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Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data from secondary source

Data source

Referenceopen allclose all

Reference Type:
secondary source
Title:
Reregistration Eligibility Decision (RED) | for test material
Author:
US EPA
Year:
1998
Bibliographic source:
Prevention, Pesticides Toxic Substances ,US EPA archive document,September 1998
Reference Type:
secondary source
Title:
Reproductive and developmental toxicity study of test material
Author:
HSDB
Year:
2018
Bibliographic source:
U.S. National Library of Medicine, National Institutes of Health, Health & Human Services, 2018
Reference Type:
secondary source
Title:
Toxicological Profile for test material
Author:
Agency for Toxic Substances and Disease Registry
Year:
2017
Bibliographic source:
Toxicological Profile for test material ,ATSDR, August 2017

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Reproductive and Developmental toxicity study of test material was performed on Sprague Dawley rats.
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available

Test material

Constituent 1
Chemical structure
Reference substance name:
N,N-diethyl-m-toluamide
EC Number:
205-149-7
EC Name:
N,N-diethyl-m-toluamide
Cas Number:
134-62-3
Molecular formula:
C12H17NO
IUPAC Name:
Diethyltoluamide
Details on test material:
- Name of test material (as cited in study report):DEET (N,N-Diethyl-Meta-Toluamide),- Molecular formula: C12H17NO- Molecular weight :191.2723g/mol - Substance type: Organic

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals or test system and environmental conditions:
No data available

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Details on exposure:
No data available
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
F0: 80 days before mating during mating, gestation, and lactation.F1: 93 days before mating during mating, gestation, and lactation.
Frequency of treatment:
daily
Details on study schedule:
No data available
Doses / concentrations
Remarks:
0, 500, 2,000, or 5,000 ppm ( 0, 25, 100, or 250 mg /kg/day)
No. of animals per sex per dose:
Total:1120 mg/kg bw/day:28 male and 28 female 25 mg/kg bw/day:28 male and 28 female100 mg/kg bw/day:28 male and 28 female250mg/kg bw/day:28 male and 28 female
Control animals:
yes
Details on study design:
No data available
Positive control:
No data available

Examinations

Parental animals: Observations and examinations:
Parental animals observation and examinationsCAGE SIDE OBSERVATIONS: yes DETAILED CLINICAL OBSERVATIONS: Yes Time schedule: twice daily BODY WEIGHT: YesTime schedule for examinations: twice dailyFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): twice dailyFood consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: no Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data availableWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data Time schedule for examinations:
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
The F1 and F2 litters were observed for number of live and stillborn pups, external anomalies, sex and body weight grouped by sex on lactation days 0, 4, 7, and 14, sex and individual body weights (only group weights reported) on lactation day 21, viability, and behavioral abnormalities at least twice daily during lactation.
Postmortem examinations (parental animals):
Postmortem examinations (Parent Animal)SACRIFICE :yes GROSS NECROPSY: yes gross necropsy and histological examination of the ovaries, prostate, seminal vesicles, testes with epididymides, uterus, vagina, and all gross lesions were conducted in all parental rats HISTOPATHOLOGY / ORGAN WEIGHTSThe tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.: macroscopic examination was performed
Postmortem examinations (offspring):
SACRIFICE - The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at ) on lactation day 21 days of age. - These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows: GROSS NECROPSY - Gross necropsy consisted of external and internal examinations ,sex and body weight HISTOPATHOLOGY / ORGAN WEIGTHS The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
No data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Hair loss appeared to be more prominent in 250mg/kg dose group F0 females than in other groups
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
There were no chemical-related deaths during the study
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weights of parental rats were lower in some of the 100mg/kg and 250 mg/kg dose groups at some points in the study, but the difference with controls was generally <10%.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Changes in food consumption tended to parallel the changes in body weight and were generally <10% different than controls.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
No treatment-related effects on reproduction or fertility were observed at any of the dose levels evaluated in this study.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
reproductive performance
Remarks on result:
other: No treatment-related effects on reproduction or fertility were observed at any of the dose levels

Target system / organ toxicity (P0)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Hair loss appeared to be more prominent in 250mg/kg dose group F1 females than in other groups
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
reduced male and female F1 pup weights in the 250mg/kg dose group on lactation days 14 and 21
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
F1 males showed mottled kidneys with incidences of 0/23, 2/23 (9%), 6/23 (26%), and 8/23 (35%) of the males (control and increasing dose groups). Microscopy revealed inflammation, hyaline droplet and granular cast formation, and regeneration of tubules.
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
body weight and weight gain
organ weights and organ / body weight ratios
Remarks on result:
other: overall no developmental toxic effects observed

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Results: F2 generation

General toxicity (F2)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
Decreased F2 pup viability in the 50mg/kg and 250mg/kg dose groups on postnatal day 4
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Reduced male and female F2 pup weights in the 250mg/kg bw dose group on lactation days 14 and 21
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not specified

Effect levels (F2)

Dose descriptor:
NOAEL
Generation:
F2
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
mortality
body weight and weight gain
Remarks on result:
other: overall no developmental toxic effects observed

Target system / organ toxicity (F2)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Any other information on results incl. tables

Body Weight (g) of Rats on Lactation Day 21 in a 2-Generation Reproductive Study

Doses (mg/kg/day)

0

25

100

250

F1 male

46.2±6.50a

46.8 ±5.06

45.7 ±4.53

40.1 ±4.22b

F1 female

44.1 ±4.64

44.6 ±4.44

44.2 ±4.51

39 1± 4.60b

F2 males

50.4 ±4.31

49.4 ±6.07

47.9 ±4.02

44.5± 3.93b

F2 Female

47.3± 4.52

47.6 ± 5.35

44.1 ±7.50

42.3± 3.23b

 

 

aMean±standard deviation.bp<0.01.

Applicant's summary and conclusion

Conclusions:
No Observed Effect Level (NOEL) for reproductive toxicity was considered to be 250mg/kg/day, and NOAEL dose-level of 100 mg/kg/day was considered to be for developmental toxicity. When male and female Sprague Dawley rats were treated with test material orally.
Executive summary:

A two-generation reproductive study of test material was performed in male and female Sprague-Dawley rats. Test material in dose concentration 0, 500, 2,000, or 5,000 ppm ( 0, 25, 100, or 250 mg /kg/day) were fed diets.The F0 parental generation consistedof 28 males and 28 females pergroup which were administered treated or control diet for at least 80 days prior to mating. Twenty-eight male and 28female offspring per group from the F1 generation were selected randomly to become the parents of the F2generation. These animals were treated for at least 93 days prior to mating. For bothparental groups, treatment wascontinued through gestation and lactation.After weaning, 10 pups/sex/groups were subjected to gross necropsy. F0 females were killed after the selection of F1 parents. F1 females were sacrificed after weaning of their litters. The parameters were used to assess toxicity were twicedaily observations for deaths and clinical signs, body weight, and food consumption (not measured during the mating periods). Additionally, gross necropsy and histological examination of the ovaries, prostate, seminal vesicles, testes with epididymides, uterus, vagina, and all gross lesions were conducted in all parental rats and 10 weanlings/sex/group in the control and 250mg/kg/daydose groups. Parameters used to assess developmental toxicity in the F1 and F2 litters included number of live and stillborn pups, external anomalies, sex and body weight grouped by sex on lactation days 0, 4, 7, and 14, sex and individual body weights (only group weights reported) on lactation day 21, viability, and behavioral abnormalities at least twice daily during lactation.

There were no chemical-related deaths during the study. Hair loss appeared to be more prominent in 250mg/kg /day dose group F0 and F1 females than in other groups. Body weights of parental rats were lower in some of the 100 mg/kg /day and 250mg/kg /day dose groups at some points in the study, but the difference with controls was generally <10%. Changes in food consumption tended to parallel the changes in body weight and were generally <10% different than controls. F1 males showed mottled kidneys with incidences of 0/23, 2/23 (9%), 6/23 (26%), and 8/23 (35%) of the males (control and increasing dose groups). Microscopy revealed inflammation, hyaline droplet and granular cast formation, and regeneration of tubules. No explicit information was provided in the review regarding the other organs examined.Neonatal toxicity as evidences by reduced pup sizes in both generations was noted for males and females250mg/kg /day groups on postnatal day 4 and reduced male and female F1 and F2 pup weights in the 250mg/kg /day dose group on lactation days 14 and 21.No treatment-related effects on reproduction or fertility were observed at any of the dose levels evaluated in this study. HenceNo Observed Effect Level (NOEL) for reproductive toxicity was considered to be 250mg/kg/day, and NOAEL dose-level of 100 mg/kg/day was considered to be for developmental toxicity.When male and femaleSprague Dawley rats were treated withtest materialorally.