Registration Dossier

Administrative data

Description of key information

No data are available for acute inhalation toxicity. However, such study is not required since PMP particle size is higher than 100 µm.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 630 mg/kg bw
Quality of whole database:
Methoxyphenol is officially classified harmful by ingestion, and old published data gave the same results.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 23 sept 2008 to 19 dec 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study, carried out without any deviations to the guideline
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
other: OECD No 423 Acute Oral Toxicity – Acute Toxic Class Method
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories Ltd
- Age at study initiation: 9 weeks for males and 11 weeks for females
- Weight at study initiation: 187.3 g - 263.0 g
- Fasting period before study: no fasting period
- Housing: individually in Makrolon type-3 cages with standard softwood bedding
- Diet (e.g. ad libitum): pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet
- Water (e.g. ad libitum): community tap water from Füllinsdorf
- Acclimation period: 7/8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 30 - 70%
- Air changes (per hr): air-conditioned with 10-15 airs changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark


IN-LIFE DATES: From: 01 oct 2008 To: 15 oct 2008
Type of coverage:
semiocclusive
Vehicle:
other: purified water
Details on dermal exposure:
TEST SITE
- Area of exposure: back of animals, skin area of 12 cm2 and 9 cm2 in the males and females
- % coverage: approximately 10% of the total body surface
- Type of wrap if used: a surgical gauze patch


TEST MATERIAL
- Concentration: 2000 mg/kg bw
- Concentration used: yes
- For solids, paste formed: yes


VEHICLE
- Amount(s) applied: 0.1 mL
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations: during the first 30 minutes, at approximately 1, 2, 3 and 5 hours after administration on test day 1 and twice daily for viability / Mortality and once daily for clinical signs during days 2-15
- Weighing : on test days 1 (prior to administration), 8 and 15
- Necropsy of survivors performed: no
- Other examinations performed: clinical signs, body weight, macroscopic examination
Statistics:
no statistical analysis was used
Preliminary study:
A single animal of each sex was treated first. Since no death as well as no severe local effects or severe systemic symptoms were observed after the 24-hour exposure, the test was completed using the four remaining male and female animals for an exposure period of 24-hours.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
no deaths occured during the study
Clinical signs:
No clinical signs were observed in all 5 males and 5 females within the first 30 minutes following the treatment. No severe clinical signs were observed in all animals. Only slight signs were observed such as:
- ruffled fur: in 4 males and 1 female at the 2-hour observation and persisted up to the 5-hour observation, test day 2, 4 or 5. The remaining male and females were observed with the same clinical signs and same severity at the 5-hour observation and persisted in one female on test day 2.
- sedation: in all males and females and was distributed from the 2-hour post-dose to test day 6.
- closed eyes: all animals, except two males, were observed with complete to almost complete closed eyes in the first hours following the treatment.
One female was more affected than the other males and females with addition clinical signs such a slightly poor coordination from the 2- to 5-hour post dose and vocalisation when touched from test day 3 to 5.
Body weight:
Two females lost slightly body weight (0.3% and 5.8%) during the first week after treatment and recovered until the end of the study.
Gross pathology:
No macroscopic findings were recorded at necropsy.
Other findings:
Local dermal signs
Delayed local dermal reactions were observed in all males and females and consisted of erythema, oedema, scaling, focal to maculated crusts. The skin was affected from test day 3 to 5 (in most of the animals) to test day 7, 8, 11, 12 or up to the end of the observation (test day 15).
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
LD 50 (rat): greater than 2000 mg/kg body weight
Executive summary:

In an acute dermal toxicity study B96175, groups of 5 Wistar male and 5 Wistar female rats were dermally exposed to Paramethoxyphenol for 24 hours to 10% of the total body surface at dose of 2000 mg/kg bw.

Animals then were observed for 15 days.

Dermal LD50 > 2000 mg/kg bw

Paramethoxyphenol is not classified based on the LD50. (PMP is also not officially classified)

Slight clinical signs (sedation and ruffled fur) and local signs (erythema and scaling crusts) were generally observed in almost all animals. There were no treatment related macroscopic examination or changes in body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Acute oral toxicity:

Two studies are available, but their reliability in Klimisch rating is 3.

In the first one (Hodge et al. 1949), groups of 1-10 rats (unknown sex and strain) were given a single oral dose of PMP at doses of 1162, 1550, 1786, 2143 and 2187 mg/kg bw. Except the mortality, no data concerning the toxicity effects are given.

The oral LD50 = ca 1630 mg/kg bw.

In the second one (Anonymous 1959, report of Dow Chemical Company), group of 2 rats (unknown strain and sex) were given by single oral dose of PMP at 1000 or 2000 mg/kg bw. At 1000 mg/kg bw, kidney damages were observed at necropsy. At 2000 mg/kg bw, convulsions were noted 10 min after administration and depression, 2 hours after dosing.

The oral LD50 is between these 2 values : 1000< LD50 < 2000 mg/kg bw

Based on the LD50 in rat given by these 2 studies, PMP can be considered as harmful if swallowed, according to the Directive 67/548/EEC criteria (Xn R22), and to the EU CLP Regulation (EC) n°1272/2008 (acute toxicity category 4). This is also the official classification.

Acute inhalation toxicity:

No data are available for this route of exposure. However, no data for acute inhalation toxicity is needed since particle size is higher than 100 µm (Sieving + laser granulometry + measurement of the dustiness - see section 4.5).

Acute dermal toxicity:

One study was chosen as key study, of reliability 1 (RCC report, 2008). In an acute toxic class method, group of 5 Wistar females and 5 males rats were applied a single dose of PMP at 2000 mg/kg bw. At this dose, slight clinical signs (sedation and ruffled fur) and slight local signs (erythema and scaling crusts) were generally observed in almost all animals. These effects disappeared at day 7 after treatment.

The dermal LD50 > 2000 mg/kg bw

Based on the LD50 in rat given by this study, PMP can be considered as not classified by dermal route, according to the Directive 67/548/EEC criteria, and to the EU CLP Regulation (EC) n°1272/2008. PMP is not officialy classified for this endpoint.

Two other studies are referenced (anonymous, 1959; Dow Chemical Company report and Blaszcak et al. 1987) but are of reliability 3 and 4 respectively and are not sufficiently documented to permit a conclusion.


Justification for selection of acute toxicity – dermal endpoint
GLP study, OECD 423 compliant

Justification for classification or non-classification

Oral route: PMP is officially classified as harmful if swallowed (Xn, R 22) and as acute oral toxicity category 4 (H302: Harmful if swallowed) according to CLP Regulation (EC) n° 1272/2008 Annex VI table 3.1 and 3.2.

Inhalation: Since PMP particle size is higher than 100 µm, no study by inhalation route is required.

Dermal route: Based on the dermal LD50 in rats greater than 2000 mg/kg bw, PMP is not classified for dermal acute toxicity.