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Administrative data

Description of key information

NOAEL (28 days, rats): 1000 mg/kg bw/day (based on overall assessment and quality of the data base)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate and reliable (Klimisch score 2) and consistent studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

A reliable oral repeated dose toxicity study (28-day) with 2 -chlorophenol (CAS 95 -57 -8) is available which was performed according to the Guideline for 28 -Day Repeated Dose Toxicity Test in Mammalian Species (Chemical Substances Control Law of Japan) and in compliance with GLP (Ministry of Health, Labour and Welfare, Japan, 2000, Study No. 8L658). Groups of 6 male and 6 female Spraque Dawely rats were exposed to the test substance at dose levels of 8, 40, 200 and 1000 mg/kg bw/day by oral gavage once daily for 28 consecutive days. A recovery group was included in the study which contained 6 males and 6 females exposed to the mid- and high-dose level for 28 days followed by test substance withdrawal for 14 days. Control animals received the vehicle corn oil. Observations and examinations of the animals included clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights, urinalysis, gross necropsy and histopathology. No mortality was observed at any dose. In the high-dose group tremors, decrease in locomotor activity, abnormal gait, salivation, and a prone or lateral position were observed in both sexes. Salivation was observed in both sexes of the mid-dose group. Clinical chemistry revealed a decrease in inorganic phosphorus in males and an increase in triglyceride in females of the high-dose group. In the liver, increases in absolute and relative weights in females and dark brownish discoloration in both sexes were observed in the high-dose group. Histopathological examination revealed centrilobular hypertrophy of hepatocytes in both sexes of the high-dose group. These changes disappeared or were diminished after withdrawal of the test substance in the recovery group. No alterations attributable to the administration of 2-chlorophenol were observed on body weight, food consumption, hematological examination, or urinalysis data. Based on the severity and reversibility of the observed effects, a NOAEL of 1000 mg/kg bw/day is considered for both sexes.

Supporting data on repeat dose toxicity are available, which include a 14 day repeat dose toxicity study and neuro-(juvenile/developmental) studies:

A 14-day repeat dose toxicity study with 2-chlorophenol was performed with male and female mice (reference 7.6.2-1). Groups of 12 male and female CD-1 mice were exposed to the test item at dose levels of 35, 69 and 175 mg/kg bw/day by oral gavage once daily for 14 consecutive days. Vehicle control animals received the vehicle corn oil. In addition, a treatment naive and a positive control group (cyclosphosphamide, 25 mg/kg bw/day) were included. Observations and examinations of the animals included clinical signs, body weight, food consumption, haematology, clinical chemistry, liver microsomal activities, immune response, genetic toxicology, certain reproductive toxicology endpoints, activity and behavioral measurements, gross necropsy and organ weights. All animals treated at 175 mg/kg bw/day died. At 69 mg/kg bw/day lower body weights were noted in both sexes. At 69 and 35 mg/kg bw/day, hyperactivity was noted in both sexes and reduced brain, liver and spleen weights were noted in females only. Due to missing clinical and pathological effects, the alterations on organ weights were not considered as adverse. Thus, based on the available data, a NOAEL of 69 mg/kg bw/day was defined.

In a further study (Hasegawa et al., 2005 as cited in ATSDR, 2013), newborn and young rats were treated with 2-chlorophenol at doses of 20, 50, 100 and 300 mg/kg bw/ day. Dosing was done by oral gavage and olive oil served as vehicle. Newborn rats (12 per sex/dose) were treated from postnatal day 4 to 21. On postnatal day 22, half of the rats were sacrificed for evaluation and the remaining animals were maintained in the study for a 9-week treatment-free recovery period. They were sacrificed at 12 weeks of age. Rats were evaluated for developmental milestones (e.g. surface righting, visual reflexes, fur appearance, tooth eruption, eye opening, preputial separation, vaginal opening and estrous cycle). Microscopic examinations of animals treated at 300 mg/kg bw/day revealed an increased incidence of basophilic tubules in males and females. No treatment-related adverse effects were observed for developmental milestones at any dose. No information was reported for examinations conducted after the recovery period. Based on the fact that no significant differences in the developmental effects determined were observed in newborn rats, a NOAEL for developmental effects of ≥ 300 mg/kg bw/day can be considered. In the same study (Hasegawa et al., 2005, as cited in ATSDR, 2013), young rats were treated orally by gavage with 2-chlorphenol at doses of 200, 500 and 1000 mg/kg bw/day for 28 days starting at an age of 5-6 weeks. Olive oil served as the vehicle. After the treatment period half of the rats were sacrificed for evaluation and the remaining animals were maintained in the study for a 2-week treatment-free recovery period and then sacrificed (11 to 12 weeks of age). At sacrifice, microscopic examinations of selected tissues (brain, pituitary, thymus, thyroid, heart, lungs, liver, spleen, kidneys, adrenals, testes epididymides, ovaries and uterus) were conducted for the 200 and 1000 mg/kg bw/day groups. The only effect noted was a slight centrilobular hypertrophy in the high dose group. No information was reported for examinations conducted after the recovery period. Based on the available data, a NOAEL ≥ 1000 mg/kg bw/day can be considered.

References not included in IUCLID

Agency for Toxic Substances and Disease Registry, Division of Toxicology and Human Health Sciences (ATSDR), 2013. Addendum to the toxicological profile for chlorophenols. Atlanta, GA 30333

Hasegawa et al., 2005 (as cited in ATSDR, 2013). Comparative susceptibility of newborn and young rats to six industrial chemicals. Congenit Anom (Kyoto) 45(4):137-145.

Justification for classification or non-classification

Based on the available data, 2-chlorophenol does not meet the classification criteria for repeated dose toxicity according to Regulation (EC) 1272/2008, which is in agreement with Annex VI of Regulation (EC) 1272/2008. Therefore, the data on repeated dose toxicity are conclusive, but not sufficient for classification.