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Key value for chemical safety assessment

Effects on fertility

Description of key information

In an enhanced combined repeated dose toxicity study with reproduction/developmental toxicity screening test in rats with oral application by gavage according to OECD guideline 422 in compliance with GLP (BASF SE, 2010) the NOAEL for reproductive performance and fertility was determined to be 1000 mg/kg body weight/day, the highest dose tested, for the F0 parental rats.

The NOAEL for general, systemic toxicity of the test substance is 1000 mg/kg body weight/day for the F0 parental animals, the highest dose tested. The NOEL (no observed effect level) is 10 mg/kg bw/d for the F0 parental rats based on treatment-related, local and non-adverse effects such as sinus histiocytosis in the mesenteric lymph nodes at 300 and 1000 mg/kg bw/d and granulomatous inflammation of one lung lobe with no corroborative clinical or pathological findings indicative of systemic toxicity at 100, 300 and 1000 mg/kg bw/d.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The key study is a combined repeated dose toxicty study with reproduction/developmental screening test according to OECD guideline 422 (BASF SE, 2010). In order to attain statistical power equivalent to that of a full-scale Generation study (e.g. OECD 416), this study enhanced the guideline recommendations of OECD TG 422 by increasing the group sizes to 22 - 25 pregnant females. The study was performed in compliance with GLP.

Kerocom F 100 was administered orally via gavage to groups of 25 male and 25 female Wistar rats (F0 animals) at doses of 10, 100, 300 and 1000 mg/kg body weight/day. Control animals were dosed daily with the vehicle (Olive oil Ph. Eur./DAB). The duration of treatment covered a 2-week pre-mating and mating period in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation in females.

Kerocom F 100 had no adverse effects on fertility of the F0 parental animals of both sexes at 10, 100, 300 and 1000 mg/kg bw/d. Almost all of the F0 parental animals proved to be fertile. The occurrence of a few infertile pairs in test groups 1, 3 and 4 (10, 300 and 1000 mg/kg bw/d) did not suggest any relation to treatment. Gross and histopathological examinations of the respective animals of both genders did not reveal test substance-induced findings, which may have accounted for the observed infertility. The test substance caused also no impairments of the reproductive performance. Mating behaviour, conception, gestation, parturition, as well as sexual organ weights and gross and histopathological findings of these organs were not influenced.

The following test substance-related adverse effects/findings were noted:

 

Test group 4 (1000 mg/kg bw/d):

F0 parental animals:

- Decreased hemoglobin values and red blood cell counts in rats of both sexes

- Increased ALT activities and globulin values in rats of both sexes

- Increased total protein, albumin, globulin and cholesterol values in males

- Increased incidences of higher blood values in the urine of males

F1 pups:

- Mmacroscopic changes related to the major pericardial blood vessels, specifically 7/282 pups from 5 litters with aneurysms in the descending aorta (1) or ductus arteriosus (6), compared to 0/248 in control pups

 

Test group 3 (300 mg/kg bw/d):

F0 parental animals:

- Increased incidences of higher blood values in the urine of males

F1 pups:

- Macroscopic changes related to the major pericardial blood vessels, specifically 2/245 pups from 2 litters with aneurysms in the ductus arteriosus, compared to 0/248 in control pups

 

Test group 2 (100 mg/kg bw/d):

F0 parental animals:

- No test substance-related adverse findings

F1 pups:

- Macroscopic changes related to the major pericardial blood vessels, specifically 1/260 pup with an aneurysm in the aorta descendens, compared to 0/248 in control pups

 

Test group 1 (10 mg/kg bw/d):

F0 parental animals:

- No test substance-related adverse findings

F1 pups:

- Macroscopic changes related to the major pericardial blood vessels, specifically 1/228 pup with an aneurysm in the ductus arteriosus, compared to 0/248 in control pups

 

Conclusion: The NOAEL for reproductive performance and fertility is 1000 mg/kg body weight/day for the F0 parental rats. The NOAEL for general, systemic toxicity of the test substance is 100 mg/kg body weight/day for the F0 parental males and 300 mg/kg body weight/day for the F0 parental females based on adverse clinical pathological findings at next higher doses.


Short description of key information:
In an enhanced combined repeated dose toxicity study with reproduction/developmental toxicity screening test in rats with oral application by gavage according to OECD guideline 422 in compliance with GLP (BASF SE, 2010) the NOAEL for reproductive performance and fertility was determined to be 1000 mg/kg body weight/day, the highest dose tested, for the F0 parental rats.

The NOAEL for general, systemic toxicity of the test substance is 1000 mg/kg body weight/day for the F0 parental animals, the highest dose tested. The NOEL (no observed effect level) is 10 mg/kg bw/d for the F0 parental rats based on treatment-related, local and non-adverse effects such as sinus histiocytosis in the mesenteric lymph nodes at 300 and 1000 mg/kg bw/d and granulomatous inflammation of one lung lobe with no corroborative clinical or pathological findings indicative of systemic toxicity at 100, 300 and 1000 mg/kg bw/d.

Effects on developmental toxicity

Description of key information

In an enhanced combined repeated dose toxicity study with reproduction/developmental toxicity screening test in rats with oral application by gavage according to OECD guideline 422 in compliance with GLP (BASF SE, 2010) a NOAEL for developmental toxicity in the F1 progeny could not be determined. The LOAEL for developmental toxicity was set to be 10 mg/kg bodyweight/day based on the finding of aneurysms of 2 major pericardial blood vessels in pups of all dose groups (10, 100, 300, and 1000 mg/kg bw/d). There was no apparent dose-related increase in the incidence of this lesion between the two lower Kerocom F100 treatment groups (0, 1, 1, 2, 7), representing a 10-fold range in administered dose.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
10 mg/kg bw/day
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

The key study is a combined repeated dose toxicty study with reproduction/developmental screening test according to OECD guideline 422 (BASF SE, 2010). In order to attain statistical power equivalent to that of a full-scale Generation study (e.g. OECD 416), this study enhanced the guideline recommendations of OECD TG 422 by increasing the group sizes to 22 - 25 (pregnant females). The study was performed in compliance with GLP. 

Kerocom F 100 was administered orally via gavage to groups of 25 male and 25 female Wistar rats (F0 animals) at doses of 10, 100, 300 and 1000 mg/kg body weight/day. Control animals were dosed daily with the vehicle (Olive oil Ph. Eur./DAB). The duration of treatment covered a 2-week pre-mating and mating period in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation in females. 

The NOAEL for general, systemic maternal toxicity of the test substance was determined to be 300 mg/kg body weight/day based on adverse clinical pathological findings at next higher dose (decreased hemoglobin values and red blood cell counts, increased ALT activities and globulin values). 

Macroscopical examination revealed aneurysms of 2 major pericardial blood vessels in pups of all dose groups (10, 100, 300, and 1000 mg/kg bw/d). The ductus arteriosus was the most frequently affected site where aneurysms occurred, thus, this seems to be the most sensitive area to develop aneurysms in this study.

Aneurysms were observed in pups from the lower dose groups (10 and 100 mg/kg bw/d), but at a lower incidence compared to the high dose group. Additionally, it must not be overlooked that there was no apparent dose-related increase in the incidence of this lesion between the two lower Kerocom F100 treatment groups (0, 1, 1, 2, 7), representing a 10-fold range in administered dose. This lack of internal consistency in the dose response at dose levels below 300 mg/kg bw/day must be taken into consideration when evaluating these findings. In other words, although the incidence of the lesion is higher in treatment groups than control, the ‘flat’ dose-response is contraindicative of a treatment-related finding below 300 mg/kg bw/day.

On the other hand, aneurysms were not observed in any control animal. In such cases, it is usual to refer to historical control data to determine if treatment groups are different to a ‘normal population’, or whether the disparity is due to an aberrant response in the concurrent control. Macroscopically visible aneurysms have so far not been observed as spontaneous findings in the Wistar rat strain. However, some of these lesions were observed in a special control study in PND 4 pups, under conditions (i.e. microscopic evaluation of the great vessels) not routinely applied to control animals in OECD 421/422 or OECD 415/416 study designs. The incidence in this control study was 1 dissecting aneurysm and 2 focal hemorrhages within the vessel wall, which are thought to be precursor lesions of aneurysm. This shows that such lesions can also develop in untreated animals, although rarely. 

In conclusion, the NOAEL for maternal toxicity of the test substance was determined to be 300 mg/kg body weight/day based on adverse clinical pathological findings at next higher dose. Based on the current limited knowledge, a NOAEL for developmental toxicity in the F1 progeny could not be determined. The LOAEL for developmental toxicity was set to be 10 mg/kg bodyweight/day based on the finding of aneurysms of 2 major pericardial blood vessels in pups of all dose groups (10, 100, 300, and 1000 mg/kg bw/d). There was no apparent dose-related increase in the incidence of this lesion between the two lower Kerocom F100 treatment groups (0, 1, 1, 2, 7), representing a 10-fold range in administered dose.

 

In a supporting study that was performed equivalent or similar to OECD guideline 421 (BASF SE, 2008) one aneurism in one pup of the 300 mg/kg bw/d dose group was observed. In this study, Kerocom F100 in olive oil was administered by gavage to groups of 10 female healthy young Wistar rats at doses of 100, 300 and 1000 mg/kg body weight/day from gestational day (GD) 6 through postnatal day (PND) 3. The dams were allowed to litter and rear their pups until PND 4. On PND 4, all pups were sacrificed and examined grossly, paying particular attention to potential pericardial blood vessel effects.

Justification for classification or non-classification

GHS classification according to Annex I 1272/2008 CLP (EU GHS):

Repr. Cat. 1B

Additional information