Item | Information |
---|---|
CAS RN | 99-76-3 |
Chemical Name | Methyl 4-hydroxybenzoate (synonym: Methylparaben) |
Substance ID | R03-B-037-METI, MOE |
Classification year (FY) | FY2021 |
Ministry who conducted the classification | Ministry of Economy, Trade and Industry (METI)/Ministry of the Environment (MOE) |
New/Revised | Revised |
Classification result in other fiscal year | FY2008 |
Download of Excel format | Excel file |
Item | Information |
---|---|
Guidance used for the classification (External link) | GHS Classification Guidance for the Japanese Government (FY2019 revised edition (Ver. 2.0)) |
UN GHS document (External link) | UN GHS document |
Definitions/Abbreviations (Excel file) | Definitions/Abbreviations |
Model Label by MHLW (External link) | MHLW Website (in Japanese Only) |
Model SDS by MHLW (External link) | MHLW Website (in Japanese Only) |
OECD/eChemPortal (External link) | eChemPortal |
Hazard class | Classification | Pictogram Signal word |
Hazard statement (code) |
Precautionary statement (code) |
Rationale for the classification | |
---|---|---|---|---|---|---|
1 | Explosives | Not classified (Not applicable) |
- |
- | - | There are no chemical groups associated with explosive properties present in the molecule. |
2 | Flammable gases | Not classified (Not applicable) |
- |
- | - | Solid (GHS definition) |
3 | Aerosols | Not classified (Not applicable) |
- |
- | - | Not aerosol products. |
4 | Oxidizing gases | Not classified (Not applicable) |
- |
- | - | Solid (GHS definition) |
5 | Gases under pressure | Not classified (Not applicable) |
- |
- | - | Solid (GHS definition) |
6 | Flammable liquids | Not classified (Not applicable) |
- |
- | - | Solid (GHS definition) |
7 | Flammable solids | Classification not possible |
- |
- | - | No data available. Besides, there is information that it is combustible (GESTIS (Accessed Aug. 2021)). |
8 | Self-reactive substances and mixtures | Not classified (Not applicable) |
- |
- | - | There are no chemical groups present in the molecule associated with explosive or self-reactive properties. |
9 | Pyrophoric liquids | Not classified (Not applicable) |
- |
- | - | Solid (GHS definition) |
10 | Pyrophoric solids | Not classified |
- |
- | - | It is estimated that it does not ignite at normal temperatures from an autoignition temperature of >600 deg C (GESTIS (Accessed Aug. 2021)). |
11 | Self-heating substances and mixtures | Classification not possible |
- |
- | - | Test methods applicable to solid (melting point <= 140 deg C) substances are not available. |
12 | Substances and mixtures which, in contact with water, emit flammable gases | Not classified (Not applicable) |
- |
- | - | The chemical structure of the substance does not contain metals or metalloids (B, Si, P, Ge, As, Se, Sn, Sb, Te, Bi, Po, At). |
13 | Oxidizing liquids | Not classified (Not applicable) |
- |
- | - | Solid (GHS definition) |
14 | Oxidizing solids | Not classified (Not applicable) |
- |
- | - | The substance is an organic compound containing oxygen (but not fluorine or chlorine) which is chemically bonded only to carbon or hydrogen. |
15 | Organic peroxides | Not classified (Not applicable) |
- |
- | - | Organic compounds containing no bivalent -O-O- structure in the molecule. |
16 | Corrosive to metals | Classification not possible |
- |
- | - | Test methods applicable to solid substances are not available. |
17 | Desensitized explosives | Not classified (Not applicable) |
- |
- | - | There are no chemical groups associated with explosive properties present in the molecule. |
Hazard class | Classification | Pictogram Signal word |
Hazard statement (code) |
Precautionary statement (code) |
Rationale for the classification | |
---|---|---|---|---|---|---|
1 | Acute toxicity (Oral) | Not classified |
- |
- | - | [Rationale for the Classification] Based on (1) to (3), it was classified as "Not classified" (Category 5 in UN GHS classification). [Evidence Data] (1) LD50 for rats: 2,100 mg/kg (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2020), EPA (2005), CIR (Int. J. Toxicol., 27 (Suppl. 4)) (2008)) (2) LD50 for rats (males): 2,100 mg/kg (OECD TG 401) (AICIS IMAP (2015), REACH registration dossier (Accessed Aug. 2021)) (3) LD50 for rats: > 5,000 mg/kg (OECD TG 401) (AICIS IMAP (2015), REACH registration dossier (Accessed Aug. 2021)) |
1 | Acute toxicity (Dermal) | Classification not possible |
- |
- | - | [Rationale for the Classification] Classification not possible due to lack of data. |
1 | Acute toxicity (Inhalation: Gases) | Not classified |
- |
- | - | [Rationale for the Classification] Solid (GHS definition). It was classified as "Not classified." |
1 | Acute toxicity (Inhalation: Vapours) | Classification not possible |
- |
- | - | [Rationale for the Classification] Classification not possible due to lack of data. |
1 | Acute toxicity (Inhalation: Dusts and mists) | Classification not possible |
- |
- | - | [Rationale for the Classification] Classification not possible due to lack of data. |
2 | Skin corrosion/irritation | Not classified |
- |
- | - | [Rationale for the Classification] Based on (1) to (3), it was classified as "Not classified." [Evidence Data] (1) As a result of application of a 5% solution of this substance to the skin of 25 male volunteers and 25 female volunteers 10 times (4 to 8 hours/time) every other day, no irritant effects were observed (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2020)). (2) It was reported that, as a result of a skin irritation test with rabbits (n=9) (24-hour occlusive application), no skin irritation was observed (AICIS IMAP (2015)). (3) It was reported that, in a skin irritation test with rabbits (n=9) (24-hour occlusive application, observation for 72 hours), the primary dermal irritation index (PDII) was 0.67 (EPA (2005), REACH registration dossier (Accessed Sep. 2021)). |
3 | Serious eye damage/eye irritation | Not classified |
- |
- | - | [Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." Also, based on the new findings, the classification result was changed. [Evidence Data] (1) 0.1 to 0.3% solutions of this substance instilled in the eyes of humans produced moderate hyperemia, slight lacrimation, and slight burning, and all symptoms disappeared within 1 minute. It was reported that it was confirmed that instillation of these solutions several times daily into the eyes of more than 100 subjects produced no eye irritation (CIR (Int . J. Toxicol., 27 (Suppl. 4)) (2008)). (2) It was reported that, in an eye irritation test with rabbits (n=6), very slight irritation (irritation score: 1/110 points) was observed, but effect was fully reversible (AICIS IMAP (2015), REACH registration dossier (Accessed Sep. 2021)). [Reference Data, etc.] (3) This substance is moderately irritating to eyes (Patty (6th, 2012)). |
4 | Respiratory sensitization | Classification not possible |
- |
- | - | [Rationale for the Classification] Classification not possible due to lack of data. |
4 | Skin sensitization | Not classified |
- |
- | - | [Rationale for the Classification] Based on (1) to (3), it was classified as "Not classified." Also, based on the new findings, the classification result was changed. [Evidence Data] (1) As a result of a patch test of 91 patients affected with contact dermatitis, 2 patients showed positive reactions to 1% and 5% solution of this substance, and another 2 patients showed positive reactions to a 5% solution of this substance, and 3 of the above patients also showed positive reactions to ethyl form, propyl form, and butyl form, and one of them also showed positive reactions to 4-hydroxybenzoic acid, and therefore, cross sensitization was suggested (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2020)). (2) As a result of application of a 5% solution of this substance to the skin of 25 male volunteers and 25 female volunteers 10 times (4 to 8 hours/time) every other day, no irritant effects were observed. In addition, as a result of re-application after 3 weeks, no sensitization reactions were observed (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2020)). (3) It was reported that, in a Maximization test with guinea pigs (n=10), no positive reactions were observed (AICIS IMAP (2015)). [Reference Data, etc.] (4) This substance causes allergic contact dermatitis (Patty (6th, 2012)). |
5 | Germ cell mutagenicity | Not classified |
- |
- | - | [Rationale for the Classification] Based on (1) and (2), it was classified as "Not classified." [Evidence Data] (1) As for in vivo, negative results were obtained in a dominant lethal assay with rats (single or 5-consecutive day gavage administration) and a chromosome aberration assay using the rats bone marrow cells (single or 5-consecutive day gavage administration) (AICIS IMAP (2015), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2020), EPA (2005), REACH registration dossier (Accessed August 2021)). (2) As for in vitro, negative results were obtained in bacterial reverse mutation assays; and positive (+S9) and negative (-S9) results in the CHL/IU cells, and negative (+/-S9) results in the CHO cells were obtained in a chromosomal aberration study with the mammalian cells (Chinese hamster lung (CHL/IU) cells and Chinese hamster ovary (CHO) cells) (AICIS IMAP (2015), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2020), REACH registration dossier (Accessed August 2021)). |
6 | Carcinogenicity | Classification not possible |
- |
- | - | [Rationale for the Classification] There are neither sufficient carcinogenicity study reports for assessment nor existing classification results by domestic or international organizations. Classification not possible due to lack of data. [Reference Data, etc.] (1) In a test with rats subcutaneously injected for 52 weeks (twice/week, 0.6 to 3.5 mg/kg/day), tumor incidences were observed at the injection site, mammary gland, uterus, and other sites in females of a treatment group, and at the injection site and other sites in males, but in the incidence in tumor-bearing animals, no dose correlation was observed among groups. Although no rigorous statistical analysis was conducted, the authors reported that tumor incidence in the treatment groups was not significantly different from the control group (Canada CMP draft Screening Assessment (2020), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2020)). (2) In addition to (1), carcinogenicity of this substance was examined with mice by subcutaneous administration or intravenous administration, and no evidence of carcinogenicity was observed (AICIS IMAP (2015), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2020)). |
7 | Reproductive toxicity | Classification not possible |
- |
- | - | [Rationale for the Classification] Since contradictory effects were observed in epidemiological studies, classification was not possible. Besides, no reproductive/developmental effects were observed in animal studies in (1) to (3), however, an epidemiological study report suggested, based on (4), placental transfer and milk transfer of this substance, and based on (5) and (6), that this substance could affect pregnancy to delivery, and postnatal development of child born in humans. [Evidence Data] (1) It was reported that, in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD TG422, GLP) with rats dosed by gavage, no effects on fertility and sexual function of male/female parent animals and no effects on development of offspring (including serum T4 measurement value on postnatal day 13) were observed up to the limit dose of 1,000 mg/kg/day, except for slightly lower serum T4 level seen in male parental animals at 1,000 mg/kg/day (REACH registration dossier (Accessed August 2021)). (2) It was reported that, in each cohort in an extended one-generation reproductive toxicity study (OECD TG443, GLP) with rats dosed by gavage, no reproductive/developmental effects, developmental neurotoxicity, or developmental immunotoxicity was observed up to the limit dose of 1,000 mg/kg/day (REACH registration dossier (Accessed August 2021)). (3) It was reported that, in a prenatal developmental toxicity study (OECD TG414, GLP, administration during the organogenesis period) with pregnant animals (rats, mice, hamsters, rabbits) dosed by gavage, no maternal toxicity or developmental toxicity was observed in any species at dosed up to 550 mg/kg/day for rats and mice and at doses up to 300 mg/kg/day for hamsters and rabbits (Canada CMP draft Screening Assessment (2020), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2020), EPA (2005)). (4) This substance was detected in breast milk at a median concentration of 0.22 microg/L in Canadian women, 3 months postpartum. This substance was detected in placenta samples of 12 women from Barcelona (maximum concentration: 11.77 ng/g) and in amniotic fluid in 40 pregnant women in India (geometric mean concentration: 8.01 microg/L) (Canada CMP draft Screening Assessment (2020)). (5) A study of 1,006 randomly selected pairs of mothers and their children from an infant cohort in China examined the relationship between the concentration of this substance in urine collected from the mothers before delivery and the body weight and height of the children at birth. As a result, a positive correlation in male infants (527 infants) and a negative correlation in female infants (479 infants) were observed between the concentration in urine and the body weight, but it was not significant. As for the body height, a significant positive correlation was observed in male infants, but no significant correlation was observed in female infants. In addition, in a study for 922 pregnant Puerto Rican women, this substance in urine during the pregnancy period was correlated with a lower odds ratio of early delivery (0.70, 95%CI: 0.49 to 0.98) and a lower odds ratio of children with low birth weight (SGA) (0.66, 95%CI: 0.47 to 0.93) (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2020)). (6) Most of epidemiological study reports did not find a significant association between the levels of this substance in urine and reproductive endpoints. However, weak positive associations were observed between the levels of this substance in urine and increased time-to-pregnancy, lower odds of live birth in intrauterine insemination, select hormone levels in pregnant females, growth rates in male neonates and toddlers, and allergic sensitization. In addition, a negative association between the levels of this substance in urine, and BMI and body weight was detected in adolescents, pregnant women, and adults. Also, there are reports such as a weak inverse association found between the level of this substance in cord blood and fetal testosterone levels. On the other hand, other than growth rates in neonates and toddlers and fetal testosterone levels, different studies of similar quality gave conflicting results (Canada CMP draft Screening Assessment (2020)). [Reference Data, etc.] (7) As a result of oral administration to female rats after weaning on postnatal days 21 to 40, delayed vaginal opening day and decreased serum T4 levels were observed at the highest dose of 1,000 mg/kg/day (Canada CMP draft Screening Assessment (2020), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2020)). (8) This substance shows very weak estrogenic effects in a uterus proliferation test with rats (Canada CMP draft Screening Assessment (2020)). |
8 | Specific target organ toxicity - Single exposure | Category 3 (Narcotic effects) |
Warning |
H336 | P304+P340 P403+P233 P261 P271 P312 P405 P501 |
[Rationale for the Classification] Based on (1) and (2), it was classified in Category 3 (narcotic effects). Also, based on the new findings, the classification result was changed. [Evidence Data] (1) It was reported that, in an acute oral toxicity test with rats and mice, ataxia, and central nervous system depression were observed at a dose below 2,000 to 8,000 mg/kg (from the upper limit of Category 2 to the range corresponding to "Not classified") (EPA (2005)). (2) It was reported that, when a 0.1% solution of this substance was put in the mouth, the local anesthetic effect caused paralysis of the tongue or blunting of sensation a few minutes later (Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2020), JECFA FAS 5 (1974)). [Reference Data, etc.] (3) It was reported that, in a case in which a patient developed paraplegia following intrathecal chemotherapy, methylparaben (this substance) contained in the chemotherapy agents caused damage to the spinal nerve roots within the subarachnoid space, accounting for the neurologic deficit (CIR (Int. J. Toxicol., 27 (Suppl. 4)) (2008)). (4) As a result of an in vitro test, which examined the anesthetic effect of methylparaben (this substance), ethylparaben, and propylparaben on the isolated peripheral nerve and isolated spinal nerve of a frog, all three kinds of paraben compounds blocked the nerve transmission (CIR (Int. J. Toxicol., 27 (Suppl. 4)) (2008)). |
9 | Specific target organ toxicity - Repeated exposure | Classification not possible |
- |
- | - | [Rationale for the Classification] Based on (1) to (4), it was classified as "Not classified" in the oral route and dermal route. However, classification was not possible due to lack of data since there was no information on toxicity in the inhalation route. [Evidence Data] (1) It was reported that, in a repeated dose 28-day oral toxicity study in rodents (OECD TG407, GLP) with rats dosed by gavage, at or above 250 mg/kg/day (in the range corresponding to "Not classified"), labored respiration, rales, and gasping (1 female) were observed; and at 1,000 mg/kg/day (in the range corresponding to "Not classified"), piloerection, hunched posture, and urgency and killing due to moribundity (2 females) were observed, and by a necropsy, erosion of the stomach, and atrophy of the thymus and spleen were observed (Canada CMP draft Screening Assessment (2020), AICIS IMAP (2015)). (2) It was reported that, in a repeated dose toxicity study with the reproduction/developmental toxicity screening test with rats dosed by gavage (males: 28 days (14-day pre-mating period and 14-day mating period), females: from 14 days before mating to day 13 of lactation (up to 63 days)) (OECD TG422, GLP), no dose-related changes were observed at 1,000 mg/kg/day (in the range corresponding to "Not classified") (REACH registration dossier (Accessed Aug. 2021)). (3) It was reported that, in a repeated dose 90-day oral toxicity study in rodents (OECD TG408, GLP) with rats dosed by gavage, no dose-related changes were observed at 1,000 mg/kg/day (in the range corresponding to "Not classified") (REACH registration dossier (Accessed Aug. 2021)). (4) It was reported that, in a repeated dose 13-week dermal toxicity study with rats, no systemic effects were observed other than lower body weight and findings in treated areas at 0.7% (approx. 288 mg/kg/day, in the range corresponding to "Not classified") (Canada CMP draft Screening Assessment (2020)). |
10 | Aspiration hazard | Classification not possible |
- |
- | - | [Rationale for the Classification] Classification not possible due to lack of data. |
Hazard class | Classification | Pictogram Signal word |
Hazard statement (code) |
Precautionary statement (code) |
Rationale for the classification | |
---|---|---|---|---|---|---|
11 | Hazardous to the aquatic environment Short term (Acute) | Category 3 |
- |
H402 | P273 P501 |
It was classified in Category 3 from 48-hour EC50 = 35.8 mg/L for crustacea (Daphnia magna) (Results of Aquatic Toxicity Tests of Chemicals conducted by Ministry of the Environment in Japan (Ministry of the Environment, 1999), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2020)). |
11 | Hazardous to the aquatic environment Long term (Chronic) | Category 2 |
- |
H411 | P273 P391 P501 |
If chronic toxicity data are used, sufficient data on rapid degradability were not obtained. It is classified in Category 2 from 21-day NOEC = 0.2 mg/L for crustacea (Daphnia magna) (AICIS IMAP, 2017, Results of Aquatic Toxicity Tests of Chemicals conducted by Ministry of the Environment in Japan (Ministry of the Environment, 1999), Environmental Risk Assessment for Chemical Substances (Ministry of the Environment, 2020)). If acute toxicity data are used for a trophic level for which chronic toxicity data are not obtained (fish), sufficient data on rapid degradability were not obtained. It is classified in Category 3 from 96-hour LC50 = 59.5 mg/L for fish (Oryzias latipes). By drawing a comparison between the above results, it was classified in Category 2. The classification result was revised from the previous classification by changing how to classify it in chronic toxicity and using new information. |
12 | Hazardous to the ozone layer | Classification not possible |
- |
- | - | This substance is not listed in the Annexes to the Montreal Protocol. |
|