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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The analogue approach is used for the hazard assessment of toxicological, eco-toxicological and environmental fate endpoints for the registration Pentamid™ KH (EC 934-047-1). The hypothesis is that data can be read-across between Pentamid™ KH and its structural analogues, based on structural similarity and common breakdown/metabolic products (Scenario 1 of the Read-Across Assessment Framework (RAAF, ECHA, 2015)).
For mammalian toxicity the “parent” substances show no significant systemic or dermal toxicity in mammals and vertebrates. One of the metabolic products of Pentamid™ KH, the well-studied terephthalic acid, has no significant systemic toxicity. The amine metabolite, however, shows diffuse mammalian systemic toxicity at moderate concentrations. This metabolite is employed in the risk assessment, in agreement with the European Union draft Risk Assessment Report of 2008.

The sole classification for Pentamid™ KH is the precautionary aquatic chronic 4 category, based on low water solubility and a log Kow higher than 4.

Read-across data, all evaluated as reliable according to Klimisch scores of 1 or 2, to estimate the toxicity of the registered substance is used for fulfilling the data requirements of the REACH registration and classifying potential hazards. This read-across approach is adequate for the purposes of risk assessment and classification and labeling.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
2001
Reference Type:
publication
Title:
Unnamed
Year:
1982

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 415 (One-Generation Reproduction Toxicity Study)
Principles of method if other than guideline:
OECD Guideline 415 (One-Generation Reproduction Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Terephthalic acid, TA-33MP, Lot SMR-4687, purified grade), was received In a shipment from Amoco Chemicals Corporation, Chicago, IL, on November 21. 1977 and thereafter stored at room temperature.

Test animals

Species:
rat
Strain:
other: CD and Wistar

Administration / exposure

Route of administration:
oral: feed
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
paternal: 90 days prior to and throughout mating
maternal: 90 days prior to mating, throughout mating, gestation, and lactation
offspring: 51 days; from birth through lactation and 30 days post weaning
Frequency of treatment:
daily ad lib
Duration of test:
at least 151 days
Doses / concentrationsopen allclose all
Dose / conc.:
14 mg/kg bw/day (nominal)
Remarks:
corresponds to 0.03%. Actual in CD strain: 14 and 17 mg/kg bw/d in males, females, respectively. Actual: 14 and 19 mg/kg bw/d in Wistar males, females respectively
Dose / conc.:
59 mg/kg bw/day (nominal)
Remarks:
corresponds to 0.125%. Actual: 59 and 67 mg/kg bw/d in CD males, females respectively. Actual: 61 and 78 mg/kg bw/d in Wistar males, females respectively.
Dose / conc.:
240 mg/kg bw/day (nominal)
Remarks:
corresponds to 0.5%. Actual: 240 and 282 mg/kg bw/d in CD males, females respectively. Actual: 249 and 307 mg/kg bw/d in Wistar males, females respectively
Dose / conc.:
960 mg/kg bw/day (nominal)
Remarks:
corresponds to 2.0%. Actual: 960 and 1107 mg/kg bw/d in CD males, females respectively.
Actual: 960 and 1219 mg/kg bw/d in Wistar males, females respectively
Dose / conc.:
2 480 mg/kg bw/day (nominal)
Remarks:
corresponds to 5.0%. Actual: 2480 and 2780 mg/kg bw/d in CD males, females respectively.
Actual: 2480 and 3018 mg/kg bw/d in Wistar males, females respectively.
No. of animals per sex per dose:
30
Control animals:
yes, plain diet
Details on study design:
Experimental conditions were identical for the two different strains of rats. Rats 15-17 weeks of age
(n=30) were grouped housed 3/cage for the first 90 days of exposure. Body weight and feed intake
were determined weekly during this time period. On Day 91, breeding pairs (n=10/sex) were housed
together for 2 weeks prior to being separated. On Day 0 (delivery) the number and viability of offspring
were evaluated and grossly examined. Offspring were recounted, sexed, and weighed on Day 1.
These measurements were repeated at weaning on Day 21. After weaning, the litters were reduced to
2/sex/dose from each of 5 litters (20 pups/dose/strain) and maintained on test diets for 30 more days
(Day 51) prior to sacrifice.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
mortality observed, treatment-related
Description (incidence):
Prior to mating, there were 5 deaths (3 CD females, and a Wistar male and female) reported during
weeks 4-13 among those given 5% TPA in the diet. After mating, 3 CD (1 male at 2.0%, and one
male and one female at 5.0%) and 4 Wistar female (2 at 5.0% and 2 at 0.03%) rats died.

Maternal developmental toxicity

Details on maternal toxic effects:
At the top two dose levels, several large litters of pups were lost to dams suffering obvious signs of toxicity. Several of these dams did not allow the pups to nurse or attend to the litters. These pups were noted not to have milk in their stomachs and presented clinically as being very weak. These dams were consuming dietary levels of TPA known to cause reduced feed consumption, diarrhea and gastric trichobezoars (hairballs) and induce the formation of renal and bladder calculi. Unscheduled deaths during the postweaning period (Day 21-51) were confined to the 5% TPA group (18 Wistar and 16 CD) and were associated with a very high incidence of renal and bladder calculi.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
240 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no data provided in review article

Maternal abnormalities

Key result
Abnormalities:
not specified

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Average body weights of high dose Wistar offspring were reduced 17-19% on PND 1 (by litter), and by 32-36% on PND 21. Body weights were not initially reduced in CD offspring, but were 57-58% lower in CD's on PND 21.
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
At 2 and 5% doses, there were 12 and 1 Wistar pups found dead at birth respecitvely; there were 7 and 15 CD pups dead at birth, respectively.
Changes in postnatal survival:
effects observed, treatment-related
Description (incidence and severity):
50% decreases in survivability of 5% CD strain maie and female pups on PND 21; no effects on 21-day viability of Wistar strain pups.
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
Bladder calculi were observed in 44 and 51% of male and female Wistar offspring. Calculi were seen in 56 and 70% of male and female CD offspring, respectively.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
240 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
fetal/pup body weight changes
changes in postnatal survival
visceral malformations

Fetal abnormalities

Abnormalities:
effects observed, treatment-related
Localisation:
other: not localized except for bladder calculi

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
1 100 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects occurring together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
not specified

Any other information on results incl. tables

At 2 and 5% doses, there were 12 and 1 Wistar pups found dead at birth respecitvely; there were 7 and 15 CD pups dead at birth, respectively. Average body weights of high dose Wistar offspring were reduced 17-19% on PND 1 (by litter), and by 32-36% on PND 21 in this strain.  Body weights were not initially reduced in CD offspring, but were 57-58% lower on PND 21. There were 50% decreases in survivability of CD strain pups on PND 21, but no effects on survivability of Wistar strain pups. Bladder calculi were observed in 44 and 51% of male and female Wistar offspring.  Calculi were seen in 56 and 70% of male and female CD offspring, respectively.

Applicant's summary and conclusion