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Administrative data

Description of key information

Studies of acute oral and acute dermal toxicity are available; reliable studies indicate low toxicity by these routes of administration.

Limited data also indicate low acute inhalation toxicity.

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:
No data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study conducted in accordance with OECD TG 423
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: Cr:CD(SD)GS
Sex:
female
Details on test animals and environmental conditions:
No further information
Route of administration:
oral: gavage
Vehicle:
other: 0.5% sodium CMC solution
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: not stated in report
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Preliminary study:
No data
Key result
Sex:
female
Dose descriptor:
LD0
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No rats died following treatment at the limit dose level, 2000 mg/kg bw.
Mortality:
None of the rats died.
Clinical signs:
Reddish coloured urine voided shortly after administration with recovery apparent within 2-3 days.
Body weight:
Slightly suppressed bodyweight gains recorded after administration with recovery apparent within 2-3 days.
Gross pathology:
No macroscopic abnormalities observed during necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
No evidence of toxicity at the limit dose of 2000 mg/kg bw when tested in female rats by single oral administration.
Executive summary:

Female rats dosed at 2000 mg/kg bw with biphenyl-4,4'-diol dispersed in 0.5% sodium CMC did not die, showed only transient signs of treatment related change - voiding reddish coloured urine in the two or three days following dosing, and having slight suppressed weight gain over the same period. Recovery was rapid and no signs of macroscopic abnormalities were apparent during necropsy.

No classification is required according to Regulation 1272/2008.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
Klimisch score = 1. Recent study conducted in compliance with modern test guidelines in female rats. Toxicity not apparent at the limit dose level.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size
other:
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
The Klimisch score for the range-finder was 3, unreliable, due to the restricted information available for test methods, results or doses administered.

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:
9 January 2011 to 8 March 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Test guideline and GLP compliant study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Italia S.p.A.
- Age at study initiation: 7-9 weeks (6-8 weeks at delivery, 176-188g on delivery)
- Weight at study initiation: 267-302g for males and 206-239g for females
- Fasting period before study: not applicable
- Housing: Individually in polycarbonate cages with stainless steel mesh lid and floor
- Diet (e.g. ad libitum): 4 RF 18 ad libitum
- Water (e.g. ad libitum): ad libitum supplied from water bottles
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-2
- Humidity (%): 55+/-15
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 9 January 2012 To: 24 January 2012
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 10% of body surface
- % coverage: 10
- Type of wrap if used:surgical gauze covered by synthetic film to provide a semi-occlusive dressing

REMOVAL OF TEST SUBSTANCE
- Washing (if done): after exposure the test material was removed by gentle swabbing with cotton wool and lukewarm water
- Time after start of exposure: 24 hrs

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- For solids, paste formed: yes, 0.5 ml of water added to weighed amount of test material at time of application
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
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 and weighing: daily observations, bodyweights recorded on days -1, 1, 8 and 15
- Necropsy of survivors performed: yes, on day 15
- Other examinations performed: clinical signs, body weight, morbidity/mortality
Statistics:
Median lethal dose exceeded the limit dose level so no statistical analysis required
Preliminary study:
Not applicable
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Median lethal dose exceeds the limit dose level of 2000 mg/kg bw
Mortality:
No rats died
Clinical signs:
No clinical signs were observed in male or female rats.
Body weight:
Bodyweight changes during the observation period were within the expected ranges.
Gross pathology:
A single ovarian cyst in one female was considered incidental.
No other macroscopic abnormalities were observed.
Other findings:
No effects were observed at the treatment site.
Interpretation of results:
GHS criteria not met
Conclusions:
The median lethal dermal dose was greater than 2000 mg/kg bw. On the basis of the results, 4,4'-biphenol does not require classification according to the requirements of Council regulation EC No 1272/2008.
Executive summary:

The acute toxicity of 4,4-Biphenol was investigated following single dermal administration to the rat. 2000 mg/kg was administered to a group of 5 male and 5 female animals for 24 hours under a semi-occlusive dressing. Following an observation period of 14 days, all animals were killed and subjected to necropsy examination.

No mortality occurred and no signs of toxicity were observed in male or female rats during the observation period. The body weight changes during the study were within the expected range. A single ovarian cyst was recorded for one female animal but was considered to be an incidental finding. No significant abnormalities were found at necropsy in the other treated animals and no abnormalities were observed at the treated site.

4,4 -Biphenol had no toxic effect on the rat following dermal exposure over a 24 hour period at a level of 2000 mg/kg. The median lethal dose was greater than 2000 mg/kg. European Directives concerning the classification, packaging and labelling of dangerous substances (Council Regulation (EC) No. 1272/2008 and subsequent revisions) indicate no classification is required.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
Klimisch score = 1. Modern study compliant with current test guidelines and GLP

Additional information

A Japanese NIHS study conducted in compliance with OECD Guideline 423 reports an acute oral LD50 value that exceeds 2000 mg/kg bw in rats. This result was consistent with information available from a less reliable range-finding result. There were no reported adverse effects in the main study either in-life or at necropsy.

A range-finding study reports a dermal LD50 of 1.78 ml/kg bw for rabbits, equivalent to 1.78 mg/kg but no information is presented for dose levels, effects or other findings. A modern dermal toxicity study in accordance with OECD Guideline 402 also shows low toxicity, the LD50 exceeds the limit dose of 2000 mg/kg bw. No signs of systemic toxicity were observed and there were no dermal reactions at the treatment site. 

The requirements for an acute inhalation toxicity study can be waived as studies by the oral and dermal routes are available, and based on the physico-chemical properties of the substance. Results from a screening study indicate the maximum atmosphere concentration that resulted in no deaths was tolerated by rats for an eight hour exposure period.


Justification for selection of acute toxicity – oral endpoint
Key study conducted in compliance with relevant test guideline .

Justification for selection of acute toxicity – inhalation endpoint
The range-finder gave limited information on lethality but confirmed absence of adverse effects. A waiver statement is presented to justify not conducting further investigations.

Justification for selection of acute toxicity – dermal endpoint
Sole study providing data from a guideline compliant study.

Justification for classification or non-classification

No classification is warranted for acute toxicity under CLP based on an absence of effects at the limit dose levels administered to rats via oral and dermal exposure routes. Generation of data via the inhalation route was waived, but information from a range-finding study indicated no adverse findings following 8 hour acute exposure to the maximum tolerated concentration.