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Description of key information

NOAEL: 150 mg/kg bw derived from an OECD TG 408 (GLP) study.


NOAEL: 91.7 mg/kg bw derived from an OECD TG 443 (GLP) study

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
91.7 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The quality of the database is high because the information fulfils the REACH requirements: a 90-day study and an extended one generation test according to OECD guidelines (and GLP)

Additional information

Several repeated dose toxicity studies are available. The first key study is the 90-day dietary study. The second key study is the Extended One Generation Reproductive toxicity study (EOGRT), which full summary is in the Reproductive section, but key information is copied here too. 


Repeated dose toxicity study according to OECD TG 408, RIFM, 1996, see also EU-RAR, 2008 


In a 13-week oral toxicity study (OECD guideline 408, GLP,  RIFM, 1996) the test item was administered to 150 Crl:CD (SD)Br rats (5 groups of 15 males and 15 females) at doses 0, 5, 15, 50, or 150 mg/kg bw/day. The doses were based on a 2-week dose range finding study with doses 300, 600 and 1000 mg/kg bw/day. The mean achieved daily intakes were respectively 5.4, 15.7, 51.8 and 155.8 mg/kg bw for males and 5.1, 15.6, 51.9 and 154.6 mg/kg bw for females. After the treatment period, 3 males and 3 females from the control and the high dose groups were maintained for a treatment-free period of 4 weeks. All parameters measured from the OECD TG 408 have been recorded. Results: Clinical signs: There were no mortalities or adverse clinical signs. Body weight and food consumption of treated groups were similar to those observed in the control group. Haematology: Some finding done but not attributable to the administration of the test article. There were no statistically significant differences in any haematological parameter or blood chemistry values between test and control animals at the end of the treatment free period. Urinalysis: Some findings were done however none was related to treatment or significance was not clear. There were no differences between the control and high dose groups in urinary parameters at the end of the treatment free period. Biochemical parameters: A variety of statistically significant differences between control and test animals were seen in haematology and blood chemistry although these differences were all small, often not proportional to dose, often seen only at one time point and/or in one sex, and, with two exceptions, well within historical controls. Organ effects weight/macroscopy and histopathology: No significant histopathological findings at any dose in any tissue. It is concluded there were no significant adverse effects at any dose level up to the highest tested level and therefore the NOAEL was determined to be >150 mg/kg bw/day according to the authors.


EOGRT (OECD TG 443, CRL, 2021)


Under the experimental conditions of this EOGRT study (CRL, 2021), HHCB administered continuously in the diet to male and female Wistar Han rats at dose levels of 470, 825 and 1650 ppm induced no parental toxicity for F0 males exposed for 10 weeks prior to mating, during mating, and up to termination or for F0 females exposed for 10 weeks prior to mating, during mating, gestation and lactation through to weaning. Results: A parental NOAEL of at least 1650 ppm was derived, corresponding to a minimum achieved intake of 94.1 and 91.7 mg/kg/day in males and females, respectively (taken into account the lowest HHCB intake prior to mating or during gestation and lactation). A more extensive summary for both repeated dose and reproductive toxicity of this study is provided under section Toxicity to reproduction.


Repeated dermal toxicity studies not used for assessment due to Kl. 4 or 3. 


Three dermal subchronic studies are available. In two of these there was some evidence of liver weight increases (at 100 mg/kg bw/day for 13 weeks) and body weight decreases (at 36 mg/kg bw/day for 26 weeks) but the magnitude of these effects were not reported and their significance cannot be determined. (Gressel et al., 1980(1), Gressel et al., 1980(2)) These studies were assigned K4, because the uncertainties in the significance of the effects reported, the study was conducted without collar or occlusion to prevent oral intake of compound making it impossible to determine actual exposures and the area of application was not reported. In a third dermal 26-week study (Estes et al., 1980), no effects were seen up to and including the highest dose administered (200 mg/kg bw/day). This study was assigned K3, because the test material was applied dermally with no occlusion and with no other method for preventing oral ingestion, and because lack of an adverse effect dose.

Justification for classification or non-classification

Based on the results of the studies available, the substance does not have to be classified for repeated dose toxicity according to EU CLP (EC 1272/2008 and its amendments).

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