Difluoroacetic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

fertility, other

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

In a one-generation study , the developmental and reproductive effects of subchronic,
low-dose exposure to dibromoacetic acid (DBA) in C57Bl/6J mice.

GLP compliance:

no

Species:

mouse

Strain:

other: C57Bl/6J mice

Sex:

male/female

Details on test animals or test system and environmental conditions:

-Source: Jackson Laboratory
-Age: Six- to eight-week-old
-Housing: Mice were housed in plastic tubs with cedar chip bedding
(Females were housed 4/tub and males were housed individually. )
-Water: ad libitum; deionized water
-Diet: ad libitum; Teklad 8640 mouse chow
- Acclimation period: two weeks


ENVIRONMENTAL CONDITIONS:
Temperature: 18°C to 26°C (64°F to 79°F);
Humidity (%): 30%to 70%.
Photoperiod: 12:12 h light:dark cycle

Route of administration:

oral: drinking water

Type of inhalation exposure (if applicable):

not specified

Vehicle:

water

Details on exposure:

Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared by adding DBA to deionized water and bringing the pH to 6.8–7.4 using 1N NaOH. Stock solutions were made twice weekly.

DIET PREPARATION
- Rate of preparation of diet (frequency): Not Available
- Mixing appropriate amounts with (Type of food): Not Available
- Storage temperature of food: Not Available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Not Available
- Concentration in vehicle: Not Available
- Amount of vehicle (if gavage): Not Available
- Lot/batch no. (if required): Not Available
- Purity: Not Available

Details on mating procedure:

- M/F ratio per cage: 1:1 ratio
- Length of cohabitation: Males were placed with females at 6:00 P.M. and removed at 6:00 A.M. the following morning
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy Presence of a vaginal plug was designated day 0 of gestation
- After … days of unsuccessful pairing replacement of first male by another male with proven fertility. Males and un-mated females were given a day of rest between successive breedings.
- Further matings after two unsuccessful attempts: [no / yes (explain)] Not Available
- After successful mating each pregnant female was caged (how): Pregnant females were separated and housed individually
- Any other deviations from standard protocol: Not Available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Not Available

Duration of treatment / exposure:

Study I: 3 weeks (pre-pubertal pups)
Study II: 7 weeks (neo-pubertal pups)

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
0, 5, 50 mg/kg/day
Basis:
nominal in water

No. of animals per sex per dose:

1) F1, pre-puberty
Control:
7-10 males and 7-10 females
5 mg/kg/day: 7-10 males and 7-10 females
50 mg/kg/day: 7-10 males and 7-10 females

2) F1, neo-puberty
Control:
15-17 males and 15-17 females
5 mg/kg/day: 15-17males and 15-17 females
50 mg/kg/day: 15-17males and 15-17 females

Control animals:

yes, concurrent vehicle

Details on study design:

Not Available

Positive control:

Not Available

Parental animals: Observations and examinations:

Pre-pubertal (3-week-old) evaluation:
Viscera and reproductive organs were examined for any abnormalities. Weights were taken for liver, kidneys, testes, and ovaries. Right testes and ovaries were fixed in 4% glutaraldehyde for 24 h then stored in 2% cacodylate while left testes and ovaries were fixed in Bouin’s solution for 48 h then stored
in 70% alcohol until further processing for histopathology

Neo-pubertal (7-week-old) evaluation:
Procedures for necropsy and tissue collection were similar to those performed at 3 weeks except that for a group of 10–11 males/treatment, half of the right testis was fixed in Bouin’s solution and the remaining half and the epididymis were fixed in glutaraldehyde. The left testis and epididymis were weighed separately and frozen in liquid nitrogen for determination of daily sperm production and epididymal sperm reserves. Frozen tissues were maintained at -80°C until processing for determination of sperm counts

Oestrous cyclicity (parental animals):

Not Available

Sperm parameters (parental animals):

No significant difference was noted between control and dosed males in sperm, seminiferous epithelial and endocrine parameters. There was no difference between control and dosed mice in testis sperm counts or DSP. DGEL did not differ significantly between control and dosed animals.

Sperm Parameters for Neo-pubertal Male Mice (7 Week) Exposed to 0, 5, or 50 mg DBA/kg/day
Dose group
0 5 50
Total sperm/testis (x106) 11.94 ± 0.25 13.53 ± 1.25 10.78 ± 0.71
Daily sperm production (x106/g testis) 30.43 ± 1.18 34.49 ± 3.68 30.20 ± 1.35
Total sperm /epididymis (x106) 14.07 ± 0.93 14.56 ± 1.44 12.05 ± 1.54

Note. Values represent mean ± SEM.

Histopathological Changes in Seminiferous Epithelium and Degree of Germinal Epithelial Loss (DGEL) for Neo-pubertal Male Mice (7 Week) Exposed to 0, 5, or 50 mg DBA/kg/day

Seminiferous tubules (%)
classified as Dose group
0 5 50
Grade 0 80.2 81.3 78.9
Grade 1 19.8 18.7 20.6
Grade 2 0 0 0.2
Grade 3 0 0 0.3
Grades 4–7 0 0 0
DGEL 4.94 ± 0.35 4.68 ± 0.41 5.59 ± 0.81

Note. Values represent mean ± SEM.

Litter observations:

Not Available

Postmortem examinations (parental animals):

Not Available

Postmortem examinations (offspring):

Not Available

Statistics:

Statview was used for all statistical analyses. All parameters were analyzed using ANOVA with a Tukey/Kramer post-hoc test. Body weight was used as a covariate for weights of liver, kidney, testis, and ovary. Body length was used as a covariate for ano-genital distance. A level of significance of p ≤0.05 was used for all tests.

Reproductive indices:

Not Available

Offspring viability indices:

Not Available

Clinical signs:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Remarks on result:

not measured/tested

Clinical signs:

not specified

Mortality / viability:

not specified

Body weight and weight changes:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Description (incidence and severity):

Testes of high dose pre-pubertal males were significantly larger than control males of the same age, but at 7 weeks of age high dose males had significantly smaller testes than control males

Gross pathological findings:

not specified

Histopathological findings:

not specified

Dose descriptor:

LOAEL

Generation:

F1

Effect level:

50 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: suffered kidney damage

Remarks on result:

other: not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

5 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant change in body & organ weight

Remarks on result:

other: not specified

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

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

Conclusions:

The developmental and reproductive effects of Dibromoacetic acid (DBA) were evaluated in a one generation study on C57Bl/6J mice (7-17 mice/sex). DBA had shown a No adverse observed effect level (NOAEL) on 5 mg /kg/day, whereas the Low adverse observed effect level (LOAEL) was found to be 50 mg/kg/day based on kidney damage and increase in testis weight.

Executive summary:

To assess the developmental and reproductive effects of Dibromoacetic acid (DBA),C57Bl/6J mice (7-17 mice/sex) were orally administered with 0, 5 or 50 mg DBA/kg/day by drinking water for 3 and 7 weeks, respectively. The observations included significant increases in testis and liver weights in the highest dose group. High dose female mice at the same age also had increased liver and kidney weights. At seven weeks of age, males in the high dose group had decreased testis and kidney weights, while DBA does not appear to be detrimental to the gametogenic potential of mice at the dose levels tested.However, the No observed adverse effect level (NOAEL) was found to be 5mg /kg/day, whereas theLow observed adverse effect level (LOAEL) was 50 mg/kg/day,based on kidney damage and increase in testis weight

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

5 mg/kg bw/day

Species:

mouse

Quality of whole database:

K2 data is referred from publication report using read across approach of RA dibromoacetic acid

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

WoE Summary of 381-73-7 for toxicity to reproduction:

Based on the various studies available with Klimish rating 2 & 4 for the target as well as read across substances for CAS: 381-73-7 based on the category approach ofsubstances that are part of a group of compounds known as substituted acetate group. Also category is based on organic functional group along with similar mechanistic approach and having structural similarities defined by QSAR toolbox. The results for target as well as analogues are summarized as follows

 

 

Sr. No	End point	Value	Species	Effects	Remarks
1.	LOEL	35.29 mg/kg bw/day	Rat	Kidney Pathology and Weight ; First generation adult parental animals( P1)	Predicted data
2.	LOAEL   NOAEL	50mg/kg bw/day   5mg/kg bw/day	Mouse	suffered kidney damage   No significant change in body & organ weight	Data from Publication for 631-64-1
3.	LOAEL     NOAEL	52.4-132 mg/kg bw/day   4.4-11.6 mg/kg bw/day	Rat	absolute and relative weights (% terminal body weight and % brain weight) of the liver and kidneys were increased and adrenal weights were reduced, as compared with control group values	Data from Publication for 631-64-1
4.	LOAEL	90 mg/kg bw/day	Rat	Mild affect in Spermiation & epididymal sperm counts.	Data from Publication for 631-64-1
5.	LOAEL	50 mg/kg bw/day	Rat	Fused sperm and other morphological abnormalities were seen.	Data from Publication for 631-64-1
6.	LOAEL	1250 mg/kg bw/day	Rat	Effects on spermiation& epididymal sperm counts.	Data from Publication for 631-64-1
7.	LOAEL	1500 mg/kg bw/day	Rat	Weight gain; increased numbers of cauda sperm with isolated heads	Data from Publication for 79-43-6
8.	NOAEL   LOAEL	18 mg/kg bw/day   54 mg/kg bw/day	Rat	increased retention of mature spermatids   Mild, unequivocal effects on spermiation	Data from Publication for 79-43-6
9.	LOAEL	31.25 mg/kg bw/day	Rat	reductions in preputial gland and epididymis weights	Data from Publication for 79-43-6
10.	NOAEL   LOAEL	14 mg/kg bw/day   140 mg/kg bw/day	Rat	caused minimal body weight depression over the test period   dose-dependent reductions in weight and length	Data from Publication for 79-43-6
11.	LOAEL	566 mg/kg bw/day	Rat	No treatment related effects observed. Litter size is decreased in the treated group.	Predicted data
12.	NOEL	45 mg/kg bw/day	Rat	decreased water consumption	Data from Publication for 75-96-7

 

 

Based on the studies summarized in the above table it can be observed that no effect values (NOAEL & NOEL) values found to be in the range of 4.4 -45 mg/kg bw/d whereas the lowest effect observed value (LOAEL & LOEL) varies from 31.25 – 1500 mg/kg bw/day based on the data from prediction as well as publication for target & read across substance. The effects observed on this doses was listed as follows:

 

·        suffered kidney damage

·        absolute and relative weights (% terminal body weight and % brain weight) of the liver and kidneys were increased and adrenal weights were reduced, as compared with control group values

·        Mild affect in Spermiation & epididymal sperm counts.

·        Fused sperm and other morphological abnormalities were seen.

·        reproductive ability of the male rat is rapidly diminished

·        Effects on spermiation& epididymal sperm counts.

·        Weight gain; increased numbers of cauda sperm with isolated heads

·        Mild, unequivocal effects on spermiation

·        reductions in preputial gland and epididymis weights

·        dose-dependent reductions in weight and length

·        No treatment related effects observed. Litter size is decreased in the treated group.

·        Kidney Pathology and Weight ; First generation adult parental animals( P1)

·        No significant change in body & organ weight

·        increased retention of mature spermatids

·        caused minimal body weight depression over the test period

·        Decreased water consumption.

 

Thus based on above discussion it can be concluded that substance that difluoroacetic acid is expected to show the similar toxicological effect based on the effects observed on the other category members. Since the Low effective dose value (LOEL) is 35.29 mg/kg bw/d and the no observed adverse effective dose value (NOAEL) is above 4.4 mg/kg bw/day thus based on this value it can be concluded that substance CAS: 381-73-7 is considered to be nontoxic to reproduction at the above mentioned dose. Also there is no known evidence of adverse effect on Human of difluoroacetic acid as well as mechanistic triggers for estrogen receptor binding affinity does not classify this substance as toxic substance in absence of the cyclic structure and thus does not exhibits the reprotoxic effects.

Short description of key information:

Difluoroacetic acid does not shows reperotoxic effects in rats.

Justification for selection of Effect on fertility via oral route:

The oral administration of dibrmoacetic acid to rat, at a dose level of 5 mg/kg bw/day, resulted in No adverse observed effect level.

Thus the NOAEL for reproductive toxicity study was considered to be 5 mg/kg bw/day.

Effects on developmental toxicity

Description of key information

Difluoroacetic acid does not shows developmental effects in rats.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

The developmental toxicity effect of dichloroacetic acid to Long-Evans rat was assessed in a parental generation of rat.

GLP compliance:

no

Species:

rat

Strain:

Long-Evans

Details on test animals or test system and environmental conditions:

Source: Charles River Breeding Laboratories
Weight range: Not available
Housing: groups of three in plastic cages with corn cob bedding (Bed O'Cobs, Anderson Cob Div., Maumee, OH), and maintained on Purina Rodent Laboratory Chow No. 5001 (St. Louis, MO)
Diet (e.g. ad libitum): Purina Rodent Laboratory Chow No. 5001, ad libitum
Water: ad libitum (distilled water)

ENVIRONMENTAL CONDITIONS:
Temperature: Temp. 70-74°F
Humidity (%): 40-60%
Photoperiod: 12-h light cycle (0630 lights on).

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared daily and their purity and stability confirmed using ion chromatography.
DCA of >99% purity was dissolved in water and adjusted to pH 7 with sodium hydroxide, such that the desired dosage, adjusted daily, could be administered at 10 ml/kg body weight.
Rate of preparation of diet (frequency):
Dosing solutions were prepared daily and their purity and stability confirmed using ion-chromatography.

Amount of dose: 10 ml/kg body weight.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- M/F ratio per cage: 1 female: 1 male
- Length of cohabitation: At 2:00 PM and checked for the presence of sperm at 9:00 AM on the following morning.
(19 Hrs)
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy Sperm-positive females were considered to be in day 0 of pregnancy and were singly housed for the duration of the study.
- After … days of unsuccessful pairing replacement of first male by another male with proven fertility. Not Available
- Further matings after two unsuccessful attempts: [no / yes (explain)] Not Available
- After successful mating each pregnant female was caged (how): Not Available
- Any other deviations from standard protocol: Not Available

Duration of treatment / exposure:

10 days

Frequency of treatment:

Daily

Duration of test:

10 days

Remarks:

Doses / Concentrations:
0, 14, 140 or 400 mg/kg-bw/day
Basis:
nominal in water

No. of animals per sex per dose:

80 rats
0mg/kg-bw/ day: 20
14 mg/kg-bw/ day: 20
140 mg/kg-bw/ day: 20
400 mg/kg-bw/ day: 20

Control animals:

yes, concurrent vehicle

Maternal examinations:

Analysis of the average percent maternal weight gain from days 0-20, adjusted for gravid uterine weight, revealed a statistically significant difference from the controls in 140 and 400 mg/kg/day, but not in the lowest dose group (14 mg/kg/day).
Reductions in weight gain, particularly during the initial phases of dosing, were seen in 140 mg/kg/day except at the 14-mg/kg/day dose.
The weight of the maternal liver (relative to body weight) was elevated above control values at all dose levels

The total number of implants per litter was unaltered by treatment with the exception of an apparently spurious reduction at 400 mg/kg/day

Ovaries and uterine content:

Reproductive outcome in pregnant Long-Evans hooded rats following exposure to dichloroacetic acid on days 6-15 of gestation

Treatment
(mg/kg/day) Sperm positive females treated Deaths Pregnant Viable litters Body weight
D0 G±SD
D20 % Wt Gain
±SD Adjusted
% Wt Gain
±SD
H2O 19 00 19 19 226.7±18 343.0±27 51.5±8 21.0±6
DCA 14 19 00 18 18 223.7±22 348.5±30 49.7±12 20.3±6
DCA 140 20 00 19 19 228.3±22 337.2±31 48.0±8 16.2±5
DCA 400 19 00 19 19 227.7±17 326.8±28 43.6±8 13.3±5

Live fetuses showed dose-dependent reductions in weight and length at doses above 140 mgkg

Fetal examinations:

Dose-related increases were seen in external, total soft tissue, cardiovascular, urogenital and orbital malformations.

Statistics:

Not Available

Indices:

Not Available

Historical control data:

Not Available

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Maternal livers, spleens and kidneys showed dose-related hypertrophy, and at all except the lowest dose (14 mg/kg/day) the adjusted percentage body weight gain in the dams was significantly reduced in comparison with the controls.

Dose descriptor:

NOAEL

Effect level:

14 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Remarks on result:

other: not specified

Dose descriptor:

NOAEL

Effect level:

14 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Remarks on result:

other: not specified

Abnormalities:

not specified

Localisation:

not specified

Description (incidence and severity):

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes. Remark: no dose-related trend in sex ratio alteration was seen at the 14 mg/kg/day

Details on embryotoxic / teratogenic effects:
no dose-related trend in sex ratio alteration was seen at the 14 mg/kg/day

Dose descriptor:

LOEL

Effect level:

140 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: embryotoxicity

Remarks on result:

other: not specified

Dose descriptor:

LOEL

Effect level:

140 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: teratogenicity

Remarks on result:

other: not specified

Abnormalities:

not specified

Localisation:

other: not specified

Description (incidence and severity):

not specified

Developmental effects observed:

not specified

Treatment related:

not specified

Relation to maternal toxicity:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

The Dichloroacetic acid treated on Long-Evans rat had shown NOAEL (no observed adverse effect level) for maternal and developmental toxicity in Long-Evans rats treated with dichloroacetic acid was found to be 14 mg/kg bw/day, while the LOEL (Low observed effect level) for embryotoxicity and teratogenicity was 140 mg/kg bw/day.

Executive summary:

The developmental toxicity of DCA (Dichloroacetic acid) was assessed in a one generation study with pregnant Long-Evans rats at dose levels of 0, 14, 140 or 400 mg/kg/day. The rats were orally administrated with DCA in distilled water on gestation days 6-15. Maternal observations included clinical signs, weight change, and gross evaluation of organ weights and uterine contents at necropsy (day20).Corpora lutea were counted and uteri stained for implantation sites. Live fetuses were examined for external, skeletal, and soft tissue malformations.While in increased post-implantation resorptions at 900+ mg/kg bw per day, reduced fetal body weights at 400+ mg/kg bw per day, maternal toxicity at 14+ mg/kg bw per day malformations shown in cardiovascular at 400+ mg/kg bw per day soft tissue at 140+ mg/kg bw per day urogenital at 1400+ mg/kg bw per day. Liver, spleen, and kidney weights increased in a dose-related manner. The mean percentage of resorbed implants per litter was significantly elevated at 2900 mg/kg/day

The No observed adverse effect level (NOAEL)for maternal and developmental toxicity was found to be 14 mg/kg-bw/day, and the Low observed effect level (LOEL)for embryotoxicity and teratogenicitywas 140 mg/kg-bw/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

14 mg/kg bw/day

Species:

rat

Quality of whole database:

K2 data is referred from publication report using read across approach of RA dichloroacetic acid

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

WoE Summary of 381-73-7 for developmental toxicity:

Based on the various studies available with Klimish rating 2 & 4 for the target as well as read across substances for CAS: 381-73-7 based on the category approach ofsubstances that are part of a group of compounds known as substituted acetate group. Also category is based on organic functional group along with similar mechanistic approach and having structural similarities defined by QSAR toolbox. The results for target as well as analogues are summarized as follows

 

Sr. No	End point	Value	Species	Route	Effects	Remarks
1	LOEL	97.90 mg/kg bw/d	Rat	Oral	Decreased crown-rump length was statistically significant Decreased	Predicted data for target chemical
2	LOEL	140 mg/kg bw/d	Rat	Oral	The body weights of the parental animals were change.	Data from Publication for 79-43-6
3	NOAEL	14 mg/kg bw/d	Rat	Oral	The body weights of the parental animals were change.	Data from Publication for 79-43-6
4	NOAEL	4.4-11.6 mg/kg bw/day	Rat	Oral	absolute and relative weights (% terminal body weight and % brain weight) of the liver and kidneys were increased and adrenal weights were reduced, as compared with control group values	Data from Publication for 631-64-1
5	LOAEL	52.4-132mg/kg bw/day	Rat	Oral	absolute and relative weights of the liver and kidneys were increased and adrenal weights were reduced, as compared with control group values	Data from Publication for 631-64-1
6	teratogenicity	----	Human	---	Non teratogenic	Danish predicted data for target chemical
8	NOEL	45 mg/kg bw/day	Rat	Oral	decreased water consumption	Data from Publication for 75-96-7

 

Based on the studies summarized in the above table with oral route, it can be observed that no effect values (NOAEL & NOEL) varies from 4.4 mg/kg bw/d & 14 mg/kg bw/d based on the data for target as well as read across substances. Whereas the lowest effect observed value (LOAEL & LOEL) varies from 32.5 - 140 mg/kg bw/day based on the data from prediction as well as publication for target & read across substance. Also the predicted LOEL for target substance is estimated to be 97.9 mg/ kg bw/d which is well with the range of LOEL for the read across substances and considered to be valid prediction. The effects observed on this doses was listed as follows:

 

·        Absolute and relative weights of the liver and kidneys were increased and adrenal weights were reduced, as compared with control group values

·        Decreased crown-rump length was statistically significant Decreased

·        The body weights of the parental animals were change.

·        Absolute and relative weights (% terminal body weight and % brain weight) of the liver and kidneys were increased and adrenal weights were reduced, as compared with control group values

·        Decreased water consumption

 

Thus based on above discussion it can be concluded that substance that difluoroacetic acid is expected to show the similar toxicological effect based on the effects observed on the other category members. Since the Low observed effective dose value (LOEL) is 97.90 mg/kg bw/d and the no observed adverse effective dose value (NOAEL) is above 4.4 mg/kg bw/day thus based on this value it can be concluded that substance CAS: 381-73-7 is considered to be nontoxic to maternal toxicity as well as developmental effects via oral route for above mentioned doses. Also the Danish EPA prediction for teratogenicity is negative which confirms CAS: 381-73-7 is nontoxic to maternal as well as developmental toxicity. Also there is no known evidence of adverse effect on Human of difluoroacetic acid as well as mechanistic triggers for estrogen receptor binding affinity does not classify this substance as toxic substance in absence of the cyclic structure and thus does not exhibits the reprotoxic & developmental effects.

Justification for selection of Effect on developmental toxicity: via oral route:

The oral administration of dichloroacetic acid to rat by oral gavage, at a dose level of 14 mg/kg bw/day, resulted in low observed effect level.

Thus the NOAEL for developmental toxicity study was considered to be 14 mg/kg bw/day.

Justification for classification or non-classification

No adverse permanant effect observed in the given route of exposure thus indicating that the substance do not have reproductive toxicity effect on animals tested.