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Administrative data

Endpoint:
extended one-generation reproductive toxicity - with developmental neurotoxicity (Cohorts 1A, 1B without extension, 2A and 2B)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2019
Report date:
2019

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
Deviations:
yes
Remarks:
The test parameters: 19-25°C, relative humidity 30-70%. During the experiment: lowest temp. 18.70°C; highest 25.10°C; highest humidity 71%. These were short-term deviations and did not affect the course of the study or the reliability of the results.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: flakes

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

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Key result
Dose descriptor:
NOAEL
Effect level:
75 mg/kg diet
Based on:
test mat.
Sex:
female
Basis for effect level:
reproductive performance
Remarks on result:
other: 4,50 mg TNT/kg body weight/24h – average dose for mothers in pregnancy period
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg diet
Based on:
test mat.
Sex:
male
Basis for effect level:
reproductive function (sperm measures)
Remarks on result:
other: 15,73 mg TNT/kg of feed/24h in case of parental generation and 26,94 mg TNT/kg body weight/24h in case of second generation F1
Dose descriptor:
NOAEL
Effect level:
300 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Remarks on result:
other: 15,73 mg TNT/kg body weight/24h – males; 22,94 mg TNT/kg body weight/24h – females
Dose descriptor:
NOAEL
Effect level:
300 mg/kg diet
Based on:
test mat.
Sex:
male
Basis for effect level:
food consumption and compound intake
Remarks on result:
other: 15,73 mg TNT/kg body weight/24h
Dose descriptor:
NOAEL
Effect level:
< 75 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology

Results: F1 generation

Effect levels (F1)

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Dose descriptor:
NOAEL
Generation:
F1 (cohort 1A)
Effect level:
300 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Remarks on result:
other: 26,94 mg TNT/kg body weight/24h – males; 26,15 mg TNT/kg body weight/24 h - females
Dose descriptor:
NOAEL
Generation:
F1 (cohort 1B)
Effect level:
< 75 mg/kg diet
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
Remarks on result:
other: <7,14 mg TNT/kg body weight/24h
Dose descriptor:
NOAEL
Generation:
F1 (cohort 2A)
Effect level:
< 75 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Remarks on result:
other: 7,72 mg TNT/kg body weight/24h – males; 7,14 mg TNT/kg body weight /24 h – females
Dose descriptor:
NOAEL
Generation:
F1 (cohort 2B)
Effect level:
300 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Remarks on result:
other: 26,94 mg TNT/kg body weight/24h – males; 26,15 mg TNT/kg body weight/24 h – females

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

NOAEL and LOAEL values were defined for parameters:

- Amount of feed consumed by parental generation in male group:

NOAEL – 300 mg TNT/kg of feed (15,73 mg TNT/kg body weight/24h)

LOAEL – 1200 mg TNT/kg of feed (70,09 mg TNT/kg body weight/24h).

- Body weight of parental generation animals in female and male group:

NOAEL – 300 mg TNT/kg of feed (15,73 mg TNT/kg body weight/24h – males; 22,94 mg TNT/kg body weight/24h – females)

LOAEL – 1200 mg TNT/kg of feed (70,09 mg TNT/kg body weight/24h – males; 81,96 mg TNT/kg body weight/24h – females).

- Body weight of F generation, cohort 1A in female and male group:

NOAEL – 300 mg TNT/kg of feed (26,94 mg TNT/kg body weight/24h – males; 26,15 mg TNT/kg body weight/24 h - females)

LOAEL – 1200 mg TNT/kg of feed (105,63 mg TNT/kg body weight/24h – males; 101,85 mg TNT/kg body weight/24 h - females).

- Body weight of F generation, cohort 1B in females and male group:

NOAEL < 75 mg TNT/kg of feed (<7,14 mg TNT/kg body weight/24h)

LOAEL < 75 mg TNT/kg of feed (7,14 mg TNT/kg body weight/24h) in case of females

NOAEL – 75 mg TNT/kg of feed (7,72 mg TNT/kg body weight/24h)

LOAEL – 300 mg TNT/kg of feed (26,94 mg TNT/kg body weight/24h) in case of males.

- Body weight of F generation, cohort 2A in female and male group:

NOAEL, LOAEL < 75 mg TNT/kg of feed (7,72 mg TNT/kg body weight/24h – males; 7,14 mg TNT/kg body weight /24 h – females).

- Body weight of F generation, cohort 2B in female and male group:

NOAEL – 300 mg TNT/kg of feed (26,94 mg TNT/kg body weight/24h – males; 26,15 mg TNT/kg body weight/24 h – females).

LOAEL – 1200 mg TNT/kg of feed (105,63 mg TNT/kg body weight/24h – males; 101,85 mg TNT/kg body weight/24 h – females.

- Birth weight of the offspring:

NOAEL – 75 mg TNT/kg of feed (4,50 mg TNT/kg body weight/24h – average dose for mothers in pregnancy period) in case of females

LOAEL – 300 mg TNT/kg of feed (16,33 mg TNT/kg body weight/24h – average dose for mothers in pregnancy period) in case of females

NOAEL – 300 mg TNT/kg of feed (16,33 mg TNT/kg body weight/24h – average dose for mothers in pregnancy period) in case of males mothers in pregnancy period) in case of females

LOAEL – 1200 mg TNT/kg of feed (61,20 mg TNT/kg body weight/24h – average dose for mothers in pregnancy period) in case of males.

- Sperm parameters – decrease in properly motile spermatozoa (live) number in the parental and F1 generation:

NOAEL – 300 mg TNT/kg of feed (15,73 mg TNT/kg of feed/24h in case of parental generation and 26,94 mg TNT/kg body weight/24h in case of second generation F1)

LOAEL – 1200 mg TNT/kg of feed (70,09 mg TNT/kg of feed/24h in case of parental generation and 105,63 mg TNT/kg body weight/24h in case of second generation F1).

- Forelimb grip strength:

NOAEL – 300 mg TNT/kg of feed (26,94 mg TNT/kg body weight/24h – males; 26,15 mg TNT/kg body weight/24 h – females)

LOAEL – 1200 mg TNT/kg of feed (105,63 mg TNT/kg body weight/24h – males; 101,85 mg TNT/kg body weight/24 h – females).

- Number of erythrocytes, females and males parental generation:

NOAEL, LOAEL < 75 mg TNT/kg of feed (<4,51 mg TNT/kg body weight/24h – males; <6,74 mg TNT/kg body weight/24h – females).

- Number of erythrocytes, females and males F1 generation, cohort 1A:

NOAEL – 75 mg TNT/kg of feed (7,14 mg TNT/kg body weight/24h) in case of females

LOAEL – 300 mg TNT/kg of feed (26,15 mg TNT/kg body weight/24h) in case of females

NOAEL – 300 mg TNT/kg of feed (26,94 mg TNT/kg body weight/24h) in case of males

LOAEL – 1200 mg TNT/kg of feed (105,63 mg TNT/kg body weight/24h) in case of males.

- Haemoglobin concentration, females and males parental generation:

NOAEL, LOAEL < 75 mg TNT/kg of feed (<4,51 mg TNT/kg body weight/24h – males; <6,74 mg TNT/kg body weight/24h – females).

- Haemoglobin concentration, females and males cohort 1A, F1 generation:

NOAEL – 300 mg TNT/kg of feed (26,15 mg TNT/kg body weight/24h) in case of females

LOAEL – 1200 mg TNT/kg of feed (101,85 mg TNT/kg body weight in case of females

NOAEL – 75 mg TNT/kg of feed (7,72 mg TNT/kg body weight/24h) in case of males

LOAEL – 300 mg TNT/kg of feed (26,94 mg TNT/kg body weight) in case of males.

- Haematocrit, males and females parental generation:

NOAEL, LOAEL < 75 mg TNT/kg of feed (<4,51 mg TNT/kg body weight/24h – males; <12,15 mg TNT/kg body weight/24h – females).

- Haematocrit, females and males cohort 1A, F1 generation:

NOAEL – 300 mg TNT/kg of feed (26,94 mg TNT/kg body weight/24h)

LOAEL – 1200 mg TNT/kg of feed (105,63 mg TNT/kg body weight/24h) in case of males – no dose dependence for females.

- Average haemoglobin concentration in erythrocytes (MCHC) in case of F1 generation males:

NOAEL – 75 mg TNT/kg of feed (7,72 mg TNT/kg body weight/24h)

LOAEL – 300 mg TNT/kg of feed (26,94 mg/kg body weight).

- Number of granulocytes (decrease):

NOAEL – 75 mg TNT/kg of feed (4,51 mg TNT/kg body weight/24h) in case of males of parental generation

LOAEL – 300 mg TNT/kg of feed (15,73 mg TNT/kg body weight/24h) in case of males of parental generation

NOAEL – 300 mg TNT/kg of feed (26,15 mg TNT/kg body weight/24h) in case of females of F1 generation, cohort 1A

LOAEL – 1200 mg TNT/kg of feed (101,85 mg TNT/kg body weight/24h) in case of females of F1 generation, cohort 1A.

- Number of granulocytes with segmented nuclei (decrease):

NOAEL, LOAEL < 75 mg TNT/kg of feed (<4,51 mg/kg body weight /24h) in case of males of parental generation

NOAEL – 300 mg TNT/kg of feed (26,15 mg TNT/kg body weight/24h) in case of females of F1 generation, cohort 1A

LOAEL – 1200 mg TNT/kg of feed (101,85 mg/kg body weight /24h) in case of females of F1 generation, cohort 1A.

- Activated partial thromboplastin time (APTT) parental generation:

NOAEL, LOAEL < 75 mg TNT/kg of feed (<4,51 mg TNT/kg body weight/24h – males; <6,74 mg TNT/kg body weight/24h – females).

- Alanine aminotransferase (activity decrease) in case of females of parental generation:

NOAEL – 75 mg TNT/kg of feed (6,74 mg TNT/kg body weight/24h)

LOAEL – 300 mg TNT/kg of feed (22,94 mg TNT/kg body weight/24h).

- Aspartic aminotransferase (activity decrease) for cohort 1A males and females of F1 generation:

NOAEL – 300 mg TNT/kg of feed (26,94 mg TNT/kg body weight/24h – males; 26,15 mg TNT/kg body weight/24 h – females)

LOAEL – 1200 mg TNT/kg of feed (105,63 mg TNT/kg body weight/24h – males; 101,85 mg TNT/kg body weight/24 h – females).

- Globulins (concentration decrease) in F1 generation males, cohort 1A:

NOAEL – 300 mg TNT/kg of feed (26,94 mg TNT/kg body weight/24h)

LOAEL – 1200 mg TNT/kg of feed (105,63 mg TNT/kg body weight/24h).

- Cholesterol (concentration decrease) in parental generation males:

NOAEL, LOAEL < 75 mg TNT/kg of feed (<4,51 mg TNT/kg body weight/24h)

- Creatinine (concentration decrease) in F1 generation males, cohort 1A:

NOAEL – 75 mg TNT/kg of feed (7,72 mg TNT/kg body weight/24h)

LOAEL – 300 mg TNT/kg of feed (26,94 mg TNT/kg body weight/24h).

- Sodium – concentration of sodium decrease: NOAEL – 75 mg TNT/kg feed – females F1 generation, cohort 1A:

NOAEL – 75 mg TNT/kg of feed (7,14 mg TNT/kg body weight/24h)

LOAEL – 300 mg TNT/kg of feed (26,15 mg TNT/kg body weight/24h).

Applicant's summary and conclusion