4-chlorophenol

Carcinogenicity

Description of key information

Based on a chronic drinking water study in rats, as a NOAEL 50 mg/kg bw/d has been derived for 2-chlorophenol (2-MCP) as surrogate substance.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

1991

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data from review article (report on chlorophenols - systematic review and critical evaluation of relevant data). Basic data given.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

GLP compliance:

not specified

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: drinking water

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

2 years (pre- and postnatal exposure of progeny)

Frequency of treatment:

periodically

Remarks:

Doses / Concentrations:
500 mg/L
Basis:
nominal in water
equivalent to 50 mg/kg bw/d

Remarks:

Doses / Concentrations:
50 mg/L
Basis:
nominal in water
equivalent to 5 mg/kg bw/d

Remarks:

Doses / Concentrations:
5 mg/L
Basis:
nominal in water
equivalent to 0.5 mg/kg bw/d

Control animals:

yes, concurrent vehicle

Observations and examinations performed and frequency:

- Reproductive performance and effects on the progeny (body and organ weights, haematology, immunocompetence and carcinogenicity).

Sacrifice and pathology:

- Moribund and tumour bearing animals were examined microscopically.

Other examinations:

Females (age 3 w): Dams (12-14/group) were exposed from weaning through gestation (bred at day 90 d) and lactation. The progeny (24-28 animals of each sex/group) from each dose regime was continued on treatment from 3 w of age (weaning) until tumour development, death or termination of the study at 24 months.

Details on results:

50 mg/kg bw/d:
- No effect on tumour incidence, latency or type.
- Increased RBC, PCV, haemoglobin content after 52 weeks (2nd study year)
- Female rats: Litter size decreased, increased number of stillborn.

5 mg/kg bw/d: No adverse effects were observed.

Carcinogenicity: Negative in both sexes.

Dose descriptor:

NOAEL

Effect level:

5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: After 52 weeks: Increased RBC, PCV, and haemoglobin content; Female rats: Litter size decreased and increased number of stillborn

Remarks on result:

other: Effect type: toxicity (migrated information)

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects for carcinogenicity.

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Exon & Koller (1981, 1985) carried out 15 to 24-month studies on the effects of pre- and postnatal exposure of rats to 2-chlorophenol (2-MCP). No evidence of tumour initiation was revealed with exposure to 2-MCP at 500 mg/L drinking-water.

However, 2-chlorophenol acted as a promoter of the carcinogenic activity of ethylnitrosoures (ENU), reducing tumour latency and increasing tumour incidence in male rats exposed both pre- and postnatally, compared with controls receiving only ENU.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Estimated Klimisch Rating: 2

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

Based on the results of a surrogate substance the test substance is not considered to be classified under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EG. The available study on a surrogate substance considered reliable and suitable for classification purposes under 67/548/EEC. Moreover, the classification is in congruence with the DSD classification (Table 3.2) for the test substance.

 

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available data on a surrogate substance are also reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the test substance is not considered to be classified under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation No 605/2014. This is also in congruence with the harmonized classification – Annex VI – Regulation (EC) No 1272/2008 for the test substance.

Additional information

Oral - chronic studies:

Rats were administered with 2-chlorophenol (2-MCP) with a concentration of 5, 50, and 500 mg/L (equivalent to 0,5, 5, and 50 mg/kg bw/d) in the drinking water over a period of 104 weeks (RIVM, 1991). Reproductive performance and the pre- and postnatal exposure of progeny were observed. Females of F1 generation were exposed from 3 weeks of age through gestation and lactation (reproductive performance) and F2-animals were continued on treatment until termination of 24 months (carcinogenicity and toxicity after pre- and postnatal exposure).

At the highest dose rate, no effect on tumour incidence, latency or type was observed. Increased RBC, PCV, haemoglobin content were noticed after 52 weeks (2nd study year). In case of female rats, the litter size decreased and an increased number of stillborn was observed. No adverse effects were observed at a dosing rate of 5 mg/kg bw/d. No evidence of tumour initiation was revealed with exposure to 2-MCP at 500 mg/L drinking-water. So, no adverse effects for carcinogenicity were noticed in both sexes.

Thus, 50 mg/kg bw/d has been derived as the NOAEL for 2-chlorophenol (2-MCP) as surrogate substance.

 

Overall, there was no evidence of carcinogenic activity of the test substance itself.

 

However, 2-chlorophenol acted as a promoter of the carcinogenic activity of ethylnitrosoures (ENU), reducing tumour latency and increasing tumour incidence in male rats exposed both pre- and postnatally, compared with controls receiving only ENU.

Justification for selection of carcinogenicity via oral route endpoint:
Reliable data from review article, 2-chlorophenol was the testing substance.