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Administrative data

Description of key information

oral
28 d, rat: systemic toxicity: NOAEL < 10 mg/kg bw/d; LOAEL = 10 mg/kg bw/d due to impaired body weight/ bw gain/ food & water consumption in both sexes; neurotoxicity: NOAEL < 10 mg/kg bw/d; LOAEL = 10 mg/kg bw/d due to impaired motoneural parameters/ motor activities (GLP, OECD 407; BASF AG 2007)
dermal
no data
inhalation
no data

Key value for chemical safety assessment

Additional information

There is a reliable study available to assess the toxicity of the test substance after subacute oral dosing.

In a GLP conform study according to OECD guideline 407, MGDN with a purity of 99.9% was administered to groups of 5 male and 5 female Wistar rats at dose levels of 0 (vehicle control), 10, 30, 60 (from day 0 till day 7) and 45 (from day 8 till day 28) mg/kg body weight/day over a period of 4 weeks (BASF AG 2007). The high dosed animals received doses of 60 mg/kg bw/day from day 0 till day 7 and 45 mg/kg bw/day from day 8 till the day 28, because of severe toxic effects at 60 mg/kg bw/day.

 

Food consumption, water consumption and body weight were determined weekly. The animals were examined for signs of toxicity or mortality at least once a day. Detailed clinical examinations in an open field were conducted prior to the start of the administration period and weekly thereafter. In addition, all animals were checked daily before and about 1 hour as well as 3 - 4 hours after administration for any clinical signs. A functional observational battery (FOB) and measurement of motor activity was carried out after 26 days of treatment in males and 27 days of treatment in females. Clinicochemical, hematological examinations and urinalyses were performed towards the end of the administration period. All animals were assessed by gross pathology, followed by histopathological examinations.

 

The various analyses demonstrated the stability of the test substance preparations over a period up to 96 hours at room temperature, showed the homogeneous distribution of the test article in the vehicle and showed the correctness of the prepared concentrations

 

The following test substance-related adverse findings were noted:

 

60 mg/kg body weight/day (from day 0 until day 7)

• 1 male and 1 female were found dead on day 6 and on day 7, respectively

• Convulsions, clonic were observed moderate in 4 females, severe in 2 females, epileptoid slight in 1 male, moderate in 1 female, severe in 2 males and 1 female, tonic slight in 1 female and severe in 1 male and 2 females

• Hyperesthesia was observed slight in 2 males and 5 females, moderate in 4 females and severe in 1 male and 2 females

• Hyperexcitability was observed slight in 2 males and 5 females, moderate in 4 females and severe in 1 male and 2 females

• Nose, discharge, red was observed moderate in 1 female

• Piloerection was observed in 2 females

• Salivation was observed slight in 2 females, moderate in 1 male and 4 females and severe in 1 male and female

• Skin, paleness was observed moderate in 2 females

• Twitching was observed slight in 3 males and 5 females, moderate in 2 males and 3 females and severe in 1 male and 3 females

• Food consumption in both sexes was statistically significantly reduced of -29.4% in males and -28.2% in females on day 7

• Water consumption in both sexes was increased of +13.9% in males and statistically significantly increased of +36.9% in females on day 7

• Body weight was statistically significantly decreased of -13.9% in males and not statistically significantly decreased of -6.5% in females on day 7

• Body weight change in both sexes was statistically significantly decreased of -60.8% in males and -50.9% in females on day 7

• Food efficiency in both sexes was statistically significantly decreased on day 7

 

45 mg/kg body weight/day (from day 8 until the end of the administration period)

• 1 female was prematurely sacrificed moribund on day 11

• Anogenital region, smeared with urine was observed severe in 1 female

• Convulsions, tonic were observed slight, moderate and severe in each 1 female

• Hyperactivity was observed in 1 female

• Hyperesthesia was observed slight in 2 males and 1 female

• Hyperexcitability was observed slight in 4 males and 3 females, moderate in 4 males and females and severe in 1 male and 2 females

• Lateral position was observed in 1 female

• Nose, discharge, red was observed slight in 1 female and severe in 2 females

• Piloerection was observed in 2 males and 2 females

• Reduced general condition was observed slight in 1 female and severe in 2 females

• Salivation was observed slight in 1 female, moderate in 2 females and severe in 1 female

• Twitching was observed slight in 4 males and 3 females, moderate in 1 male and 4 females and severe in 2 females

• Food consumption in both sexes was reduced during the administration period, with a maximum of -11.9% in males and statistically significantly of -15.3% in females on day 14

• Water consumption in both sexes was increased during the administration period, with the exception of day 14 (-8.5%) in males and a maximum of +8.1% in males on day 28 and +24.7% in females on day 14

• Body weight in both sexes was decreased during the administration period, with a maximum of -8.6% in males and -4.4% in females on day 14

• Body weight change in both sexes was decreased during the administration period, with a maximum of -24.4% in males and -20.5% in females on day 14

• Food efficiency in males was statistically significantly increased on day 14

• Twitching was observed during FOB (home cage observation) in 3/4 males on day 26 and

3/3 females on day 27

• Twitching was observed during FOB (sensorimotor tests/reflexes) in 2/4 males on day 26 and 2/3 females on day 27

• Rearing during FOB (quantitative parameters) was increased of +48.0% in males and

+63.7% in females

• Grip strength forelimbs and grip strength hindlimbs during FOB (quantitative parameters) was reduced of -9.2% and -16.8% in males and -9.9% and -5.9% in females

• Motor activity was statistically significantly increased in both sexes

• Decreased total protein and globulin levels in both sexes

• Decreased albumin levels in the females

 

30 mg/kg body weight/day (during the entire administration period)

• Convulsions, tonic were observed moderate in 1 male

• Hyperactivity was observed in 1 female

• Hyperesthesia was observed slight in 1 male and 5 females

• Hyperexcitability was observed slight in 5 males and 5 females, moderate in 3 males and 4 females and severe in 1 female

• Piloerection was observed in 1 male

• Twitching was observed slight in 5 males and females, moderate in 4 females and severe in 1 female

• Food consumption in both sexes was reduced during the administration period, with a maximum of -9.8% in males and statistically significantly of -18.0% in females on day 7

• Water consumption in both sexes was increased during the administration period, with the exception of day 14 (-13.6%) in males and a maximum of +6.3% in males on day 21, a maximum of +26.4% in females on day 14 and statistically significantly of +24.6% in females on day 28

• Body weight in both sexes was decreased during the administration period, with a maximum of -7.7% in males on days 7 and 21 and -6.3% in females on day 7

• Body weight change in both sexes was decreased during the administration period, with a statistically significantly maximum of -37.7% in males and -48.7% in females on day 7

• Food efficiency in both sexes was statistically significantly decreased on day 7

• Rearing during FOB (quantitative parameters) was increased of +26.3% in males and +21.4% in females

• Grip strength hindlimbs during FOB (quantitative parameters) was reduced of -24.4% in males and in forelimbs and hindlimbs of -39.9% and -26.2% in females

• Motor activity was statistically significantly increased in both sexes

• Decreased total protein level in the males

 

10 mg/kg body weight/day (during the entire administration period)

• Food consumption in both sexes was reduced during the administration period, with a maximum of -6.1% in males and statistically significantly of -12.3% in females on day 14

• Water consumption in both sexes was increased during the administration period, with a maximum of +14.0% in males on day 21 and +27.3% in females on day 14

• Body weight in both sexes was decreased during the administration period, with a maximum of -4.8% in males on days 7 and 28 and -4.3% in females on day 7

• Body weight change in both sexes was decreased during the administration period, with a maximum of -20.9% in males and statistically significantly of -35.3% in females on day 7

• Food efficiency in females was statistically significantly decreased on day 7

• Rearing during FOB (quantitative parameters) was increased of +10.5% in males and +14.3% in females

• Grip strength hindlimbs during FOB (quantitative parameters) was reduced of -17.9% in males and in forelimbs of -8.8% in females

• Motor activity was statistically significantly increased in both sexes

 

In conclusion, the oral administration of MGDN by gavage over a period of 4 weeks caused severe, substance-related as well as adverse systemic and neurotoxic effects throughout all dose levels in both sexes. However, the treatment with the test article did not lead to any pathomorphological changes in respect to the tissue and organs examined during necropsy, organ weight determinations and light microscopy.

Therefore, the no observed adverse effect level (NOAEL) for systemic toxicity and neurotoxicity under the conditions of this study was below 10 mg/kg body weight/day for male as well as female Wistar rats.

dermal

no data

inhalation

no data

Justification for classification or non-classification

There were neurotoxic effects on the PNS observed after subacute oral dosage of >= 10 mg test substance/kg bw/d. Therefore, the substance has to be classified with R48/25 according to 67/548/EEC and with STOT rep. dose Cat. 1 (PNS as target organ) according to EU-GHS and OECD-GHS.