Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Read across from source substance:

Subacute repeat oral dose toxicity study (OECD 407): NOAEL 10 mg/kg bw/day (Umano 2012)

Combined repeat dose toxicity study with reproductive toxicity screening (OECD 422): NOAEL 30 mg/kg/day; Anon (2011)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subacute
Species:
rat
System:
other: The NOAEL was based on the duced body weight gain and abnormal estrous cycles in the female rat in the intermediate dose group

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

During the treatment period, a dose-dependent decrease in overall mean body weight gain was apparent in all groups of toxicity and recovery phase males and females exposed to the test item when compared to controls; this decrease in overall weight gain was largely attributable to lower body weight gain and body weight losses. The reduction in body weight performance was evident among the reproductive phase females in the gestation and lactation period and was considered to be an adverse effect. Another finding is the possible endocrine effects as demonstrated by the Leydig cell atrophy and irregular estrous cycles noted in both the OECD 407 and OECD 422. This effect correlate with the reduced secretory content in prostate and seminal vesicles with no evidence of recovery. Effect on estrous cycles also correlate with the failure in mating and inability to achieve pregnancy

Additional information

In a subacute toxicity study conducted on rats in accordance with OECD 407 under GLP (Umano, 2012), The substance was administered to 30 male and 30 female Sprague-Dawley rats by oral gavage at dose levels of 10, 30 and 100 mg/kg bw/day for up to 28 consecutive days.  Although there was no recovery phase, this is not a guideline requirement.  The key findings in this study were lower body weight gain at 100 mg/kg/day for males and at 30 and 100 mg/kg/day for females; lower white cell counts in males at 100 mg/kg/day; lower cholesterol levels in both sexes at 100 mg/kg/day; lower cholinesterase and higher bilirubin levels in females at 100 mg/kg/day; longer oestrous cycles in females at 100 mg/kg/day; lower absolute and relative prostate and seminal vesicles weights at 100 mg/kg/day, possibly reflecting the lower body weight; higher adrenal weight in males at 100 mg/kg/day; Leydig cell atrophy at 100 mg/kg/day in 5/10 males; hypertrophy of the adrenal zona fasciculata at 100 mg/kg/day in 8/10 males, 2/10 females; atrophy of mammary glands in 3/10 males at 100 mg/kg/day; decreased haematopoiesis in bone marrow and extramedullary haematopoiesis in spleen at 100 mg/kg/day in 4/10 and 2/10 males, respectively.  Many findings were related to endocrine effects, but had not considered that some may have been secondary to the lower body weights.  Without having the individual data, it is not possible to comment further.  In conclusion, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity was 10 mg/kg bw/day due to findings of reduced body weight gain and abnormal estrous cycles in the female rat treated at 30 mg/kg bw/day.

In a combined repeated dose toxicity study with reproductive toxicity screening OECD TG 422 conducted in rats according to GLP, dose levels of 30, 100 and 300 mg/kg bw/day and generally followed OECD Guideline 422, but the males were dosed for a total of 6 weeks, with a recovery group maintained for a further 2 weeks.  All non-recovery females were mated after 2 weeks dosing, then reared until around Day 4 post partum.  Recovery females were not mated, were dosed for a total of 6 weeks followed by 2 weeks recovery.  Although mating was not obviously affected, there were no pregnancies at 300 mg/kg bw/day.  At 30 and 100 mg/kg bw/day, there were 10/12 and 8/12 females pregnant, respectively, although only 9 and 7 females had live offspring compared with 11 control females.  Because of these findings, inter-group comparisons for females were confounded by the different pregnancy statuses of the females.  Reproductive findings will be discussed under developmental/ reproductive toxicology.  The other key findings were lower body weight gain of both sexes at 100 and 300 mg/kg bw/day; lower haemoglobin, red cell counts and haematocrit in males at 300 mg/kg bw/day; lower cholesterol levels in both sexes at all dose levels; lower albumin levels in males at 100 and 300 mg/kg bw/day; lower epididymides and testis weights at 300 mg/kg bw/day; higher liver and adrenal weights in males at 300 mg/kg bw/day; lower heart weights in females at 30 and 100 mg/kg bw/day possibly reflecting lower body weights; Leydig cell atrophy in males at 100 and 300 mg/kg bw/day, with almost complete regression after 14 days recovery; reduced secretory content in prostate and seminal vesicles with no evidence of recovery; centrilobular hepatocyte enlargement in males at all levels and in females at 100 and 300 mg/kg bw/day, with evidence of recovery.

Based on the 2 studies, the key findings were lower weight gain in males at ≥100 mg/kg/day and in females at ≥ 30 mg/kg/day; lower cholesterol levels in both sexes at ≥100 mg/kg/day and possibly at 30 mg/kg/day; lower epididymides and testis weights at 300 mg/kg/day; higher liver and adrenal weights in males at 300 mg/kg/day, with possible increase in adrenal weights at 100 mg/kg/day; Leydig cell atrophy at ≥100 mg/kg/day with regression during recovery period; reduced secretory content in prostate and seminal vesicles with no evidence of recovery at ≥100 mg/kg/day; centrilobular hepatocyte enlargement in males at ≥30 mg/kg/day and in females at ≥100 mg/kg/day, with evidence of recovery.

The key value for chemical safety assessment used was NOAEL = 10 mg/kg bw/day (Umano, 2012).

In another repeated dose toxicity study (Klimisch 3 - unreliable study; Feng 2012), the substance was administered to 30 Sprague-Dawley male rats by gavage at dose levels of 2, 10, 50 and 100 mg/kg bw/day along with a vehicle control group for 14 days.  Key finding included, decreased total serum cholesterol at dose of 50 and 200 mg/kg/day,   Reduced serum testosterone and increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were observed in rats in the higher dose groups. Dose related accumulation of the testate in the testes, decline in genes and protein involved in cholesterol biosynthesis, transport and steroid biosynthesis. Similarly, the testicular mRNA levels of inhibin B, estrogen receptor (ER) and luteinizing hormone receptor (LHR) also decreased in rats given a dosage of 200 mg/kg/d. The NOEAL for male Sprague-Dawley rats was < 10 mg/kg/bw.

In an uterotrophic and Hershberger repeated dose test (Klimisch 3 - unreliable study; Yamasaki 2003), the test item was administered to rats via subcutaneous injections and oral garage at dose levels of 8, 40 and 100 mg/kg bw/day and 50, 200 and 600 mg/kg bw/day respectively. Test item related effects were noted in both female and male individuals in their respective tests at the tested concentrations, significant reduction in weight increase and significant increase glans penis weight observed in the 200 and 600 mg/kg bw/day male treatment groups. Mortality of two individuals was also observed in the male Hershberger test at the highest dose group.  There was also significant increase in relative uterus weight in the 8 and 40 mg/kg bw/day dose groups. The NOAEL for male and female rats was < 8 mg/kg bw/day based on histopathology results, where a significant increase in organ weight (uterus) was observed in female individuals, there is an implication that the test item has estrogen agonistic properties.

Justification for classification or non-classification

The analogous source substance meets the criteria for classification as STOT-RE Category 2 in accordance with Regulation (EC) No 1272/2008 (CLP). This classification is based on the following:

- Lower absolute and relative prostate and seminal vesicle weights ar 100 mg/kg bw/day (Umano et al., 2012)

- Higher adrenal weights in males at 100 mg/kg bw/day (Umano et al., 2012)

- Leydig cell atrophy at 100 mg/kg bw/day (Umano et al., 2012)

- Lower epididymide & testes weights at 300 mg/kg bw/day (OECD 422, Anon., 2011)

- Higher liver & adrenal weights in males at 300 mg/kg bw/day (OECD 422, Anon., 2011)

- Leydig cell atrophy at 100 mg/kg bw/day (OECD 422, Anon., 2011)

- Reduced secretory content of prostate and seminal vesicle at 100 mg/kg bw/day (OECD 422, Anon., 2011)

Based on an analogue approach to related degradation products BPAF  (the source substance), one may conclude the target substance is also having the same toxicological profile for Repeated dose toxicity, meeting the criteria to classify STOT RE cat.2, in accordance with Regulation (EC) No 1272/2008 (CLP).