Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Effect on fertility: via dermal route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information

In a reproduction/developmental toxicity screening test according to OECD 421 and GLP, 4-methylanisol was given daily via gavage (100, 300 and 1000 mg/kg bw/d in olive oil) to groups of 10 male and 10 female Wistar rats (BASF90R0506/09068). The duration of treatment covered premating period of 2 weeks and a mating period (max. of 2 weeks) in both sexes, and in females the entire gestation period as well as 4 days of lactation and approximately 1 week thereafter.

 

Clinical observations indicated distinct toxicity in the exposed parental animals (300 and 1000 mg/kg bw/d) but not in the animals receiving 100 mg/kg bw/d:

The high-dose parental animals of both sex showed clinical signs of systemic toxicity such as abdominal position shortly after treatment, apathy, unsteady gait / ataxia in single animals after several occasions during study. Alterations of food consumption had been observed at 300 and 1000 mg/kg bw/d. At 1000 mg/kg bw/d a decrease of food consumption had been observed in both sexes during treatment weeks 0-1. In the following treatment period week 1-2, food consumption increased over control in both sexes. In females this increased food consumption was also observed in the beginning of gestation (GD 0-14), normalized afterwards and finally decreased during lactation (-52%, PND 1-4). At 300 mg/kg bw/d, decreased food consumption could only be observed in females during lactation, but increased food consumption was observed during treatment weeks 1-2 in both sexes and in females during the

whole time period of gestation. The observed alterations of feeding resulted in decreased body weight gain in males in treatment weeks 0-4 (-39%) and in females during gestation (-36%) and lactation (-70%) in the high-dose group. A decreased body weight resulted in males in treatment weeks 3-4 and in females on GD 20 and PND 4 at 1000 mg/kg bw/d. Finally, the terminal body weight was decreased in both sexes (up to -9%) at high dose and in males at mid dose (-5%).

Regarding pathology, at 300 and 1000 mg/kg bw/d male and female test animals showed a dose-dependent enlargement of the liver characterized by centrilobular hypertrophy of hepatocytes.

 

The test compound did not adversely affect fertility of the F0 generation parental animals at all dose levels as there were no changes of male/female mating and fertility indices, time until successful copulation, duration of pregnancy and mean number of implantations. The test substance led to no treatment-related changes in the genital organs of males (testes and epididymides) and females (ovaries). These results confirmed, that adverse effects of the test substance on fertility were not observed in this study.

 

Overall, under the conditions of this reproduction/developmental toxicity screening test, the NOAEL for fertility is 1000 mg/kg bw/d for the F0 parental rats.

The NOAEL for general, systemic toxicity of the test substance is 100 mg/kg bw/d for the F0 parental animals based on clinical signs observed, reduced food consumption and decreased body weight/body weight gain in both sexes at 1000 mg/kg bw/d and the findings at 300 mg/kg bw/d. Although food consumption in both sexes as well as decreased terminal body weight in males was altered with a low magnitude at 300 mg/kg bw/d, these effects showed a dose dependency and were therefore considered for the derivation of the NOAEL.

 

A dermal reproduction/developmental toxicity screening test according to OECD 421 and GLP has been performed in order to provide data on the most appropriate route of administration, since the dermal route represents the most likely route of human exposure for 4-methylanisol (BASF82R0506/09C017). In this key study, 4-methylanisol was administered via dermal administration (6 hours/day; 7 days/week, semi-occlusive dressing) to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 (corn oil served as vehicle control), 100, 300 and 1000 mg/kg bw/ d. The duration of treatment covered premating period of 2 weeks and a mating period (max. of 2 weeks) in both sexes, approximately 1 week post-mating in males, and the entire gestation period until gestation day (GD) 19 in females. The females were not treated during at the end of gestation and during lactation.

Regarding clinical examinations, no signs of general toxicity were observed for males and females up to a dose level of 1000 mg/kg bw/d 4-methylanisol.

Regarding pathology, there were no treatment-related necropsy or histological findings in ovaries, testes or epididymides associated with dermal administration of 4-methylanisol at any dose level.

 

 

Concerning fertility parameters, 4/10 males in the 100 mg/kg bw/d test group and 1/10 males in the 300 mg/kg bw/d test group did not generate F1 pups, having an impact on the male and female fertility indices. No histomorphological correlate was found to explain these apparent infertilities and no relation to dosing was observed making a relation to treatment unlikely. Other fertility parameters did also not indicate adverse effects of 4-methylanisol at any dose level tested.

 

Overall, under the conditions of this reproduction/developmental toxicity screening study the NOAEL for general systemic toxicity as well as reproductive performance and fertility in male and female Wistar rats was 1000 mg/kg bw/d.


Short description of key information:
Reproduction/developmental toxicity screening test (according to OECD 421 and GLP) - oral (BASF90R0506/09068):
NOAEL general systemic toxicity = 100 mg/kg bw/d
NOAEL fertility >= 1000 mg/kg bw/d


Reproduction/developmental toxicity screening test (according to OECD 421 and GLP) - dermal (BASF82R0506/09C017):
NOAEL general systemic toxicity >= 1000 mg/kg bw/d
NOAEL fertility >= 1000 mg/kg bw/d

Effects on developmental toxicity

Description of key information
Reproduction/developmental toxicity screening test (according to OECD 421 and GLP) - oral (BASF90R0506/09068): 
NOAEL general systemic toxicity = 100 mg/kg bw/d
NOAEL developmental toxicity = 100 mg/kg bw/d
Reproduction/developmental toxicity screening test (according to OECD 421 and GLP) - dermal (BASF82R0506/09C017):
NOAEL general systemic toxicity >= 1000 mg/kg bw/d
NOAEL developmental toxicity >= 1000 mg/kg bw/d
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
100 mg/kg bw/day
Effect on developmental toxicity: via dermal route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information

In a reproduction/developmental toxicity screening test according to OECD 421 and GLP, 4-methylanisol was given daily via gavage (100, 300 and 1000 mg/kg bw/d in olive oil) to groups of 10 male and 10 female Wistar rats (BASF90R0506/09068). The duration of treatment covered premating period of 2 weeks and a mating period (max. of 2 weeks) in both sexes, and in females the entire gestation period as well as 4 days of lactation and approximately 1 week thereafter.

 

Clinical observations indicated distinct toxicity in the exposed parental animals (300 and 1000 mg/kg bw/d) but not in the animals receiving 100 mg/kg bw/d:

The high-dose parental animals of both sex showed clinical signs of systemic toxicity such as abdominal position shortly after treatment, apathy, unsteady gait / ataxia in single animals after several occasions during study. Alterations of food consumption had been observed at 300 and 1000 mg/kg bw/d. At 1000 mg/kg bw/d a decrease of food consumption had been observed in both sexes during treatment weeks 0-1. In the following treatment period week 1-2, food consumption increased over control in both sexes. In females this increased food consumption was also observed in the beginning of gestation (GD 0-14), normalized afterwards and finally decreased during lactation (-52%, PND 1-4). At 300 mg/kg bw/d, decreased food consumption could only be observed in females during lactation, but increased food consumption was observed during treatment weeks 1-2 in both sexes and in females during the whole time period of gestation. The observed alterations of feeding resulted in decreased body weight gain in males in treatment weeks 0-4 (-39%) and in females during gestation (-36%) and lactation (-70%) in the high-dose group. A decreased body weight resulted in males in treatment weeks 3-4 and in females on GD 20 and PND 4 at 1000 mg/kg bw/d. Finally, the terminal body weight was decreased in both sexes (up to -9%) at high dose and in males at mid dose (-5%).

Regarding pathology, at 300 and 1000 mg/kg bw/d male and female test animals showed a dose-dependent enlargement of the liver characterized by centrilobular hypertrophy of hepatocytes.

 

Dose-dependent adverse effect of 4-methylanisol on pre-/postnatal development of the F1 offspring at 300 and 1000 mg/kg bw/d was observed. At 1000 mg/kg bw/d, this was indicated by an increased postimplantation loss, decreased live birth index and increased number of stillborn pups, and a total litter loss of all females. At 300 mg/kg bw/d, the same effects were noted at a lower incidence and a decreased pup weight / gain could be determined based on the higher number of surviving pups. At least partially, the reduced pup survival may be secondary to a disturbance of maternal care as it became obvious by empty stomachs in pups which have been observed in 20% of mid-dose and 15% of high-dose offspring.

 

Overall, the NOAEL for developmental toxicity is 100 mg/kg bw/d based on pre/postnatal offspring mortality at 300 and 1000 mg/kg bw/d as well as reduced pup weight/gain at 300 mg/kg bw/d.

The NOAEL for general, systemic toxicity of the test substance is 100 mg/kg bw/d for the F0 parental animals based on clinical signs observed, reduced food consumption and decreased body weight/body weight gain in both sexes at 1000 mg/kg bw/d and the findings at 300 mg/kg bw/d. Although food consumption in both sexes as well as decreased terminal body weight in males was altered with a low magnitude at 300 mg/kg bw/d, these effects showed a dose dependency and were therefore considered for the derivation of the NOAEL.

Since the dermal route represents the most likely route of human exposure for 4-methylanisol, a

dermal reproduction/developmental toxicity screening test according to OECD 421 and GLP has been performed in order to provide data on the most appropriate route of administration (BASF82R0506/09C017). In this key study, 4-methylanisol was administered via dermal administration (6 hours/day; 7 days/week, semi-occlusive dressing) to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 (corn oil served as vehicle control), 100, 300 and 1000 mg/kg bw/ d. The duration of treatment covered the premating period of 2 weeks and a mating period (max. of 2 weeks) in both sexes, approximately 1 week post-mating in males, and the entire gestation period until gestation day (GD) 19 in females. The females were not treated during at the end of gestation and during lactation.

Regarding clinical examinations, no signs of general toxicity were observed for males and females up to a dose level of 1000 mg/kg bw/d 4-methylanisol.

Regarding pathology, there were no treatment-related necropsy or histological findings in ovaries, testes or epididymides associated with dermal administration of 4-methylanisol at any dose level.

 

Concerning developmental toxicity, no adverse treatment related effects were observed on pup numbers, status at delivery, pup viability, sex ratio, pup clinical observations, pup body weights or in pup necropsy. A significant increase of the postimplantation loss in the 100 mg/kg bw/d dose group was found, but lacked a dose response relationship and is therefore not considered to be treatment related.

 

Overall, under the conditions of this reproduction/developmental toxicity screening study the NOAEL for general systemic toxicity as well as reproductive performance and fertility in male and female Wistar rats was 1000 mg/kg bw/d. The NOAEL for developmental toxicity was 1000 mg/kg bw/d.

 

Justification for classification or non-classification

Developmental toxicity in the presence of general systemic toxicity has been observed in an oral reproduction/developmental toxicity screening test in rats, providing evidence for a putative developmental toxicity effect of 4-methylanisol.

However, the dermal route represents the most likely route of human exposure for 4-methylanisol, and a dermal reproduction/developmental toxicity screening test in rats, covering the most appropriate route of administration, did not reveal any developmental toxicity up to the limit dose. Given the lack of developmental toxicity when applied via the relevant human route of exposure (i.e. dermal) and the exposure situation which leads to the conclusion that the hazardous situation will not be expressed in humans, the relevance of the observed effects for humans is doubtful.

No adverse effects on fertility have been observed up to the limit dose after dermal or oral administration of 4-methylanisol.

Overall, the present data on reproductive toxicity fulfill the criteria laid down in 67/548/EEC and regulation (EU) 1272/2008 and a classification as Repr. Cat3; R63 (67/548/EEC) and reproductive toxicant; Cat2 (regulation (EU) 1272/2008) is warranted. Concerning fertility, a non-classification is warranted.