw: Body weight; E: Oestrogen modality; F₁/F₂: First / second generation offspring; HDL: High-density lipoprotein; HP: Histopathology; LABC:Levator ani bulbocavernosus; LDL: Low-density lipoprotein; MP: Methyl paraben; N: Not assignable to a given modality; n. e.: Not evaluated; n. r.: Not requested; NAE: No adverse effect; NOAEL: No-observed adverse effect level; P₀: Parental animals; PP: Propyl paraben; S: Steroidogenic modality; T: Thyroid modality; TG: Test guideline.

Colour legend:Greyshading: required as per Table 14 in EFSA and ECHA (2018); “optional”: as per that Table 14 and corresponding OECD TG.

The rows of this table list all parameters listed in Table 14 of EFSA and ECHA (2018). In addition to the TGs listed in the columns, Table 14 lists the following TGs:

·        OECD TG 407 (28-day repeated dose toxicity study): Not relevant for the assessment of endocrine disrupting potential of propyl paraben (or methyl paraben) since the impact of 28-day substance exposure is addressed in the (available) OECD TG 422.

·        OECD TG 415 und 416 (one- and two-generation reproductive toxicity studies): Not relevant for the assessment of endocrine disrupting potential of propyl paraben (or methyl paraben) since the (available) OECD TG 443 is the preferred method for the assessment of transgenerational effects.

·        OECD TG 426 (DNT study): not relevant for the assessment of endocrine disrupting potential of propyl paraben (or methyl paraben) since the (available) DNT cohort from OECD TG 443 provides comparable results.

Applicant's summary and conclusion

Executive summary:

For substances with endocrine disrupting properties, EU legislation specifically mandates regulation via a hazard-based approach (Brescia 2020). In line with these provisions, the present research article has focused on hazard identification of methyl paraben, ethyl paraben and propyl paraben (while also considering the further category member butyl paraben and briefly referring to the sodium salts of methyl paraben, ethyl paraben and propyl paraben). For methyl paraben and propyl paraben, all higher-tier studies of relevance for the determination of repeated-dose toxicity, DART and endocrine disrupting potential have been requested under REACH, and the findings from these studies have been presented herein. For both methyl paraben and propyl paraben, the NOAEL with regard to repeated-dose toxicity and DART was set at 1000 mg/kg bw/day. For ethyl paraben, a NOAEL of 1000 mg/kg bw/day for repeated-dose toxicity and DART was estimated by interpolation from methyl paraben and propyl paraben, i.e. the two category members on both sides of the target substance (ECHA 2008; OECD 2014). The chemical category of shorter-chained linearn-alkyl parabens is founded on their high structural similarity (the only difference between these parabens is their increasing chain length) and, importantly, on their common metabolic pathway. All category members exhibit similar physico-chemical properties and similar acute toxicity, local toxicity and genotoxicity potential. A rat toxicokinetics screening studies consistently showed that due to the very rapid elimination of these parabens and their major metabolite (that is further non-toxic), systemic target organs and tissues are not exposed to these compounds for a sufficiently long period of time for effects to evolve. Due to the consistency of the findings, the interpolation of a NOAEL of 1000 mg/kg bw/day for repeated-dose toxicity and DART for ethyl paraben is assessed as acceptable with high confidence. Performing the corresponding higher-tier studies, that encompass large numbers of animals, for the hazard assessment of ethyl paraben would breach the 3Rs principle implemented in Directive 2010/63/EU (EP and Council 2010) and Article 25(1) of the REACH Regulation (EP and Council 2006) that requires that testing on vertebrate animals shall be undertaken only as a last resort.

Additionally, for the sodium salts of methyl paraben, ethyl paraben and propyl paraben, read-across of the NOAEL of 1000 mg/kg bw/day for repeated-dose toxicity and DART also appears justifiable on account of their very high similarities (Tc0.98) as compared to the respective paraben.

To the best of the authors’ knowledge, this is the first time that a comprehensive dataset from higher-tier studies conducted following internationally agreed OECD TG test protocols and in full compliance with the GLP principles has become available for linear-alkyl parabens. The data also enable a comprehensive evaluation of the endocrine disrupting potential of these parabens according to all five levels of the OECD CF for Testing and Assessment of Endocrine Disrupting Properties(OECD 2012).The higher-tier (OECD CF Level 4 and 5) studies do not provide any indication that any endocrine activity (if it were presentin vivo) would be sufficiently pronounced to overwhelm the physiological adaptive capacities of endocrine systems leading to adversity as indispensable prerequisite for endocrine disruption (WHO IPCS 2002).

As compared to the hazard-based approach pursued under the REACH Regulation for the assessment of endocrine disruptors, a risk-based approach is applied in other jurisdictions, such as USA, Canada, Australia and Japan (Brescia 2020). Risk-based approaches include exposure assessment in addition to hazard assessment to derive a conclusion on the safety of the respective substance. As highlighted by Brescia (2020), the application of a risk-based approach for the assessment of endocrine disruptors is scientifically justified since the available scientific evidence indicates that endocrine disruption exhibits a concentration threshold below which no effects will occur (Brescia 2020). Accordingly, the setting of concentration limits provides an additional safeguard to ensure consumer protection. For example, for all four shorter-chained linearn-alkyl parabens, EFSA (2004), SCCS (2013), and EMA (2015) have concluded that they are safe to the consumer when used in food, cosmetics and human medicinal products for oral use, respectively, provided that specific concentrations are not exceeded. This estimation has been re-confirmed by the findings from the present research article.