Registration Dossier

Administrative data

Description of key information

oral: OECD 401: LD50 rat = 2733 mg/kg bw
inhalation: comparable to OECD403: LC50 rat (1h) > 949 mg/m³
dermal: comparable to OECD 402: LD50 rabbit >2000 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
30 Mar 1994 - 29 Jul 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
(1987)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
(1988)
Deviations:
no
Qualifier:
according to
Guideline:
other: EPA Pesticide Assessment Guidelines, Section 81-1 (1984)
Deviations:
no
Qualifier:
according to
Guideline:
other: MAFF Acute Oral Toxicity Study (1985)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc., Kingston, New York
- Age at study initiation: 51 or 52 days (animals were born on 7 Feb 1994 and dosed on 30 or 31 Mar 1994)
- Weight at study initiation: 146.4-162.8 g (males) and 92.4-109.7 g (females)
- Fasting period before study: overnight
- Housing: 2-3 animals per cage
- Diet: Purina Certified Rodent Chow #5002 (Purina Mills Inc., St. Louis, MO), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 40-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 30 or 31 Mar 1994 To: 13 Apr 1994
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 50%
Doses:
500, 2500, 5000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 or 15 days, respectively
- Frequency of observations: frequently on the day of treatment and at least once each working day thereafter
- Frequency of weighing: prestudy, on the day of treatment and on test days 2, 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
Means and standard deviations of body weights were calculated. The data were evaluated for statistical outliers by a sequential test, however, they were not routinely excluded from statistical analysis. The oral lethal dose 50 calculation was done by nonlinear interpolation.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 733 mg/kg bw
Based on:
test mat.
Mortality:
- 5000 mg/kg bw: 5/5 males, 5/5 females
- 2500 mg/kg bw: 2/5 males, 2/5 females
- 500 mg/kg bw: 0/5 males, 0/5 females
Clinical signs:
- 5000 mg/kg bw: laterally recumbent, decreased activity, faecal soiling, lacrimation
- 2500 mg/kg bw: salivation, decreased activity, urine soiling, laterally recumbent, laboured respiration, lacrimation, chromorhinorhea, faecal soiling
- 500 mg/kg bw: No clinical findings were noted throughout the study period.
Body weight:
All surviving rats gained body weight throughout the study period.
Gross pathology:
- 5000 mg/kg bw: haemolysed blood in digestive tract in 2/5 males; perineal soiling and lung congestion in 1/5 males; no grossly visible lesions in 5/5 females and 2/5 males
- 2500 mg/kg bw: haemolysed blood in digestive tract in 2/4 animals that died; perineal soiling in 2/4 animals that died; fibrous adhesions between the serosa of the nonglandular portion of the stomach and the liver in 3/3 surviving males; no visible gross lesions in 3/3 surviving females
- 500 mg/kg bw: No grossly visible lesions were noted at necropsy.

The findings of adhesions from the nonglandular portion of the stomach in the 3 surviving males of the 2500 mg/kg bw dose group suggests a direct effect of the test material, since nonspecific, stress related gastric lesions usually involve the glandular portion of the stomach. This direct effect probably was secondary to erosions or ulcers of the gastric mucosa that had healed by the end of the two week observation period. The other findings, haemolysed blood in the digestive tract and perineal soiling, seen in rats that died, are considered nonspecific by the authors.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
DSD: not classified
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
2 733 mg/kg bw
Quality of whole database:
The available information comprises an adequate and reliable study (reliability 1) and supporting data with slight qualitative deficiencies. Taken together, the information from these independent sources is consistent and provides sufficient quality for hazard assessment. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VII, 8.5 of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP, no guideline followed, but essentially compliant with acceptable standards
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
(only 1 h exposure, no individual animal data given, no data given on environmental conditions during exposure, only nominal concentration determined, no data on particle size distribution given, no necropsy performed)
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Weight at study initiation: 170-190 g
- Housing: in Makrolon cages Type III
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: ethanol/PEG 400
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: dynamic inhalation apparatus
- System of generating particulates/aerosols: The dissolved test item was dynamically sprayed into the inhalation chamber as an aerosol
Analytical verification of test atmosphere concentrations:
yes
Remarks:
The test item was sprayed along with oil red and adsorbed on cotton wool. From this, oil red was eluted quantitatively with xylene and recorded photometrically at 225 nm. The percentage of oil red/L air corresponded to the percentage of test material.
Duration of exposure:
1 h
Concentrations:
228, 447 or 949 mg/m³ air
No. of animals per sex per dose:
20 males
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days
- Necropsy of survivors performed: no
Sex:
male
Dose descriptor:
LC50
Effect level:
> 949 mg/m³ air
Based on:
test mat.
Exp. duration:
1 h
Remarks on result:
other: No clinical symptoms observed
Mortality:
There was no mortality observed throughout the study period.
Clinical signs:
other: There were no clinical signs observed throughout the study period.
Body weight:
There was no effect on body weight development observed throughout the study period.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
DSD: not classified
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
Value:
949 mg/m³
Quality of whole database:
The available information comprises adequate and reliable studies (reliability 1 and 2) and supporting data with slight qualitative deficiencies. Taken together, the information from these independent sources is consistent and provides sufficient quality for hazard assessment. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5 of Regulation (EC) No 1907/2006.

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:
27 Nov 1990 - 11 Dec 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: 84/449/EEC (Gazette of the European Community, No. L 251, p. 103) (1984)
Deviations:
no
GLP compliance:
yes
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: Winkelmann, Borchen, Germany
- Age at study initiation: young adult
- Weight at study initiation:229 g (males) and 191 g (females)
- Fasting period before study: no
- Housing: individually in Makrolon Type-II cages on low-dust wood granules (Ssniff, Soest/Westphalia, Germany)
- Diet: fixed formula standard diet Altromin 1324 Pellets (Altrmin GmbH and Co KG, Lage, Germany), ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 50±10
- Air changes (per hr): approximately 10
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Vehicle:
other: test substance was worked up into a paste using several drops of Cremophor E (non-ionic organic emulgator)
Details on dermal exposure:
TEST SITE
- Area of exposure: back and flanks
- % coverage: approximately 10% of the body surface
- Type of wrap if used: skin plaster (Fermoflexband, Beiersdorf AG, Germany)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with luke-warm water
- Time after start of exposure: 24 h

TEST MATERIAL
- Constant volume or concentration used: no (application volume for each animal was based on its body weight just prior to application)
- For solids, paste formed: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): several drops
Duration of exposure:
24 h
Doses:
2000 mg/kg bw (Limit test)
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: several times on the day of administration, twice daily thereafter (once daily on weekends and holidays)
- Frequency of weighing: directly before administration (day 1), after 1 week and at study termination
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred throughout the study period.
Clinical signs:
There were no test material related signs of systemic toxicity noted throughout the study period.
As a local skin change slight reddening was observed in males and females on the day after application, this redness turned to incrustation on day 5 and was more severe on females than on males. On day 10 (males) and 14 (females) skin of all animals was normal.
Body weight:
There were no test material related effects on body weights noted in 5/5 males and 2/5 females throughout the study period. In 3/5 females, a slight decrease in body weights was noted, however, at study termination all animals had surpassed their initial body weights again.
Gross pathology:
There were no test material related changes noted at necropsy.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
DSD: not classified
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
The available information comprises an adequate and reliable study (reliability 1) and supporting data with slight qualitative deficiencies. Taken together, the information from these independent sources is consistent and provides sufficient quality for hazard assessment. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5 of Regulation (EC) No 1907/2006.

Additional information

Acute toxicity: via oral route

A key study for acute oral toxicity in the rat was conducted with the test substance 2-phenylphenol (OPP) (Gilbert, K. S. and Crissmann, J. W., 1994 and Bomhard, E. M. et al., 2002). The methods complied with the OECD Guideline 401 (1987), the US-EPA-Guideline, Subdivision F, Series 81-1 (1984), Japanese MAFF Acute Oral Toxicity Study (1985) and EEC Method B.1 (1988). Five male and five female Fischer 344 rats per dose level received 500, 2500 or 5000 mg OPP/kg bw as a 50% suspension in corn oil by single-dose oral gavage. In-life observations were made frequently on the day of treatment and at least once each working day throughout the two-week observation period. Each surviving animal was weighed before study, the day of treatment, and on test days 2, 8 and 15. Necropsy was performed on all animals. LD50 was calculated by linear interpolation. The clinical signs observed (lacrimation, salivation, chromorhinorrhea, laboured respiration, decreased activity, lateral recumbency and urine and faecal soiling in the perineal area), occurred shortly after administration and lasted until the 9th day at the latest. Clinical signs were noted at doses ≥ 500 mg/kg bw. Mortalities occurred from 2500 mg/kg bw on. Two of the rats in the 2500 mg/kg group that died on day 2 had haemolysed blood in the digestive tract; three of the surviving males had fibrous adhesions between the serosa of the non-glandular portion of the stomach and the liver. In the 5000 mg/kg group, all of the females and two of the males died on day 1 without presenting gross lesions. Two males that died on day 2 had haemolysed blood in the digestive tract. The last male died on day 6 and had perineal soiling and lung congestion. Under the conditions of this study, the acute oral LD50 value of the test item was 2733 mg/kg bw.

Three further sources are available, supporting the result of the key study with acute oral LD50 values of >2500 mg/kg bw for male rats (Kimmerle, G. and Lorke, D., 1969), 2980 mg/kg bw for male rats (Loser, E. 1981 and Bomhard, E. M. et al., 2002) and 2700 mg/kg bw for male rats (Hodge, H. C. et al., 1952), respectively. A review on the toxicological assessment of OPP is further available presenting additional supporting studies (Bomhard, E. M. et al., 2002).

Acute toxicity: via inhalation route

A key study for acute inhalation toxicity in the rat was conducted with the test substance 2-phenylphenol (OPP) (Landry, T. D., 1992 and Bomhard, E. M. et al., 2002). The methods complied with the OECD Guideline 403 (1987), the US-EPA-Guideline, Subdivision F, Series 81-3 (1984) and Japanese MAFF Acute Inhalation Toxicity Study (1985). Five male and five female Fischer 344 rats were nose-only exposed for four hours to a solid aerosol of OPP. The physical properties of OPP limited the attainable aerosol concentration. The time-weighted average concentration during exposure was 36 mg/m³, which was approximately the highest attainable. More than 50% of the particles were less than 1 µm aerodynamic diameter and might thus reach the alveolar region when inhaled. In-life animal observations were made and body weights were taken during a two week post-exposure period. A complete gross pathological examination was conducted on each rat at the end of the 2-week post-exposure period. The test item as an aerosol exhibited no inhalation toxicity to the rat at the maximal technically producible concentration of 36 mg/m³ air. There were no clinical signs noted throughout the study period. Thus, the LC50 value of OPP is >36 mg/m³ air.

The second key study was conducted similar to the OECD Guideline 403. 20 male Wistar rats were exposed to an aerosol of the registered substance dissolved in ethanol/PEG 400 (Mihail, F. and Kimmerle, G., 1977 and Bomhard, E. M. et al., 2002). The LC50 value (1 h) for OPP was reported to be in excess of the highest concentration of 949 mg/m³ tested. No clinical symptoms were observed during exposure or the post-exposure period of 7 days. There was no effect on body weight development noted in any of the dose groups throughout the study period.

A further study is available, supporting the results of the key studies. Thyssen J. (1982) observed no mortality in male and female rats exposed to time saturated air for 7 h (as cited in Bomhard, E. M. et al., 2002).

In summary, three studies are available indicating that OPP is practically non-toxic after single inhalation exposure. There was no mortality observed in any of the available studies, neither were any signs of systemic toxicity noted. It can therefore be concluded that the LC50 is >949 mg/m³, even though this effect level is derived from a study conducted with exposure duration of 1 h. In general, 1 h of exposure is not sufficient for classification purposes; however, for substances, which are locally active, toxicity is concentration dependent rather than time dependent (ECHA, 2012f and ECHA, 2012g). The registered substance is locally active, as it is harmonised classified as irritating to the respiratory tract and data available to the registrant justify classification for skin irritation and serious eye damage (for further details see Section5.3.4). Thus, time scaling for the acute inhalation LC50 >949 mg/m³ is not deemed necessary. This is further supported by the fact that exposure to time saturated air for 7 h did not produce any signs of toxicity. Therefore, an acute inhalation LC50 >949 mg/m³ will be applied for the risk assessment.

Acute toxicity: via dermal route

A key study for acute dermal toxicity in the rat was conducted with the test substance 2-phenylphenol (OPP) (Bomhard, E., 1991 and Bomhard, E. M. et al., 2002). The methods complied with the guideline 84/449/EEC (Gazette of the European Community, No. L 251, p. 103) (1984) and was comparable to the OECD Guideline 402 (1981. The test item was applied dermally to young-adult male and female Wistar rats. Five rats were used per sex. The study was performed as a limit test using 2000 mg/kg body weight. The test substance was prepared as a paste using several drops of Cremophor E and applied semi-occlusively to the shaved skin of the animals (approximately 10% of body surface). The dressing was removed after 24 h and residual test substance was removed with tepid water. The animals were inspected several times on the day of administration and twice daily during the 14-day observation period (once on weekends and holidays). During inspections, type, onset, duration, and intensity of clinical signs were recorded; dead animals were removed if necessary. The animals were weighed individually directly before administration (day 1), after one week and at the end of the 14-day observation period. Gross pathological examinations were performed on all animals at the end of the study. No deaths resulted from the treatment at the dermal limit dose, therefore, additional dose levels were not tested and LD50 values were not determined. Only a slight reddening of the application site was observed on all animals on the day after application. This reddening became incrusted on the 5th day after application and was resolved at the end of the observation period. Body weight gain was only affected in 3 female rats during the first week after application, but all affected animals had surpassed their initial body weights at study termination again. No treatment-related gross lesions were observed. The dermal LD50 value for OPP was >2000 mg/kg bw.

A further source is available, supporting the result of the key study with an acute dermal LD50 value of >5000 mg/kg bw for male and female rats (Carreon, R. E. and New, M. A., 1981 and Bomhard, E. M. et al., 2002).

References:

ECHA. (2012f). Guidance on the application of the CLP criteria. Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures.European Chemicals Agency, Helsinki.

ECHA. (2012g). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health.European Chemicals Agency, Helsinki.


Justification for selection of acute toxicity – oral endpoint
The most reliable study (guideline study in compliance with GLP, reliability 1) was selected as key study and therefore chosen for the hazard assessment.

Justification for selection of acute toxicity – inhalation endpoint
The study with the most reliable outcome was chosen for the hazard assessment.

Justification for selection of acute toxicity – dermal endpoint
The most reliable study (guideline study in compliance with GLP, reliability 1) was selected as key study and therefore chosen for the hazard assessment.

Justification for classification or non-classification

Based on the available data for the registered substance, 2-phenylphenol does not meet the criteria to be classified for acute toxicity according to EU Directive 67/548/EEC and Regulation (EC) No 1272/2008.