Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information
NOEL (developmental toxicity, rabbit): 300 mg/kg bw/d
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
May 1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well performed and reported study. Relevant aspects (treatment, examinations etc.) are in line with the current guideline.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
only 12 animals in high dose group, body weight every 6 days recorded
GLP compliance:
no
Remarks:
performed before GLP guidelines
Limit test:
no
Species:
rabbit
Strain:
other: Dutch-belted
Details on test animals and environmental conditions:
Husbandry:
Virgin, adult female rabbits were individually housed in mesh bottom cages in temperature and humidity-controlled quarters with free access to food and fresh tap water.

.
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Beginning on Day 6 and continuing daily through Day 18 the females were dosed with 3, 14, 65 or 300 mg Methylparaben/kg bw or 2.5 mg 6-Aminonicotinamide/kg bw (positive control on Day 9). The negative controls were treated with the vehicle (water) at a level equivalent to the group receiving the highest dose level.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Details on mating procedure:
On Day 0, each doe was given an injection of 0.4 mL human chorionic gonadotropin (400 IU) via the marginal ear vein. 3 hours later, each doe was inseminated artificially with 0.3 mL of diluted semen from a proven donor buck using approximately 20 x 10(exp 6) motile sperm.
Duration of treatment / exposure:
Methylparaben:
Day 6 to Day 18 of gestation

6-Aminonicotinamide:
on Day 9 of gestation
Frequency of treatment:
Daily
Duration of test:
29 days
Remarks:
Doses / Concentrations:
3.0 mg/kg bw/d
Basis:
actual ingested
Remarks:
Doses / Concentrations:
14.0 mg/kg bw/d
Basis:
actual ingested
Remarks:
Doses / Concentrations:
65.0 mg/kg bw/d
Basis:
actual ingested
Remarks:
Doses / Concentrations:
300.0 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
Control: 14 mated animals (11 pregnant animals)
6-Aminonicotinamide: 17 mated animals (10 pregnant animals)
3.0 mg/kg bw/d Methylparaben: 20 mated animals (9 pregnant animals)
14.0 mg/kg bw/d Methylparaben: 20 mated animals (9 pregnant animals)
65.0 mg/kg bw/d Methylparaben: 14 mated animals (10 pregnant animals)
300.0 mg/kg bw/d Methylparaben: 12 mated animals (9 pregnant animals)
Control animals:
yes, concurrent vehicle
Details on study design:
None
Maternal examinations:
Body weight: on Days 0, 6, 12, 18 and 29 of gestation
Clinical signs/mortality: daily
Food consumption
Ovaries and uterine content:
On Day 29 of gestation all does were subjected to Caesarean section under surgical anethesia and the numbers of Corpora lutea, implantation sites, resorption sites and dead fetuses were recorded. The urogenital tract of each animal was examined in detail for normality.
Fetal examinations:
Body weights of the live pups were recorded. All fetuses underwent a detailed gross examination for the presence of external congenital abnormalities. The live fetuses of each litter were then placed in an incubator for 24 hours for the evaluation of the neonatal survival. All surviving pups were sacrificed and examined for visceral abnormalities (by dissection). All fetuses were cleared in potassium hydroxide, stained with Alizarin S dye and examined for skeletal defects.
Statistics:
None
Indices:
No data
Historical control data:
No data
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
- All pregnant animals (except of 1 female in the control group) survived until scheduled necropsy and no clinical signs were noted
- Body weights were not affected by treatment
- The relevant reproduction parameters (no. of Corpora lutea, implantation sites/dam, resorptions etc.) were not affected by treatment with the test item
Dose descriptor:
NOEL
Effect level:
300 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOEL
Effect level:
300 mg/kg bw/day (actual dose received)
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- Sex ratio and fetal body weight were not affected by treatment
- No dose related skeletal findings or soft tissue abnormalities
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
The administration of Methylparaben up to 300 mg/kg bw/d to pregnant rabbits (on days 6 to 18 of gestation) did not have any effect on maternal or developmental parameters. Based on the result of this study the NOEL for maternal and developmental effects can be set at 300 mg/kg bw/d.
Executive summary:

Methylparaben was administered to female pregnant rabbits from day 6 to day 18 of gestation. The test item was administered orally at dose levels of 3, 14, 65 and 300 mg/kg bw/d.

The administration up to 300 mg Methylparaben/kg bw/d had no clearly discernable effect on nidation or maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occuring spontaneously in the vehicle treated controls.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The study has Klimisch score 2.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no data available on developmental toxicity for sodium methylparaben. However, there are reliable data on methylparaben which is considered suitable for read-across using the analogue approach.

Sodium methylparaben (sodium 4-(methoxycarbonyl)phenolate) is the sodium salt of methylparaben (methyl 4-hydroxybenzoate). The substance is highly water soluble (418 g/L), dissociates in aqueous solutions and is hydrolysed to sodium hydroxide and the source substance methylparaben. Based on the assumption that upon oral and dermal administration, sodium methylparaben dissociates and is hydrolysed to methylparaben and sodium hydroxide, it was predicted that after exposure the primary effect is local irritation/corrosion at the site of contact due to sodium hydroxide.

Target and source substance are of low acute toxicity. No systemic or local effects were found up to single doses of 5000 mg/kg bw for sodium methylparaben and 2100 mg/kg bw for methylparaben. A dermal absorption of 80% was calculated for sodium methylparaben using QSAR and the available physico-chemical properties. For methylparaben, the dermal absorption was estimated in an in vitro test to be 84.7% in human skin (Fasano, 2004).

The results of several repeated dose toxicity studies indicate a low toxicological concern for methylparaben. Methylparaben caused no systemic toxicity and no effects on fertility or developmental toxicity. Moreover, toxicokinetic data have shown that methylparaben is completely absorbed after oral and dermal administration, hydrolysed, conjugated and rapidly excreted in urine. Thus, there is no evidence of accumulation.

As bioavailability and metabolism and therefore mammalian toxicity of sodium methylparaben were considered to be comparable to that of methylparaben, the assessment of systemic toxicity based on analogue approach can be considered as justified.

The developmental toxicity of methylparaben was evaluated in four studies in rabbits, rats, mice and hamsters similar to OECD guideline 414 study. No maternal and developmental effects were observed up to the highest tested dosages (300 mg/kg bw/d – rabbit; 550 mg/kg bw/d – rat; 550 mg/kg bw/d – mouse; 300 mg/kg bw/d – hamster).
Therefore, it is concluded that sodium methylparaben is not subject to classification and labelling according to Directive 67/548/EEC and Regulation 1272/2008/EC regarding developmental toxicity.


Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Toxicity to reproduction: other studies

Additional information

There are no data available on reproductive toxicity for sodium methylparaben. However, there are reliable data on methylparaben which is considered suitable for read-across using the analogue approach.

Sodium methylparaben (sodium 4-(methoxycarbonyl)phenolate) is the sodium salt of methylparaben (methyl 4-hydroxybenzoate). The substance is highly water soluble (418 g/L), dissociates in aqueous solutions and is hydrolysed to sodium hydroxide and the source substance methylparaben. Based on the assumption that upon oral and dermal administration, sodium methylparaben dissociates and is hydrolysed to methylparaben and sodium hydroxide, it was predicted that after exposure the primary effect is local irritation/corrosion at the site of contact due to sodium hydroxide.

Target and source substance are of low acute toxicity. No systemic or local effects were found up to single doses of 5000 mg/kg bw for sodium methylparaben and 2100 mg/kg bw for methylparaben. A dermal absorption of 80% was calculated for sodium methylparaben using QSAR and the available physico-chemical properties. For methylparaben, the dermal absorption was estimated in an in vitro test to be 84.7% in human skin (Fasano, 2004).

Therefore, it can reasonably be deduced that no higher amounts than tested in the acute oral toxicity study will be systemically available via the intact skin barrier. Inhalation is of no concern for the target as well as the source substance because of the low vapour pressure.

The results of several repeated dose toxicity studies indicate a low toxicological concern for methylparaben. Methylparaben caused no systemic toxicity and no effects on fertility or developmental toxicity. Moreover, toxicokinetic data have shown that methylparaben is completely absorbed after oral and dermal administration, hydrolysed, conjugated and rapidly excreted in urine. Thus, there is no evidence of accumulation.

As bioavailability and metabolism and therefore mammalian toxicity of sodium methylparaben were considered to be comparable to that of methylparaben, the assessment of systemic toxicity based on analogue approach can be considered as justified.

There are data available from a subacute oral toxicity study as well as from uterotrophic studies and male reproductive toxicity studies. All studies were used as part of a weight of evidence approach for the assessment of the reproductive toxicity potential of the test substance.

In a 28-day oral gavage study in rats (NOAEL 250 mg/kg bw/day), methylparaben did not cause any effects on estrous cycle and spermatogenesis of rats (Beerens-Heijnen, 2009). No effects on male and female reproductive organs (cervix, clitoral gland, epididymides, mammary gland, ovaries, preputial gland, prostate gland, seminal vesicles, testes, uterus and vagina) were observed during necropsy and histopathology.

Furthermore, methylparaben did not induce effects on reproductive organs (testes, epididymides, ventral prostates, seminal vesicles and preputial glands) and had no influence on sperm parameters (sperm motility, sperm count, sperm morphology and daily sperm production) and testosterone, LH/FSH blood levels when applied up to approximately 1140 mg/kg bw/d to male rats in two 56 day dietary studies (Hobermann, 2005; Oishi, 2004).

In two uterotrophic assays, methylparaben was orally applied to mice and rats and did not show any significant effect on uterus weight up to 100 and 800 mg/kg bw/d, respectively (Routledge, 1998; Hossaini, 1999). Furthermore, the premature vaginal opening and vaginal cornification was determined in rats. No increase in premature vaginal opening and vaginal cornification was observed up to the highest dose of 800 mg/kg bw/d. In two further uterotrophic assays, methylparaben was injected subcutaneously to mice and rats in doses up to 165 mg/kg bw/d (Lemini, 2003 and 2004). Due to significant increases in uterus weights, the estimated LOAELs for mice and rats were 16.5 and 55 mg/kg bw/d, respectively. However, this route is not relevant for exposure assessment. Moreover, a subcutaneously application of the test substance is considered to be a worst case scenario.

In summary, it can be concluded with sufficient certainty that sodium methylparaben will not cause toxicity to reproduction.

Justification for classification or non-classification

The available data on the toxicity to reproduction and the developmental toxicity of the test substance does not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and is therefore conclusive but not sufficient for classification.